CN116655592A - Preparation method of intermediate of fluorothiazole pyrithione - Google Patents
Preparation method of intermediate of fluorothiazole pyrithione Download PDFInfo
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- CN116655592A CN116655592A CN202210145518.9A CN202210145518A CN116655592A CN 116655592 A CN116655592 A CN 116655592A CN 202210145518 A CN202210145518 A CN 202210145518A CN 116655592 A CN116655592 A CN 116655592A
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- fluorothiazole
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- FGVVTMRZYROCTH-UHFFFAOYSA-N pyridine-2-thiol N-oxide Chemical compound [O-][N+]1=CC=CC=C1S FGVVTMRZYROCTH-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229960002026 pyrithione Drugs 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 32
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 35
- 239000003960 organic solvent Substances 0.000 claims description 28
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 22
- 239000011230 binding agent Substances 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 239000011593 sulfur Substances 0.000 claims description 22
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 16
- DLCHCAYDSKIFIN-UHFFFAOYSA-N 5-methyl-3-(trifluoromethyl)-1h-pyrazole Chemical compound CC1=CC(C(F)(F)F)=NN1 DLCHCAYDSKIFIN-UHFFFAOYSA-N 0.000 claims description 16
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000001339 alkali metal compounds Chemical class 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 claims description 5
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 4
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract description 26
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 10
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 abstract description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 abstract description 5
- -1 glycolate compound Chemical class 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- YSLFXWOZZNHTEM-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine-4-carbonitrile Chemical compound ClCCN1CCC(C#N)CC1 YSLFXWOZZNHTEM-UHFFFAOYSA-N 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- BOMXNVKTSSSTNJ-UHFFFAOYSA-N C1CC=NO1.C1CCN(CC1)c1nccs1 Chemical compound C1CC=NO1.C1CCN(CC1)c1nccs1 BOMXNVKTSSSTNJ-UHFFFAOYSA-N 0.000 description 1
- 241000233654 Oomycetes Species 0.000 description 1
- 241000233679 Peronosporaceae Species 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000817 effect on oomycetes Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZANNOFHADGWOLI-UHFFFAOYSA-N ethyl 2-hydroxyacetate Chemical compound CCOC(=O)CO ZANNOFHADGWOLI-UHFFFAOYSA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PKMPMUHWHIIFBJ-UHFFFAOYSA-N piperidin-1-ium-4-carbonitrile;chloride Chemical compound Cl.N#CC1CCNCC1 PKMPMUHWHIIFBJ-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- NORCOOJYTVHQCR-UHFFFAOYSA-N propyl 2-hydroxyacetate Chemical compound CCCOC(=O)CO NORCOOJYTVHQCR-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a preparation method of an intermediate of fluorothiazole pyrithione. The preparation method of the intermediate of the fluorothiazole pyrithione comprises the following steps: the compound I reacts with sulfonyl chloride derivatives to obtain a compound II. In the synthesis process of the method, the glycolate compound reacts with the sulfonyl chloride derivative, so that the problems that an intermediate in the synthesis process is easy to hydrolyze and difficult to store in the prior art are solved; and the problem of high operation risk caused by adopting chloroacetyl chloride or bromoacetyl chloride in the synthesis process is avoided. The invention takes glycollate compounds as raw materials, and can obtain the 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine with high yield and high purity through four-step chemical reaction.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of an intermediate of fluorothiazole pyrithione.
Background
The fluorothiazole pyrithione is the first piperidyl thiazole isoxazoline bactericide, has protection and treatment activity on oomycete diseases, has long lasting period, novel target sites, and has excellent prevention effect on oomycete diseases such as late blight, downy mildew, root rot, stem rot and epidemic diseases. 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine (abbreviated as thiocarboxamide piperidine) is an intermediate for the synthesis of fluorothiazolepezine. The preparation of 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine is a key step in the industrial production of fluorothiazolyl ethanone.
In the prior art, in the patent application with the publication number of CN101888843A, 1- (2-chloroethyl) piperidine-4-carbonitrile and 5-methyl-3- (trifluoromethyl) -1H-pyrazole are used as starting materials for reaction, and the thioformamide piperidine is obtained through substitution reaction and 2-step reaction of thio reaction. However, the intermediate 1- (2-chloroethyl) piperidine-4-carbonitrile of the synthetic method is easy to hydrolyze and unstable, and the product has good water solubility and is not easy to extract, so that the reaction yield is low, and the total yield of the two steps is less than 70%; in addition, the preparation of the intermediate 1- (2-chloroethyl) piperidine-4-carbonitrile uses chloroacetyl chloride or bromoacetyl chloride with pungent smell, and the reagent is corrosive and has high operation danger coefficient; also, the thio reaction is generally carried out as H 2 S gas is used as a vulcanizing agent, the gas inlet amount is not easy to control, the operation danger coefficient is high, and the three-waste treatment amount is greatly increased.
In the patent application with publication number of CN102227423A, the thioformamide piperidine is prepared by introducing an amine protecting group, and the method improves the reaction yield and the stability of an intermediate, but has the advantages of multiple steps, long route, greatly increased production cost and inapplicability to industrial production.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a preparation method of an intermediate of fluorothiazole pyrithione, which adopts a glycolate compound to react with sulfonyl chloride derivatives in a synthetic route, solves the problems that the intermediate is easy to hydrolyze and difficult to preserve in the synthetic process, and avoids the defect of high synthesis operation risk caused by using chloracetyl chloride or bromoacetyl chloride.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
the invention provides a preparation method of a fluorothiazole piridon intermediate, which comprises the following steps:
reacting the compound I with a sulfonyl chloride derivative to obtain a compound II;
the structural formula of the compound I is as follows:
the structural formula of the compound II is as follows:
wherein R is an alkyl group having 1 to 6 carbon atoms; r is R 1 Is alkyl, phenyl or substituted phenyl with 1-3 carbon atoms.
Further, the preparation method of the intermediate of the fluorothiazole pyrithione further comprises the following steps: the compound II reacts with 5-methyl-3- (trifluoromethyl) -1H-pyrazole to obtain a compound III;
the structural formula of the compound III is as follows:
wherein R is an alkyl group having 1 to 6 carbon atoms.
Further, the preparation method of the intermediate of the fluorothiazole pyrithione further comprises the following steps: the compound III reacts with 4-cyano piperidine to obtain a compound IV;
the structural formula of the compound IV is as follows:
further, the preparation method of the intermediate of the fluorothiazole pyrithione further comprises the following steps: the compound IV reacts with a sulfur-containing compound to obtain an intermediate of the fluorothiazole pyrithione;
wherein, the structural formula of the intermediate of the fluorothiazole piridon is as follows:
preferably, the sulfur-containing compound comprises a sulfur-containing alkali metal compound and/or ammonium sulfide.
Preferably, the sulfur-containing alkali metal compound comprises sodium sulfide and/or sodium hydrosulfide.
Further, the compound I and the sulfonyl chloride derivative are subjected to condensation reaction in an organic solvent under the action of an acid binding agent to obtain the compound II.
Preferably, the sulfonyl chloride derivative comprises one or more of p-toluenesulfonyl chloride, methylsulfonyl chloride and benzenesulfonyl chloride.
Preferably, the acid binding agent comprises one or more of triethylamine, potassium carbonate, N-diisopropylethylamine and pyridine.
Preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane.
Preferably, the temperature of the condensation reaction is 50-70 ℃, and the time of the condensation reaction is 1.5-3 h.
Further, the molar ratio of the compound I to the sulfonyl chloride derivative is 1:0.8 to 1.2.
Preferably, the molar ratio of the compound I to the acid-binding agent is 1:1 to 1.2.
Further, the compound II reacts with the 5-methyl-3- (trifluoromethyl) -1H-pyrazole in an organic solvent under the action of alkali to obtain the compound III.
Preferably, the base comprises one or more of potassium carbonate, sodium hydroxide, sodium carbonate and sodium bicarbonate.
Preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane.
Preferably, the temperature of the reaction is 70-90 ℃, and the time of the reaction is 3-5 h.
Further, the molar ratio of the compound II to the 5-methyl-3- (trifluoromethyl) -1H-pyrazole is 1:0.8 to 1.2.
Preferably, the molar ratio of the compound II to the base is 1:1.3 to 1.6.
Further, the compound III and the 4-cyano piperidine react in an organic solvent under the action of an acid binding agent to obtain the compound IV.
Preferably, the acid binding agent comprises one or more of triethylamine, potassium carbonate, N-diisopropylethylamine and pyridine.
Preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane.
Preferably, the molar ratio of the compound III to the 4-cyanopiperidine is 1-1.3: 1.
preferably, the molar ratio of the compound III to the acid-binding agent is 1:9 to 12.
Preferably, the temperature of the reaction is-1-5 ℃, and the time of the reaction is 1.5-3 h.
Further, the compound IV and the sulfur-containing compound react in an organic solvent to obtain the intermediate of the fluorothiazole pyrimidone.
Preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane.
Preferably, the molar ratio of the compound IV to the sulfur-containing compound is 1: 8-10.
Preferably, the temperature of the reaction is 20-30 ℃, and the time of the reaction is 16-20 h.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, the glycolate compound reacts with the sulfonyl chloride derivative to obtain a compound II; by adopting sulfonyl chloride derivatives such as p-toluenesulfonyl chloride, the problems that an intermediate in the synthesis process is easy to hydrolyze and difficult to preserve, and the operation danger caused by adopting chloroacetyl chloride or bromoacetyl chloride in the synthesis process is high are solved.
(2) The invention provides a preparation method of a fluorothiazole piridon intermediate, which takes glycolate compounds as raw materials, and the glycolate compounds react with sulfonyl chloride derivatives to obtain a compound II; reacting the compound II with 5-methyl-3- (trifluoromethyl) -1H-pyrazole to obtain a compound III; reacting the compound III with 4-cyanopiperidine to obtain a compound IV; reacting the compound IV with a sulfur-containing compound to obtain 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine; the product purity of the method is high, the product yield of each step is more than 90%, and the total yield can reach more than 70%; in addition, the method has the advantages of simple and easily obtained reaction raw materials, low cost and simple synthetic route, and is suitable for large-scale industrialized production.
Detailed Description
The technical solution of the present invention will be clearly and completely described in conjunction with the specific embodiments, but it will be understood by those skilled in the art that the examples described below are some, but not all, examples of the present invention, and are intended to be illustrative only and should not be construed as limiting the scope of the present 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. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The following describes a preparation method of the intermediate for synthesizing fluorothiazole pyridone in the embodiment of the invention.
In some embodiments of the invention, there is provided a method for preparing an intermediate of fluorothiazole pyridone, comprising: reacting the compound I with a sulfonyl chloride derivative to obtain a compound II;
the structural formula of the compound I is as follows:
the structural formula of the compound II is as follows:
wherein R is an alkyl group having 1 to 6 carbon atoms; r is R 1 Is alkyl, phenyl or substituted phenyl with 1-3 carbon atoms.
In the preparation method of the compound II, the glycolate compound reacts with the sulfonyl chloride derivative, so that the defect that an intermediate in the synthesis process in the prior art is easy to hydrolyze and difficult to store, and the reaction yield is low is overcome; and the defect of high operation risk caused by adopting chloracetyl chloride or bromoacetyl chloride in the synthesis process, so that the synthesis process is more suitable for industrialized mass production.
In some embodiments of the present invention, the preparation method of the intermediate of fluorothiazole pyridone further comprises: reacting the compound II with 5-methyl-3- (trifluoromethyl) -1H-pyrazole to obtain a compound III;
the structural formula of the compound III is as follows:
wherein R is an alkyl group having 1 to 6 carbon atoms.
In some embodiments of the present invention, the preparation method of the intermediate of fluorothiazole pyridone further comprises: reacting the compound III with 4-cyanopiperidine to obtain a compound IV;
the structural formula of the compound IV is as follows:
in some embodiments of the present invention, the preparation method of the intermediate of fluorothiazole pyridone further comprises: the compound IV reacts with a sulfur-containing compound to obtain an intermediate of the fluorothiazole pyrimidone;
wherein, the structural formula of the intermediate of the fluorothiazole piridon is as follows:
in some embodiments of the invention, the sulfur-containing compound comprises a sulfur-containing alkali metal compound and/or ammonium sulfide.
In some embodiments of the invention, the sulfur-containing alkali metal compound comprises sodium sulfide and/or sodium hydrosulfide.
In the preparation method of the invention, sulfur-containing alkali metal compound and/or ammonium sulfide is used for replacing H 2 S gas is used as a vulcanizing agent, so that the problems of difficult control of gas inflow, high operation danger coefficient and the like are avoided, and the treatment capacity of three wastes is greatly reduced.
In some specific embodiments of the present invention, the preparation method of the intermediate of fluorothiazole pyridone comprises the following steps:
(A) Reacting the compound I with a sulfonyl chloride derivative to obtain a compound II;
(B) Reacting the compound II with 5-methyl-3- (trifluoromethyl) -1H-pyrazole to obtain a compound III;
(C) Reacting the compound III with 4-cyanopiperidine to obtain a compound IV;
(D) The compound IV reacts with a sulfur-containing compound to obtain an intermediate of the fluorothiazole pyrimidone.
The glycolic acid ester compound provided by the invention is used as a raw material, and the 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine can be obtained in high purity and high yield through four steps of chemical reactions, and the yield of each step of reaction can reach more than 90%.
In some embodiments of the present invention, in step (a), compound I is condensed with a sulfonyl chloride derivative in an organic solvent under the action of an acid-binding agent to give compound II.
In some embodiments of the invention, in step (a), the sulfonyl chloride derivative comprises one or more of p-toluenesulfonyl chloride, methylsulfonyl chloride, benzenesulfonyl chloride; preferably, the sulfonyl chloride derivative is p-toluenesulfonyl chloride.
In some embodiments of the invention, in step (a), the acid-binding agent comprises one or more of triethylamine, potassium carbonate, N-diisopropylethylamine, and pyridine; preferably, the acid binding agent is triethylamine.
In some embodiments of the invention, in step (a), the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane; preferably, the organic solvent is N, N-dimethylformamide.
In some embodiments of the invention, in step (a), the temperature of the reaction is 50-70 ℃, typically but not limited to, for example, 50 ℃, 55 ℃, 60 ℃, 65 ℃ or 70 ℃ and the like; the reaction time is 1.5-3 h; typical but non-limiting, for example, the reaction time is 1.5h, 2h, 2.5h or 3h, etc.; preferably, the temperature of the reaction is 60℃and the time of the reaction is 2 hours.
In some embodiments of the invention, in step (a), the molar ratio of compound I to sulfonyl chloride derivative is 1:0.8 to 1.2; typically, but not by way of limitation, the molar ratio of compound I to sulfonyl chloride derivative is 1:0.8, 1:0.9, 1: 1.1: 1.1 or 1:1.2, etc.; preferably, the molar ratio of compound I to sulfonyl chloride derivative is 1:1.
in some embodiments of the invention, in step (a), the molar ratio of compound I to acid-binding agent is 1:1 to 1.2; typically, but not by way of limitation, the molar ratio of compound I to acid-binding agent is 1: 1.1: 1.1 or 1:1.2, etc.
In some embodiments of the present invention, in step (a), the condensation reaction is followed by extraction to obtain an extract, and the extract is concentrated to obtain compound II.
In some embodiments of the invention, in step (B), compound II is reacted with 5-methyl-3- (trifluoromethyl) -1H-pyrazole in an organic solvent under the action of a base to give compound III.
In some embodiments of the invention, in step (B), the base comprises one or more of potassium carbonate, sodium hydroxide, sodium carbonate, and sodium bicarbonate; preferably, the base is potassium carbonate.
In some embodiments of the invention, in step (B), the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane; preferably, the organic solvent is N, N-dimethylformamide.
In some embodiments of the invention, in step (B), the temperature of the reaction is 70-90 ℃, typically but not limited to, e.g., 70 ℃, 75 ℃, 80 ℃, 85 ℃, or 90 ℃, etc.; the reaction time is 3-5 h; typical but non-limiting, for example, the reaction time is 3 hours, 4 hours, or 5 hours, etc.; preferably, the temperature of the reaction is 80℃and the time of the reaction is 4 hours.
In some embodiments of the invention, in step (B), the molar ratio of compound II to 5-methyl-3- (trifluoromethyl) -1H-pyrazole is 1:0.8 to 1.2; typical, but not limiting, for example, the molar ratio of compound II to 5-methyl-3- (trifluoromethyl) -1H-pyrazole is 1:0.8, 1:0.9, 1: 1.1: 1.1 or 1:1.2, etc.; preferably, the molar ratio of compound II to 5-methyl-3- (trifluoromethyl) -1H-pyrazole is 1:1.
in some embodiments of the invention, in step (B), the molar ratio of compound II to base is 1:1.3 to 1.6; typically, but not by way of limitation, the molar ratio of compound II to base is 1:1.3, 1:1.4, 1:1.5 or 1:1.6, etc.
Under the reaction conditions, the reaction of the compound II and the 5-methyl-3- (trifluoromethyl) -1H-pyrazole is more sufficient, and the yield of the product is high.
In some embodiments of the present invention, in step (B), the method further comprises, after the reaction, extracting to obtain an extract, and concentrating the extract to obtain compound III.
In some embodiments of the invention, in step (C), compound III is reacted with 4-cyanopiperidine in an organic solvent under the influence of an acid-binding agent to give compound IV.
In some embodiments of the invention, in step (C), the acid-binding agent comprises one or more of triethylamine, potassium carbonate, N-diisopropylethylamine, and pyridine; preferably, the acid binding agent is triethylamine.
In some embodiments of the invention, in step (C), one or more of the organic solvents N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane; preferably, the organic solvent is methylene chloride.
In some embodiments of the invention, in step (C), the molar ratio of compound III to 4-cyanopiperidine is from 1 to 1.3:1, a step of; typically, but not by way of limitation, the molar ratio of compound III to 4-cyanopiperidine is 1:1. 1.1: 1. 1.2:1 or 1.3:1, etc.
In some embodiments of the invention, in step (C), the molar ratio of compound III to acid-binding agent is 1:9 to 12; typically, but not by way of limitation, the molar ratio of compound III to acid-binding agent is 1: 9. 1: 10. 1:11 or 1:12, etc.
In some embodiments of the invention, in step (C), the temperature of the reaction is from-1 to 5 ℃, typically, but not limited to, for example, the temperature of the reaction is-1 ℃,0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃, or 5 ℃, etc.; the reaction time is 1.5-3 h; typical but non-limiting, for example, the reaction time is 1.5h, 2h, 2.5h or 3h, etc.; preferably, the temperature of the reaction is 0℃and the time of the reaction is 2 hours.
In some embodiments of the present invention, in step (C), further comprising, after the reaction, adding water to the reaction solution, standing to obtain an aqueous layer and an organic solution layer, and concentrating the organic solution layer to obtain the compound IV.
In some embodiments of the invention, in step (D), compound IV is reacted with a sulfur-containing compound in an organic solvent to provide an intermediate of fluorothiazolyl pyrithione.
In some embodiments of the invention, in step (D), one or more of the organic solvents N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane; preferably, the organic solvent is methanol and/or N, N-dimethylformamide.
In some embodiments of the invention, in step (D), the molar ratio of compound IV to sulfur-containing compound is 1: 8-10; typically, but not by way of limitation, the molar ratio of compound IV to sulfur-containing compound is 1: 8. 1:9 or 1:10, etc.
In some embodiments of the invention, in step (D), the temperature of the reaction is from 20 to 30 ℃; typical but non-limiting, for example, the temperature of the reaction is 20 ℃, 25 ℃ or 30 ℃, etc.; the reaction time is 16-20 h; typical but non-limiting, for example, the reaction time is 16h, 17h, 18h, 19h or 20h, etc., preferably the reaction temperature is 25℃and the reaction time is 18h.
In some embodiments of the present invention, in step (D), the method further comprises, after the reaction, extracting to obtain an extract, and concentrating the extract to obtain an intermediate of the fluorothiazolyl pyrithione.
Example 1
The preparation method of the compound III provided in the embodiment has the following synthetic route:
the specific preparation method of the compound III comprises the following steps:
(A) Methyl glycolate (20.6 g,0.22 mol), 50g of N, N-dimethylformamide and 23g of triethylamine are added into a reaction device, the temperature is raised to 60 ℃, 50mL of N, N-dimethylformamide containing p-toluenesulfonyl chloride (39.9 g,0.21 mol) is added into the reaction device in a dropwise manner, and the temperature is controlled to be 60+/-2 ℃ in the dropwise process; after the completion of the dropwise addition, the reaction was carried out for 2 hours at a constant temperature, then the temperature was reduced to 20 ℃, 100g of water and 200g of ethyl acetate were added for extraction, and 50.5g of Compound II was obtained after concentration. The yield of the reaction was 98.5%.
(B) Compound II (4.9 g,0.02 mol), 50g of n, n-dimethylformamide, 4g of potassium carbonate and 5-methyl-3- (trifluoromethyl) -1H-pyrazole (3.0 g,0.02 mol) were charged into the reaction apparatus, heated to 80 ℃ and reacted for 4 hours; after cooling to 20 ℃, 100g of water and 200g of ethyl acetate are added for extraction, and 4.2g of compound III is obtained after concentration. The yield of the reaction was 95%.
Example 2
The preparation method of the compound III provided in the present example is the same as that of example 1, except that:
(A) Ethyl glycolate (23.6 g,0.22 mol), 50g of N, N-dimethylformamide and 23g of triethylamine are added into a reaction device, the temperature is raised to 60 ℃, 50mL of N, N-dimethylformamide containing p-toluenesulfonyl chloride (39.9 g,0.21 mol) is added into the reaction device in a dropwise manner, and the temperature is controlled to be 60+/-2 ℃ in the dropwise process; after the completion of the dropwise addition, the reaction was carried out for 2 hours at a constant temperature, then the temperature was reduced to 20 ℃, 100g of water and 200g of ethyl acetate were added for extraction, and after concentration, 52.8g of Compound II was obtained. The yield of the reaction was 98.2%.
Example 3
The preparation method of the compound III provided in the present example is the same as that of example 1, except that:
(A) Propyl glycolate (26.0 g,0.22 mol), 50g of N, N-dimethylformamide and 23g of triethylamine are added into a reaction device, the temperature is raised to 60 ℃, 50mL of N, N-dimethylformamide containing p-toluenesulfonyl chloride (39.9 g,0.21 mol) is added into the reaction device in a dropwise manner, and the temperature is controlled to be 60+/-2 ℃ in the dropwise process; after the completion of the dropwise addition, the reaction is carried out for 2 hours at a constant temperature, then the temperature is reduced to 20 ℃, 100g of water and 200g of ethyl acetate are added for extraction, and 56.3g of compound II is obtained after concentration. The yield of the reaction was 98.6%.
Example 4
The preparation method of the compound III provided in the present example is the same as that of example 1, except that:
(A) Methyl glycolate (20.6 g,0.22 mol), 50g of N, N-dimethylformamide and 23g of triethylamine are added into a reaction device, the temperature is raised to 60 ℃, 50mL of N, N-dimethylformamide containing benzenesulfonyl chloride (37.0 g,0.21 mol) is added into the reaction device in a dropwise manner, and the temperature is controlled to be 60+/-2 ℃ in the dropwise process; after the completion of the dropwise addition, the reaction was carried out for 2 hours at a constant temperature, then the temperature was lowered to 20 ℃, 100g of water and 200g of ethyl acetate were added for extraction, and 49.5g of Compound II was obtained after concentration. The yield of the reaction was 96.6%.
Example 5
The compound 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine provided in this example was prepared as follows:
a specific preparation method of 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine, which comprises the following steps:
(A) The product compound III (4.9 g,0.022 mol), 20g of triethylamine and 50g of methylene chloride obtained in the step (B) in example 1 were charged into a reaction apparatus at a temperature of 0℃and then 4-cyanopiperidine hydrochloride (2.9 g, 0.020mol) was charged into the reaction apparatus to react for 2 hours; then, 50g of water was added thereto, and the mixture was allowed to stand and separate to obtain an aqueous layer and a methylene chloride layer, and the methylene chloride layer was concentrated to obtain 5.94g of Compound IV. The yield of the reaction was 98.8%.
(B) Compound IV (5.1 g,0.017 mol) and 50g of n, n-dimethylformamide were added to the reaction apparatus, followed by addition of 20g of ammonium sulfide solution (mass fraction 10-15%) and reaction at 25 ℃ for 18 hours; then 100g of water and 50g of methylene chloride are added for extraction, and 5.1g of target product 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine is obtained after concentration. The yield of the reaction was 90%. The purity of the product was 99%.
Example 6
The preparation method of 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine provided in this example is the same as in example 5, except that:
(B) Compound IV (5 g,0.017 mol) and 50g of n, n-dimethylformamide were added to the reaction apparatus, followed by addition of 20g of sodium sulfide solution (mass fraction 10-15%) and reaction at 25 ℃ for 18 hours; then 100g of water and 50g of methylene chloride are added for extraction, and 4.8g of target product 1- [2- [ 5-methyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetyl ] -4-thiocarboxamide piperidine is obtained after concentration. The yield of the reaction was 85%.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A method for preparing an intermediate of fluorothiazole piridon, which is characterized by comprising the following steps: reacting the compound I with a sulfonyl chloride derivative to obtain a compound II;
the structural formula of the compound I is as follows:
the structural formula of the compound II is as follows:
in the method, in the process of the invention,r is alkyl with 1-6 carbon atoms; r is R 1 Is alkyl, phenyl or substituted phenyl with 1-3 carbon atoms.
2. The method for preparing the intermediate of the fluorothiazole pyridone according to claim 1, further comprising: the compound II reacts with 5-methyl-3- (trifluoromethyl) -1H-pyrazole to obtain a compound III;
the structural formula of the compound III is as follows:
wherein R is an alkyl group having 1 to 6 carbon atoms.
3. The method for preparing the intermediate of the fluorothiazole pyridone according to claim 1, further comprising: the compound III reacts with 4-cyano piperidine to obtain a compound IV;
the structural formula of the compound IV is as follows:
4. the method for preparing the intermediate of the fluorothiazole pyridone according to claim 1, further comprising: the compound IV reacts with a sulfur-containing compound to obtain an intermediate of the fluorothiazole pyrithione;
wherein, the structural formula of the intermediate of the fluorothiazole piridon is as follows:
preferably, the sulfur-containing compound comprises a sulfur-containing alkali metal compound and/or ammonium sulfide;
preferably, the sulfur-containing alkali metal compound comprises sodium sulfide and/or sodium hydrosulfide.
5. The method for preparing the intermediate of the fluorothiazole pyrithione according to claim 1, which is characterized in that the compound I and the sulfonyl chloride derivative are subjected to condensation reaction in an organic solvent under the action of an acid binding agent to obtain the compound II;
preferably, the sulfonyl chloride derivative comprises one or more of p-toluenesulfonyl chloride, methylsulfonyl chloride and benzenesulfonyl chloride;
preferably, the acid binding agent comprises one or more of triethylamine, potassium carbonate, N-diisopropylethylamine and pyridine;
preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane;
preferably, the temperature of the condensation reaction is 50-70 ℃, and the time of the condensation reaction is 1.5-3 h.
6. The method for preparing an intermediate of fluorothiazole pyridone according to claim 5, wherein the molar ratio of said compound I to said sulfonyl chloride derivative is 1:0.8 to 1.2;
preferably, the molar ratio of the compound I to the acid-binding agent is 1:1 to 1.2.
7. The method for preparing the intermediate of the fluorothiazole pyrithione according to claim 2, which is characterized in that the compound II reacts with the 5-methyl-3- (trifluoromethyl) -1H-pyrazole in an organic solvent under the action of alkali to obtain the compound III;
preferably, the base comprises one or more of potassium carbonate, sodium hydroxide, sodium carbonate and sodium bicarbonate;
preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane;
preferably, the temperature of the reaction is 70-90 ℃, and the time of the reaction is 3-5 h.
8. The process for the preparation of an intermediate of fluorothiazolyl ethanone according to claim 7, characterized in that the molar ratio of said compound II to said 5-methyl-3- (trifluoromethyl) -1H-pyrazole is 1:0.8 to 1.2;
preferably, the molar ratio of the compound II to the base is 1:1.3 to 1.6.
9. A process for the preparation of an intermediate of fluorothiazolyl ethanone according to claim 3, characterized in that said compound III is reacted with said 4-cyanopiperidine in an organic solvent under the action of an acid-binding agent to give said compound IV;
preferably, the acid binding agent comprises one or more of triethylamine, potassium carbonate, N-diisopropylethylamine and pyridine;
preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane;
preferably, the molar ratio of the compound III to the 4-cyanopiperidine is 1-1.3: 1, a step of;
preferably, the molar ratio of the compound III to the acid-binding agent is 1:9 to 12;
preferably, the temperature of the reaction is-1-5 ℃, and the time of the reaction is 1.5-3 h.
10. The method for preparing the intermediate of the fluorothiazole pyrithione according to claim 4, which is characterized in that the compound IV and the sulfur-containing compound react in an organic solvent to obtain the intermediate of the fluorothiazole pyrithione;
preferably, the organic solvent comprises one or more of N, N-dimethylformamide, dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, toluene, ethyl acetate, and dioxane;
preferably, the molar ratio of the compound IV to the sulfur-containing compound is 1: 8-10;
preferably, the temperature of the reaction is 20-30 ℃, and the time of the reaction is 16-20 h.
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