CN115260011A - Preparation method of fluoro diether - Google Patents
Preparation method of fluoro diether Download PDFInfo
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- CN115260011A CN115260011A CN202210729106.XA CN202210729106A CN115260011A CN 115260011 A CN115260011 A CN 115260011A CN 202210729106 A CN202210729106 A CN 202210729106A CN 115260011 A CN115260011 A CN 115260011A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 125000001153 fluoro group Chemical group F* 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- 238000000034 method Methods 0.000 claims abstract description 51
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 229910052705 radium Inorganic materials 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- -1 p-toluenesulfonyl group Chemical group 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 8
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000012216 screening Methods 0.000 description 12
- 239000007791 liquid phase Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003792 electrolyte Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ODHVDARHRMSQQX-UHFFFAOYSA-N 1,1,1-trifluoro-2-[2-(2-fluoroethoxy)ethoxy]ethane Chemical compound FCCOCCOCC(F)(F)F ODHVDARHRMSQQX-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical class CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- CQEZINWOTGMJQC-UHFFFAOYSA-N 1,2-bis(2-fluoroethoxy)ethane Chemical compound FCCOCCOCCF CQEZINWOTGMJQC-UHFFFAOYSA-N 0.000 description 1
- WDACQQSJUBWPNU-UHFFFAOYSA-N 1-ethoxy-2-(2-fluoroethoxy)ethane Chemical compound CCOCCOCCF WDACQQSJUBWPNU-UHFFFAOYSA-N 0.000 description 1
- TUFLPRIGKRNYIP-UHFFFAOYSA-N 2-(2-ethoxyethoxy)-1,1-difluoroethane Chemical compound CCOCCOCC(F)F TUFLPRIGKRNYIP-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- UFMVNSFONAZFOT-UHFFFAOYSA-N dichloromethane;n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound ClCCl.CCN(C(C)C)C(C)C UFMVNSFONAZFOT-UHFFFAOYSA-N 0.000 description 1
- QIGYDSTVZKNHEY-UHFFFAOYSA-L dipotassium;dichloromethane;carbonate Chemical compound [K+].[K+].ClCCl.[O-]C([O-])=O QIGYDSTVZKNHEY-UHFFFAOYSA-L 0.000 description 1
- TTWOEDISEICFCH-UHFFFAOYSA-L dipotassium;oxolane;carbonate Chemical compound [K+].[K+].[O-]C([O-])=O.C1CCOC1 TTWOEDISEICFCH-UHFFFAOYSA-L 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VSPPONOIKZXUBJ-UHFFFAOYSA-N n,n-diethylethanamine;oxolane Chemical compound C1CCOC1.CCN(CC)CC VSPPONOIKZXUBJ-UHFFFAOYSA-N 0.000 description 1
- 239000011255 nonaqueous electrolyte Substances 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WINYCIXPFGVTOS-UHFFFAOYSA-M sodium;dichloromethane;hydroxide Chemical compound [OH-].[Na+].ClCCl WINYCIXPFGVTOS-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- 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
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of fluoro diether, belonging to the field of organic synthesis. The invention provides a preparation method of fluoro diether, wherein the reaction formula is any one of the following formulas:
in the reaction formulae I andin reaction formula II, R1、R2、R3And R4Independently of one another, from F or H, RaIs sulfonyl, n =0-5, m =1-5, p =0-5. The invention selects a specific reaction substrate and screens out reaction conditions suitable for the substrate, so the invention opens up an effective new method for synthesizing the fluoro diether compound.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of fluoro diether.
Background
The electrolyte in the battery is related to various functions such as the operating voltage of the battery, the operating temperature of the battery, the life of the battery, and the safety of the battery.
In the japanese meeting paper, "physical and electrolyte properties of fluorinated diethoxyethane with different fluorine numbers" (i.e., outer properties of フ ッ, outer properties of な る フ ッ carbonized ジ エ ト キ シ エ タ ン, physical properties of と electrolyte properties, the major teaching of the electronics society gathering 77, 84), 1- (2-fluoroethoxy) -2- (2,2,2-trifluoroethoxy) ethane, 1- (2,2-difluoroethoxy) -2- (2,2,2-trifluoroethoxy) ethane, 1,2-bis (2-fluoroethoxy) ethane, 1- (2-fluoroethoxy) -2-ethoxyethane, and 1- (2,2-difluoroethoxy) -2-ethoxyethane have excellent electrolyte properties and have potential as non-aqueous electrolytes in secondary batteries.
However, no efficient synthesis of these diether compounds has been reported in the prior art.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object thereof is to provide a production method capable of efficiently synthesizing a fluorinated diether (hereinafter, referred to as scheme a) and a production method of a sulfonic acid ester (hereinafter, referred to as scheme B) which can be used as a raw material for synthesizing a fluorinated diether-based compound.
Scheme A:
the present invention provides a process for producing a fluoro diether compound, characterized in that the reaction formula is any one of the following formulae:
in the reaction formulae I and II, R1、R2、R3And R4Independently of one another, from F or H, RaIs sulfonyl, n =0-5, m =1-5, p =0-5.
The method for producing a fluoro diether compound according to the present invention may further have the following features: wherein n =1,m =2,p =1.
The method for producing a fluoro diether compound according to the present invention may further have the following features: wherein the sulfonyl group is a p-toluenesulfonyl group or a methanesulfonyl group, preferably the sulfonyl group is a p-toluenesulfonyl group.
The method for producing a fluoro diether compound according to the present invention may further have the following features: the method comprises the following reaction steps:
reacting the compound A, the compound B, the alkali A and a solvent at 50-120 ℃, and performing post-treatment to obtain a compound E; or
Reacting the compound C, the compound D, the alkali A and the solvent at 50-120 ℃, and carrying out post-treatment to obtain a compound E.
Preferably, the post-treatment comprises the steps of:
cooling the reaction system after the reaction to 10-30 ℃, dropwise adding the reaction system into a mixed solution of tert-butyl methyl ether and water, extracting, taking an organic phase, adjusting the pH value of the system to 5-7, carrying out reduced pressure rectification, and collecting fractions at 66-72 ℃ to obtain the target compound.
More preferably, the reaction steps for preparing compound E from compound C and compound D are as follows:
adding a solvent and alkali into a reaction container, protecting by inert gas, controlling the temperature of a system to be below 10-30 ℃, adding a compound C, stirring for 0.5-2h, adding a compound D, heating to 50-120 ℃, reacting for 10-20h, cooling the reaction system to 10-30 ℃, dropwise adding the reaction system into a mixed solution of tert-butyl methyl ether and water, extracting, taking an organic phase, adjusting the pH value of the system to be 5-7, carrying out reduced pressure rectification, and collecting fractions at 66-72 ℃ to obtain the target compound.
The method for producing a fluoro diether compound according to the present invention may further have the following features: wherein the alkali A is any one or more of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate or sodium hydride.
The method for producing a fluoro diether compound according to the present invention may further have the following features: wherein the solvent is any one of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or 2-methyltetrahydrofuran.
The method for producing a fluoro diether compound according to the present invention may further have the following features: wherein the molar ratio of the compound C to the compound D is 1: (1.2-1.5).
The method for producing a fluoro diether compound according to the present invention may further have the following features: wherein the molar ratio of the compound C to the alkali is 1: (1.5-1.8).
Scheme B:
the invention also provides a preparation method of the sulfonate, which has the following characteristics: for the preparation of compounds
The reaction formula is as follows:
in the formula, R1And R2Independently of one another, from F or H, RaIs sulfonyl, X is Cl or Br, n =0-5, m =1-5,
the method comprises the following reaction steps:
dissolving a compound F and an alkali B in a solvent to obtain a solution A;
dropwise adding a solution of a compound G into the solution A at a temperature of between 5 ℃ below zero and 5 ℃ to obtain a reaction solution;
and returning the reaction liquid to room temperature for reaction for 0.5-3h, and performing post-treatment to obtain the catalyst.
In the method for producing a sulfonic acid ester provided by the present invention, there may be further provided: wherein the post-treatment comprises the following steps:
adding water, extracting, collecting organic phase, washing with 5-15wt% hydrochloric acid water solution, and removing solvent.
In the method for producing a sulfonic acid ester provided by the present invention, there may be further provided: wherein, the base B is an organic base, preferably diisopropylethylamine or triethylamine.
Action and Effect of the invention
According to the method for producing a fluorodiether compound of the present invention, since reaction conditions suitable for a specific reaction substrate are selected for the substrate, the present invention is directed to synthesis
An effective new method is developed.
According to the method for producing a sulfonic acid ester of the present invention, since the order of addition is adjusted, the reaction can be ensured to obtain the desired product in a high yield using a weak base.
Drawings
FIG. 1 is a hydrogen spectrum of compound E in example 17 of the present invention;
FIG. 2 is a carbon spectrum of compound E in example 17 of the present invention; and
FIG. 3 is a fluorine spectrum of compound E in example 17 of the present invention.
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described below by combining the embodiment and the attached drawings.
In the following examples, each compound is a commercially available product unless otherwise specified.
In the following examples, the meaning of partial nouns is as follows:
trace: trace amount of
N.R.: no reaction
DMAP: 4-dimethylaminopyridine
Ms: mesyl radical
Ts: p-toluenesulfonyl group
MsCl: methanesulfonyl chloride
TsCl: p-toluenesulfonyl chloride
< example 1>
Preparation of Compound A1
This example provides a process for the preparation of compound A1, of the formula:
the method comprises the following reaction steps:
4.7g of the compound D1 (57.2mmol, 1.0eq) and 3.4g of the compound F (38.9 mmol, 0.68 eq) are dissolved in 15g of tetraethylene glycol dimethyl ether, 0.16g of NaOH (4.0 mmol, 0.07 eq) is added, the temperature is increased to 140 ℃, the mixture is stirred and reacted for 6 hours, the mixture is naturally cooled to the room temperature, the filtrate is taken and subjected to reduced pressure distillation by a water pump, and fractions at the temperature of 80-85 ℃ are collected, so that 4.87g of the target compound is obtained, the yield is 99.2%, and the purity is 99.6%.
< example 2>
Screening of Process for preparation of Compound A1
In this example, the solvent or base used in the reaction was screened based on the method for producing compound A1 described in example 1. The preparation method described in this example is basically the same as that of example 1, except that the solvent or base used is different.
The specific screening results are shown in table 1.
TABLE 1 screening of the preparation of Compound A1
| Serial number | Alkali | Solvent(s) | Yield of |
| 1 | NaOH | Phenylmethyl ether | Trace |
| 2 | NaOH | N-methyl pyrrolidone | 92.1％ |
| 3 | - | Tetraethylene glycol dimethyl ether | N.R. |
| 4 | NaHCO3 | Tetraethylene glycol dimethyl ether | 86.5％ |
| 5 | NaOH | Anisole/watera | 79.4％ |
a. NaOH was added and then 0.5g of water was added
As can be seen from table 1, the applicant has unexpectedly found that not all ether solvents serve as solvents in the preparation process related to this example, and that only trace amounts of the target product can be obtained, especially when anisole is used as the solvent.
The applicant has also found that in the reactions involved in the present application, at least a catalytic amount of base needs to be added to ensure that the reaction proceeds smoothly. The strength of the base also has a certain influence on the reaction, and the use of the base with stronger alkalinity (such as NaOH) as the catalyst is better than the use of the weak base (such as NaHCO)3) Better yields can be obtained.
In addition, the addition of water to the reaction system does not increase the reaction yield by increasing the solubility of NaOH, but rather decreases the reaction yield, probably due to the susceptibility of the starting compound F to water, which is decomposed to some extent in the presence of water.
< example 3>
Preparation of Compound A2
This example provides a process for the preparation of compound A2, of the formula:
the method comprises the following reaction steps:
5.0g of the compound D2 (50.0 mmol,1.0 eq) and 3.0g of the compound F (34.0 mmol, 0.68 eq) are dissolved in 15g of tetraethylene glycol dimethyl ether, 0.14g of NaOH (3.5 mmol, 0.07 eq) is added, the temperature is raised to 140 ℃, the reaction is stirred for 6 hours, the temperature is naturally reduced to room temperature, the filtration is carried out, the filtrate is taken and subjected to reduced pressure distillation by a water pump, and fractions at the temperature of 80-85 ℃ are collected, so that 4.71g of the target compound is obtained, the yield is 96.1%, and the purity is 99.5%.
< example 4>
Preparation of Compound B1
This example provides a process for the preparation of compound B1, of the formula:
the method comprises the following reaction steps:
10g of the compound D2 (0.10mol, 1.0eq), 12.6g of MsCl (0.111mol, 1.1eq) and 14.7g of DMAP (0.12mol, 1.2eq) were dissolved in 30g of dichloromethane, and the mixture was stirred at room temperature for reaction for 5 hours, 60g of water was added, an organic phase was taken, the solvent was removed under reduced pressure, and flash column chromatography was performed to obtain 9.94g of the target compound, the yield was 55.8%, and the purity was 99.5%.
< example 5>
Preparation of Compound B2
This example provides a method for the preparation of compound B2, having the following reaction formula:
the method comprises the following reaction steps:
10g of the compound D2 (0.10mol, 1.0eq), 21.0g of TsCl (0.111mol, 1.1eq) and 14.7g of DMAP (0.12mol, 1.2eq) were dissolved in 30g of dichloromethane, and the mixture was stirred at room temperature for reaction for 5 hours, 60g of water was added to obtain an organic phase, the solvent was removed under reduced pressure, and flash column chromatography was performed to obtain 25.2g of the target compound with a yield of 99.1% and a purity of 99.4%.
< example 6>
Preparation of Compound B3
This example provides a process for the preparation of compound B3, of the formula:
the method comprises the following reaction steps:
10g of compound D1 (0.12mol, 1.0eq), 14.9g of MsCl (0.13mol, 1.1eq) and 17.1g of DMAP (0.14mol, 1.2eq) were dissolved in 30g of dichloromethane, stirred at room temperature for reaction for 5 hours, 60g of water was added, the organic phase was taken, the solvent was removed under reduced pressure, and flash column chromatography was performed to obtain 11.5g of the target compound, the yield was 59.8%, and the purity was 99.0%.
< example 7>
Preparation of Compound B4
This example provides a process for the preparation of compound B4, of the formula:
the method comprises the following reaction steps:
10g of Compound D1 (0.12mol, 1.0eq), 24.8g of TsCl (0.13mol, 1.1eq) and 17.1g of DMAP (0.14mol, 1.2eq) were dissolved in 30g of dichloromethane, and the mixture was stirred at room temperature for 5 hours, and 60g of water was added to obtain an organic phase, and the solvent was removed under reduced pressure and subjected to flash column chromatography to obtain 28.2g of the objective compound with a yield of 99.5% and a purity of 99.4%.
< example 8>
Preparation of Compound E
This example provides a method for the preparation of compound E, having the formula:
the method comprises the following reaction steps:
4.0g NaH (purity 60%,101.0mmol, 1.8eq) and 40g anhydrous tetrahydrofuran are added into a reaction bottle, the temperature is controlled to 15 ℃ under the protection of nitrogen, 10.6g of compound A1 (84.2mmol, 1.5eq) are added, after stirring for 1h at 15 ℃, 10.0g of compound B1 (56.1mmol, 1.0eq) are added, the temperature is increased to 70 ℃, the reaction is stirred for 16h, sampling is carried out, liquid-phase analysis is carried out, and the liquid phase shows that only trace target products exist.
< example 9>
Preparation of Compound E
This example provides a method for the preparation of compound E, having the formula:
the method comprises the following reaction steps:
2.8g of NaH (purity 60%,70.7mmol, 1.8eq) and 40g of anhydrous tetrahydrofuran were charged in a reaction flask, the temperature was controlled to 15 ℃ under nitrogen protection, 7.4g of Compound A1 (59.0mmol, 1.5eq) were added, and after stirring at 15 ℃ for 1 hour, 10.0g of Compound B2 (39.3mmol, 1.0eq) was added, the temperature was raised to 70 ℃, the reaction was stirred for 16 hours, and sampling and liquid-phase analysis were carried out, whereby the liquid-phase yield of Compound E was 14.4%.
< example 10>
Preparation of Compound E
This example provides a method for the preparation of compound E, having the formula:
the method comprises the following reaction steps:
4.6g NaH (purity 60%,115.6mmol, 1.8eq) and 40g anhydrous tetrahydrofuran are added into a reaction bottle, nitrogen is protected, the temperature is controlled to 15 ℃, 13.5g of compound A2 (93.6mmol, 1.5eq) is added, after stirring for 1h at 15 ℃, 10.0g of compound B3 (62.4mmol, 1.0eq) is added, the temperature is increased to 70 ℃, the reaction is stirred for 16h, sampling is carried out, liquid-phase analysis is carried out, and the liquid phase shows that only trace amount of target product exists.
< example 11>
Preparation of Compound E
This example provides a method for the preparation of compound E, having the formula:
the method comprises the following reaction steps:
3.0g NaH (60% pure, 76.1mmol, 1.8eq) and 40g anhydrous tetrahydrofuran were charged into a reaction flask, and the temperature was controlled to 15 ℃ under nitrogen protection, 9.1g of Compound A2 (63.4mmol, 1.5eq) was added, and after stirring at 15 ℃ for 1 hour, 10.0g of Compound B4 (42.3mmol, 1.0eq) was added, and the temperature was raised to 70 ℃ under stirring for 16 hours, and sampling and liquid-phase analysis were carried out, and the liquid phase showed only a trace amount of the target product.
< example 12>
Preparation of Compound C1
This example provides a process for the preparation of compound C1, of the formula:
the method comprises the following reaction steps:
10g of dichloromethane, 5.0g of compound A1 (39.6 mmol, 1.0eq) and 4.4g of triethylamine (43.6 mmol, 1.1eq) are added into a reaction vessel, the temperature is reduced to 0 ℃, a dichloromethane solution (7.5 g of TsCl is dissolved in 15g of dichloromethane) in which 7.5g of TsCl (39.6 mmol, 1.0eq) is dissolved is dropwise added into the system, the temperature is increased to 25 ℃ after the dropwise addition is finished, the reaction is carried out for 2 hours, 5g of water is added, extraction is carried out, an organic phase is taken, 1g of 10wt% hydrochloric acid aqueous solution is used for washing once, the solvent is removed under reduced pressure, 11.0g of target compound C1 is obtained, the yield is 99.0%, the purity is 95.3%, and the target compound can be used for the next reaction without further purification.
< example 13>
Preparation method screening of Compound C1
In this example, a base and/or a solvent were screened based on the method for preparing compound C1 provided in example 12. The preparation method described in this example is basically the same as that of example 13, except that the solvent or base used is different.
The screening results are shown in table 2.
TABLE 2 screening of the preparation of Compound C1
| Serial number | Alkali | Solvent(s) | Yield of |
| 1 | DMAP | Methylene dichloride | 25.5％a |
| 2 | Pyridine compound | Methylene dichloride | 18.7％a |
| 3 | Diisopropylethylamine | Methylene dichloride | 98.6％b |
| 4 | DMAP | Tetrahydrofuran (THF) | 15.3％a |
| 5 | Triethylamine | Tetrahydrofuran (THF) | 98.7％b |
a. Liquid phase yield; b. isolation yield
As is clear from table 2, the reaction solvent does not greatly affect the yield of the compound C1, but the selection of the base greatly affects the yield of the reaction, and under the production conditions as in this example, the tertiary amines such as triethylamine and diisopropylethylamine are more likely to accelerate the reaction, while the aromatic compounds such as pyridine and DMAP are used as the base, which is less likely to accelerate the reaction.
Further, in contrast to the reactions described in Table 2 of this example under numbers 1 and 4 and examples 5 and 7, the applicants have unexpectedly found that the structure of the reaction substrate has an important influence on the acylation reaction as described in this example. The reactivity of the alkoxy alcohols in this example is significantly lower than that of the alkyl alcohol substrates in examples 5 and 7, and therefore, even if the same acylation conditions as those for acylating the alkyl alcohol substrates are employed, acylation of the alkoxy alcohols in this example cannot necessarily be effectively achieved.
< example 14>
Preparation of Compound C1
This example provides a method for the preparation of compound C1, having the following reaction formula:
the method comprises the following reaction steps:
under an ice-water bath, 25g of dichloromethane, 5.0g of compound A1 (39.6 mmol,1.0 eq), 7.5g of TsCl (39.6 mmol, 1.0eq) and 4.4g of triethylamine (43.6 mmol,1.1 eq) were sequentially added to a reaction vessel, the temperature was raised to 25 ℃, reaction was carried out for 2 hours, 5g of water was added, extraction was carried out, an organic phase was taken, washed once with 1 10g of 10wt% aqueous hydrochloric acid solution, the solvent was removed under reduced pressure, and flash column chromatography was carried out to obtain 9.3g of target compound C1, yield was 84.2%, and purity was 98.5%.
< example 15>
Preparation of Compound C1
This example provides a process for the preparation of compound C1, of the formula:
the method comprises the following reaction steps:
in an ice-water bath, 5.0g of the compound A1 (39.6 mmol, 1.0eq) was added to 10mL of a 4.6mol/L aqueous NaOH solution, and a tetrahydrofuran solution (7.5 g of TsCl dissolved in 15g of tetrahydrofuran) in which 7.5g of TsCl (39.6 mmol, 1.0eq) was dissolved was further added dropwise, and the mixture was heated to 25 ℃ to react for 2 hours, and 5g of water was added to extract the resulting mixture, and the organic phase was collected, washed once with 10g of a 10wt% aqueous hydrochloric acid solution, and subjected to solvent removal under reduced pressure and flash column chromatography to obtain 6.7g of the objective compound C1 with a yield of 60.3% and a purity of 99.0%.
< example 16>
Preparation method screening of Compound C1
In this example, a base and/or a solvent in which TsCl is dissolved were screened based on the method for the preparation of compound C1 provided in example 15. The preparation method described in this example is basically the same as that of example 15, except that a solvent or base dissolving TsCl is used.
The screening results are shown in table 3.
TABLE 3 screening of the preparation of Compound C1 2
| Serial number | Alkali | Solvent for dissolving TsCl | Yield of |
| 1 | Potassium carbonate | Tetrahydrofuran (THF) | 35.1％ |
| 2 | Sodium hydroxide | Methylene dichloride | 55.8％ |
| 3 | Potassium carbonate | Methylene dichloride | 34.3％ |
As can be seen from table 3, when an inorganic base is used, an appropriate amount of water needs to be added to dissolve the inorganic base, but the presence of water greatly reduces the yield of the target compound.
< example 17>
Preparation of Compound E
This example provides a method for the preparation of compound E, having the formula:
the method comprises the following reaction steps:
under the protection of nitrogen and at room temperature, 50g of tetrahydrofuran and 2.6g of NaH (purity 60%,64.3mmol and 1.8eq) are added into a reaction vessel, 5.4g of compound D2 (53.6 mmol and 1.5eq) and 10.0g of compound C1 (35.7mmol and 1.0eq) are sequentially added, the temperature is increased to 70 ℃, the reaction is stirred for 16 hours, the temperature is reduced to 20 ℃, 50g of tert-butyl methyl ether and 30g of water are added, extraction is carried out, an aqueous phase is extracted by using 20g of tert-butyl methyl ether, organic phases are combined, the pH value is adjusted to 6 by using 10wt% of hydrochloric acid aqueous solution, liquid separation is carried out, the organic phases are taken, the solvent is removed by atmospheric distillation, the water pump is subjected to reduced pressure distillation, fractions at 66-72 ℃ are collected, and the target compounds with the yield of 6.7g, 90.2% and the purity of 99.9% are obtained.
The hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound E obtained in this example are shown in FIGS. 1 to 3, respectively.
< example 18>
Preparation method screening of Compound E
In this example, the equivalent amounts of NaH, compound C1, and compound D2 were screened based on the method for preparing compound E provided in example 17. The preparation method described in this example is basically the same as that of example 17, except that the equivalent weight of at least one of NaH, compound C1 and compound D2 is different.
The screening results are shown in table 4.
TABLE 4 preparation of Compound E screening 1
| Serial number | NaH equivalent | Compound C1 equivalent | Compound D2 equivalents | Yield of |
| 1 | 1.5 | 1.0 | 1.0 | 49.4％ |
| 2 | 1.5 | 1.2 | 1.0 | 67.2％ |
| 3 | 1.5 | 1.0 | 1.2 | 85.8％ |
| 4 | 1.2 | 1.0 | 1.5 | 71.3％ |
| 4 | 2.0 | 1.0 | 1.5 | 80.4％ |
As can be seen from table 4, in the reaction according to this example, when the equivalent of compound D2 is larger than the equivalent of compound C1, the product yield is higher than in the case where the equivalent of compound C1 is larger than compound D2. Furthermore, it was surprising that the yield decreased slightly when the NaH dosage was further increased from 1.5 to 2.0.
< example 19>
Preparation of Compound E
This example provides a method for the preparation of compound E, having the formula:
the method comprises the following reaction steps:
under the protection of nitrogen and at room temperature, 50g of N, N-dimethylformamide and 20.9g of Cs are added2CO3(64.1mmol, 1.8eq) was charged into a reaction vessel, 5.4g of the compound D2 (53.6mmol, 1.5eq) and 10.0g of the compound C1 (35.7mmol, 1.0eq) were sequentially charged, the temperature was raised to 70 ℃ and the reaction was stirred for 16 hours, and sampling was carried out, and liquid-phase analysis was carried out, whereby the liquid-phase yield was 20.5%.
Effects and effects of the embodiments
According to the method of producing a fluorodiether compound of the present invention, a specific reaction substrate is selected and reaction conditions suitable for the substrate are selected, so that the present invention is directed to synthesis
An effective new method is developed.
In particular, when the reaction substrate is
When the desired product is obtained in a satisfactory yield.
According to the preparation method of sulfonic acid ester related to the above examples, because sulfuryl chloride is added at the end of the feeding stage, higher yield can be obtained compared with other feeding modes.
Further, the base used in the reaction was selected based on the above-mentioned feeding method, and triethylamine or diisopropylethylamine was used as the base for the alkoxy alcohol substrate such as compound A1 in the above example, which gave a better reaction yield than other bases.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. A process for preparing a fluorodiether, characterized in that the reaction formula is any one of the following formulae:
in the reaction formulae I and II, R1、R2、R3And R4Independently of one another, from the group consisting of F or H,
Rais a sulfonyl group, and is a carboxyl group,
n＝0-5，m＝1-5，p＝0-5。
2. the process for producing a fluorodiether according to claim 1,
wherein n =1,m =2,p =1.
3. The process for the preparation of fluorodiethers according to claim 1, characterized in that:
wherein the sulfonyl group is a p-toluenesulfonyl group or a methanesulfonyl group.
4. The process for the preparation of fluorodiethers according to claim 1, characterized by comprising the following reaction steps:
reacting the compound A, the compound B, the alkali A and a solvent at 50-120 ℃, and performing post-treatment to obtain a compound E;
or
Reacting the compound C, the compound D, the alkali A and the solvent at 50-120 ℃, and performing post-treatment to obtain a compound E.
5. The process for the preparation of fluorodiethers according to claim 4, characterized in that:
wherein the alkali A is any one or more of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate or sodium hydride.
6. The process for the preparation of fluorodiethers according to claim 4, characterized in that:
wherein the solvent is any one of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran or 2-methyltetrahydrofuran.
7. The process for producing a fluorodiether according to claim 4,
wherein the molar ratio of the compound C to the compound D is 1: (1.1-1.5).
8. A process for the preparation of a fluorodiether according to claim 4,
wherein the molar ratio of the compound C to the base is 1: (1.1-1.8).
9. Preparation method of sulfonate for preparing compound
The reaction formula is as follows:
in the formula, R1And R2Independently of one another, from F or H, RaIs sulfonyl, X is Cl or Br, n =0-5, m =1-5,
the method is characterized by comprising the following reaction steps:
dissolving a compound F and an alkali B in a solvent to obtain a solution A;
dropwise adding a solution of a compound G into the solution A at the temperature of between 5 ℃ below zero and 5 ℃ to obtain a reaction solution;
and returning the reaction liquid to room temperature for reaction for 0.5-3h, and performing post-treatment to obtain the catalyst.
10. The process for producing sulfonic acid ester according to claim 9, characterized in that:
wherein the base B is triethylamine or diisopropylethylamine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008303161A (en) * | 2007-06-06 | 2008-12-18 | Panasonic Corp | Method for producing fluorine-containing alkoxyalkane |
| CN112778336A (en) * | 2019-11-02 | 2021-05-11 | 上海凌达生物医药有限公司 | Nitrogen-containing fused ring STING regulator compounds, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008303161A (en) * | 2007-06-06 | 2008-12-18 | Panasonic Corp | Method for producing fluorine-containing alkoxyalkane |
| CN112778336A (en) * | 2019-11-02 | 2021-05-11 | 上海凌达生物医药有限公司 | Nitrogen-containing fused ring STING regulator compounds, preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| ZHENG YUE 等: "Synthesis and electrochemical properties of partially fluorinated ether solvents for lithiumesulfur battery electrolytes", 《JOURNAL OF POWER SOURCES》, vol. 401, pages 272 * |
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