CN115260103B - Preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole - Google Patents
Preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 58
- 239000003960 organic solvent Substances 0.000 claims abstract description 32
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 28
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000005695 dehalogenation reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000012298 atmosphere Substances 0.000 claims abstract description 11
- 239000011261 inert gas Substances 0.000 claims abstract description 11
- 125000001979 organolithium group Chemical group 0.000 claims abstract description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 239000012074 organic phase Substances 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 13
- 229910052744 lithium Inorganic materials 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical group [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims 5
- 239000002168 alkylating agent Substances 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- GAWRKSJOQLXMAY-UHFFFAOYSA-N FC(N(C=N1)C(Br)=C1Br)F Chemical compound FC(N(C=N1)C(Br)=C1Br)F GAWRKSJOQLXMAY-UHFFFAOYSA-N 0.000 description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 11
- VXYWJMIHCRGSIB-UHFFFAOYSA-N 2,4,5-tribromo-1-(difluoromethyl)imidazole Chemical compound C1(=C(N(C(=N1)Br)C(F)F)Br)Br VXYWJMIHCRGSIB-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- -1 1-N-difluoromethyl-4,5 disubstituted imidazole Chemical class 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- JCGGPCDDFXIVQB-UHFFFAOYSA-N 2,4,5-tribromo-1h-imidazole Chemical compound BrC1=NC(Br)=C(Br)N1 JCGGPCDDFXIVQB-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CPHGOBGXZQKCKI-UHFFFAOYSA-N 4,5-diphenyl-1h-imidazole Chemical compound N1C=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 CPHGOBGXZQKCKI-UHFFFAOYSA-N 0.000 description 1
- BIZYMGHNRLSEAQ-UHFFFAOYSA-N 4-bromo-1-(difluoromethyl)imidazole Chemical compound FC(F)N1C=NC(Br)=C1 BIZYMGHNRLSEAQ-UHFFFAOYSA-N 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/68—Halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole. The method comprises the steps of carrying out high-area selective exchange on 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole and a dehalogenation reagent in an organic solvent under the atmosphere of inert gas to generate an intermediate state, and then reacting the intermediate state in the presence of water to generate 4,5-dihalo-1- (difluoromethyl) -1H-imidazole, wherein the dehalogenation reagent is selected from a Grignard reagent or an organolithium reagent, the Grignard reagent is R-Mg-Br, the organolithium reagent is R-Li, wherein R is C1-6 alkyl or phenyl, the molar ratio of the dehalogenation reagent to 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole is 1-1.5: 1. the preparation method can obtain the target compound with high selectivity and high yield, does not generate an isomer of the target compound, has simple subsequent separation, and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole.
Background
Researches show that the 1-position N atom of the imidazole derivative has a substituent and the 4,5-dialkyl substituted imidazole derivative has good stability, and further, the hydrolysis stability and the thermal stability of the derivative are good when the 1-position N atom of the imidazole derivative is substituted by polyfluoromethyl. The difluoromethyl group has good metabolic stability and lipophilic property, so that the solubility or permeability of the compound can be improved, and the bioavailability and metabolic stability of the compound can be improved. Hydrogen in the difluoromethyl group has weak acidity, can form a hydrogen bond, and is beneficial to the combination of a medicament and a receptor so as to improve the activity of the medicament. The 1-N-difluoromethyl-4,5 disubstituted imidazole derivative is used as an important molecular building block for synthesizing a KRAS mutation inhibitor, and has important application value in developing therapeutic drugs for malignant tumors such as pancreatic cancer, colorectal cancer, lung cancer and the like; meanwhile, the fluorine-containing imidazole carbene can be used as a key material for preparing fluorine-containing imidazole carbene with high stability, and the fluorine-containing imidazole carbene is widely used as a complexing agent and a catalyst.
In the prior disclosed preparation method of 4,5-disubstituted-1- (difluoromethyl) -1H-imidazole, the difluoromethylation reaction of imidazole has poor selectivity and low yield. In addition, the large-scale production of 4,5-disubstituted-1- (difluoromethyl) -1H-imidazoles, which typically uses freon as the difluoromethylating agent, is environmentally hazardous.
For example, the difluoromethylation of 4,5-diphenyl-1H imidazole is disclosed in the foreign Journal of Russian Journal of Organic Chemistry, vol.46, no. 6, p.903-910, 2010, using chlorodifluoromethane as the fluoroalkylating agent, in an alkaline medium in the presence of a phase transfer catalyst at 30-40 ℃ with a product yield of only 37%.
For another example, WO2020085493A1 discloses a difluoromethylation reaction of 4,5-disubstituted-1H imidazole, which uses sodium difluorochloroacetate as a fluoroalkylation reagent, and the reaction is carried out in a microwave reactor at 150 ℃ for 16 hours with a product yield of only 11%.
Disclosure of Invention
The invention aims to solve the technical problems of the prior art and provide a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole, which has high selectivity of target products and extremely high yield.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method of making 4,5-dihalo-1- (difluoromethyl) -1H-imidazole, said method of making comprising: reacting a compound of formula II
With dehalogenation reagent in organic solvent,Reacting under inert gas atmosphere to generate intermediate state shown in formula IV
And then reacting the intermediate state shown in the formula IV in the presence of water to generate the compound shown in the formula I
(ii) a The dehalogenation reagent is selected from a Grignard reagent or an organolithium reagent; the Grignard reagent is R-Mg-Br, the organolithium reagent is R-Li, wherein R is C1-6 alkyl or phenyl, in the formula I, the formula II and the formula IV, X is selected from Br or I, and the molar ratio of the Grignard reagent to the compound shown in the formula II is 1 to 1.5:1.
in some preferred embodiments, the dehalogenation reagent is a grignard reagent.
In some embodiments, the molar ratio of the dehalogenating agent to the compound of formula II is from 1 to 1.2:1.
in some embodiments, the grignard reagent is selected from a combination of one or more of methyl magnesium bromide, ethyl magnesium bromide, and phenyl magnesium bromide; the organolithium reagent is selected from the group consisting of methyl lithium, butyl lithium, sec-butyl lithium, isobutyl lithium and tert-butyl lithium in combination.
In some embodiments, in formula I, formula II, and formula IV, X is Br.
In some embodiments, the organic solvent is selected from one or a combination of two of tetrahydrofuran and diethyl ether.
In some embodiments, the volume-to-mass ratio of the organic solvent to the compound of formula II is 5 to 20ml:1g.
In some embodiments, the dehalogenation reagent is a grignard reagent and the reaction to produce the intermediate state of formula IV is at a temperature of-5 to 5 ℃ for a time of 1 to 2 hours.
In some embodiments, the dehalogenation reagent is an organolithium reagent and the reaction to produce the intermediate state of formula IV is at a temperature of-60 to-30 ℃ for 1 to 2 hours.
The temperature of the reaction in the present invention means a temperature measured by an external temperature control means of the reaction system, for example, a temperature measured in a water bath or cooling equipment outside the reaction apparatus.
In some embodiments, the dehalogenation reagent is a grignard reagent, the compound represented by formula II is dissolved in the organic solvent under an inert gas atmosphere, the organic solvent is cooled to-5 to 5 ℃, the grignard reagent is added dropwise to the organic solvent, and the reaction is carried out at-5 to 5 ℃ for 1 to 2 hours.
In some embodiments, the dehalogenation reagent is an organolithium reagent, the compound represented by formula II is dissolved in the organic solvent under an inert gas atmosphere, the organic solvent is cooled to-60 to-30 ℃, the organolithium reagent is added dropwise into the organic solvent, and the reaction is carried out at-60 to-30 ℃ for 1 to 2 hours.
In some embodiments, the dehalogenation reagent is a grignard reagent, and the reaction to produce the compound of formula I is at a temperature of from-5 to 5 ℃ for a time of from 10 to 30 minutes.
In some embodiments, the dehalogenation reagent is an organolithium reagent and the reaction to produce the compound of formula I is at a temperature of-5 to 5 ℃ for a time of 10 to 30 minutes. In some embodiments, the water is in large excess relative to the grignard reagent, while simultaneously acting as a post-treatment solvent.
In some embodiments, reacting the compound of formula IV in the presence of water to produce the compound of formula I is specifically: and adding water for reaction and layering to obtain an organic phase and a water phase, and drying, filtering, concentrating and carrying out column chromatography on the organic phase to obtain the compound shown in the formula I.
The inventors of the present invention have found that the regioselective exchange of a compound of formula II with a dehalogenating agent results in a specific intermediate state as shown in the following structure
And after water is added, the carbanion is combined with the proton in the water to finally form the compound shown in the formula I. And by controlling the mole of dehalogenating agent to the compound of formula IIThe molar ratio may be such that one halogen substituent at a particular position of the compound of formula II is selectively substituted to yield the target compound of formula I. The reaction has high regioselectivity, the yield of the target product is high, no isomer of the target product is generated, and the separation process of the target product is simple.
In some embodiments, the method of preparation further comprises a compound of formula III
And (3) carrying out a fluoro-alkylation reaction with a fluoro-alkylation reagent in a solvent under the alkaline condition to generate a compound shown as a formula II, wherein X in the formula III is selected from Br or I, and the fluoro-alkylation reagent is selected from one or a combination of two of ethyl difluorobromoacetate and sodium difluorochloroacetate.
In some embodiments, in formula III, X is Br.
In some embodiments, the solvent is selected from one or a combination of two of tetrahydrofuran and acetonitrile.
In some embodiments, the volume-to-mass ratio of the solvent to the compound of formula III is 5 to 10ml:1g of the total weight of the composition.
In some embodiments, the fluoroalkylation reaction is at a temperature of 35 to 70 ℃ for a time of 12 to 18 hours.
In some embodiments, the basic conditions are formed by the addition of one or both bases selected from sodium hydroxide and potassium carbonate.
In some embodiments, the molar ratio of the base to the compound of formula III is 2 to 5:1.
in some embodiments, the molar ratio of the fluoroalkylating agent to the compound of formula III is 1.2 to 3:1.
in some embodiments, the step of producing the compound of formula II comprises: dissolving the compound shown in the formula III in a solvent, adding alkali, heating to 35-70 ℃, adding the fluorinated alkylation reagent, and carrying out fluorinated alkylation reaction for 12-18 hours.
In some embodiments, the step of producing the compound of formula II further comprises: after the fluoroalkylation reaction is finished, cooling, concentrating, adding ice water and ethyl acetate for layering to obtain an organic phase and a water phase, washing, drying, filtering and concentrating the organic phase to obtain a crude product of the compound shown in the formula II, and recrystallizing to obtain the compound shown in the formula II.
The invention also provides a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole, which comprises the following steps: under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-5 ℃, dripping the Grignard reagent into the organic solvent, reacting for 1-5 hours at-5 ℃, then adding water, and layering the system to obtain the compound shown in formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; in the formula I and the formula II, X is selected from Br or I, and the molar ratio of the Grignard reagent to the compound shown in the formula II is 1-1.5: 1.
the invention also provides a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole, which comprises the following steps: under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-60-30 ℃, dripping organic lithium reagent into the organic solvent, reacting for 1-5 hours at-60-30 ℃, then adding water, layering the system to obtain the compound containing the formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; in the formulas I and II, X is selected from Br orWherein the molar ratio of the organic lithium reagent to the compound represented by the formula II is 1-1.5: 1.
the invention also provides 4,5-dihalo-1- (difluoromethyl) -1H-imidazole having the structural formula shown in formula I:
in the formula I, X is Br.
The present invention also provides a compound suitable for use in the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole, said compound having the structure shown in formula IV below:
；
wherein X is selected from Br or I, and Y is selected from MgBr or Li.
Preferably, X is Br.
Preferably, Y is MgBr.
Compared with the prior art, the invention has the following technical advantages:
1. the method uses 2,4,5-trihalo-1H-imidazole as a substrate to carry out difluoromethylation reaction, does not generate selectivity problem, then adopts a dehalogenation reagent with a specific molar ratio to react with a compound shown in a formula II, and subsequently adds water to carry out further reaction, so that a target compound can be obtained with high selectivity and high yield, isomers of the target compound cannot be generated, and the target product is simple to separate. The present invention can achieve a yield of the target compound of 90% or more.
2. The invention avoids using Freon and other reagents with environmental hazard, and the synthetic route is green and environment-friendly.
3. The target compound obtained by the preparation method has high purity which can reach 97 percent and can be used as a synthetic intermediate of medicines and fluorine-containing imidazole carbene.
4. The reaction and purification process of the invention is simple to operate, the reaction condition is mild and controllable, and the invention is beneficial to industrial production.
Drawings
FIG. 1 is a nuclear magnetic spectrum of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole prepared in example 1;
FIG. 2 is a nuclear magnetic spectrum of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole prepared in example 1;
FIG. 3 is a mass spectrum of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole prepared in example 1.
Detailed Description
The present invention is further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The technical features of the embodiments described below can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described below are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The following examples only express several embodiments of the present invention, and the description is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Example 1
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole:
step 1: preparation of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1H-imidazole (50.0 g,164.1 mmol) was dissolved in acetonitrile (300 ml) and potassium carbonate (45.4 g,328.2 mmol) was added with stirring. The reaction was warmed to 50 ℃ and ethyl difluorobromoacetate (40.0 g,196.9 mmol) was slowly added to the reaction and stirred at 50 ℃ overnight. TLC spot plate reaction is complete, the reaction solution is cooled to room temperature, and the solvent is removed by concentration. Ice water (200 ml) and ethyl acetate (300 ml) were added, the layers were separated, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, which was recrystallized to give 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole 57.0 g as a white solid with 98% yield.
ESI-MS (m/z) of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole is 352.65[ m ] +H ]] + In CDCl 3 The hydrogen spectrum of Nuclear Magnetic Resonance (NMR) is shown in figure 1, and the specific values are as follows: 1 H NMR (400 MHz, CDCl 3 )：7.31 (s, 0.25H)，7.16 (s, 0.5H)，7.02 (s, 0.25H)。
step 2: preparation of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (20.0 g,56.4 mmol) was dissolved in tetrahydrofuran (400 mL) under nitrogen to give a reaction solution. After cooling to 0 ℃, ethyl magnesium bromide (1M, 56.4 mL,56.4 mmol) was slowly added dropwise to the reaction mixture, and the reaction was stirred for 1 hour. TLC spot plate reaction is complete. Water (400 mL) was added, and the mixture was stirred at 0 ℃ for 15 minutes, and the mixture was allowed to separate into layers, and the organic phase was collected. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography to afford 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 14.4 g as a colorless oil in 93% yield and 97% purity.
4,5 dibromo-1- (difluoromethyl) -1H-imidazole in CDCl 3 The hydrogen spectrum of Nuclear Magnetic Resonance (NMR) is shown in FIG. 2, and the specific values are as follows: 1 H NMR (400 MHz, CDCl 3 ): 7.89 (s, 1H), 7.20 (s, 0.26H), 7.05 (s, 0.52H), 6.90 (s, 0.26H). The mass spectrum of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole is shown in FIG. 3, and the specific values are as follows: ESI-MS (m/z): 276.80 [ M + H +2 ]] + ，317.85 [M+H+MeCN+2]+。
Example 2
This example provides a process for large scale production of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole:
step 1: preparation of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1H-imidazole (2.00 kg,6.6 mol) was dissolved in acetonitrile (14L) and sodium hydroxide (528 g,13.2 mol) was added with stirring. The temperature was raised to 50 ℃ and ethyl difluorobromoacetate (2.68 kg,13.2 mol) was slowly added to the reaction system, followed by stirring at 50 ℃ overnight. TLC spot plate reaction is complete, the reaction solution is cooled to room temperature, and the solvent is removed by concentration. Ice water (10L) and ethyl acetate (10L) were added, the layers were separated, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. Crude recrystallization afforded 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole 2.29 kg as a white solid in 98% yield.
Step 2: preparation of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (1.70 kg,4.8 mol) was dissolved in anhydrous tetrahydrofuran (17L) solution under nitrogen and cooled to 0 ℃. Ethyl magnesium bromide (3M, 1.83L, 5.5 mol) was slowly added dropwise to the reaction solution, and the reaction was stirred for 1.5 hours. TLC spot plate reaction is complete. Water (17L) was added, and the mixture was stirred at 0 ℃ for 30 minutes, and the mixture was allowed to separate into layers, and the organic phase was collected. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was distilled under reduced pressure to give 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 1.26 kg as a colorless oil in 95% yield and 97% purity.
Example 3
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 1 is the same as example 1, and step 2 is basically the same as example 1, except that: the ethyl magnesium bromide was replaced with the same molar amount of methyl magnesium bromide. The final 4,5-dibromo-1- (difluoromethyl) -1H-imidazole was in 95% yield and 96% purity.
Example 4
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 2 is the same as example 1, and step 1 is basically the same as example 1, except that: ethyl difluorobromoacetate was replaced with the same molar amount of sodium difluorochloroacetate. The final 4,5-dibromo-1- (difluoromethyl) -1H-imidazole was in 95% yield and 96% purity.
Example 5
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 1 as in example 1, step 2 was as follows:
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (20.0 g,56.4 mmol) was dissolved in tetrahydrofuran (400 ml) under nitrogen to give a reaction solution. After cooling to-60 ℃, tert-butyllithium (1.3M, 43.4 mL,56.4 mmol) was slowly added dropwise to the reaction mixture, and the reaction was stirred for 1 hour. TLC spot plate reaction is complete. Adding water (400 mL), stirring at 60 ℃ for 15 minutes, demixing the system, and collecting an organic phase. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography to give 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 14.0g as a colorless oil in 90% yield and 95% purity.
Specific values of the hydrogen spectrum of nuclear magnetic resonance are as follows: 1 H NMR (400 MHz, CDCl 3 )：7.89 (s, 1H), 7.19 (s, 0.25H), 7.04 (s, 0.50H), 6.89 (s, 0.25H)。
example 6
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 1 as in example 1, step 2 was as follows:
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (20.0 g,56.4 mmol) was dissolved in tetrahydrofuran (400 ml) under nitrogen to give a reaction solution. The reaction mixture was cooled to-60 ℃ and butyllithium (1.3M, 43.4 mL,56.4 mmol) was slowly added dropwise to the reaction mixture, followed by stirring for 1 hour. TLC spot plate reaction is complete. Adding water (400 mL), stirring at 60 ℃ for 15 minutes, demixing the system, and collecting an organic phase. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography to give 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 13.2g as a colorless oil in 85% yield and 95% purity.
Comparative example 1
This comparative example provides a preparation method: step 1 is the same as example 1, and step 2 is basically the same as example 1, except that: the amount of ethyl magnesium bromide was increased from 56.3 mmol to 112.6 mmol. As a result, it was found that 4,5-dibromo-1- (difluoromethyl) -1H-imidazole was not prepared, and 4-bromo-1- (difluoromethyl) -1H-imidazole was obtained.
Comparative example 2
This comparative example provides a preparation method: step 1 is the same as example 1, and step 2 is basically the same as example 1, except that: the ethyl magnesium bromide was replaced with the same molar amount of sodium sulfite. As a result, it was found that the reaction yield was as low as 35%, the reaction was incomplete and a large amount of by-products were produced.
Comparative example 3
This comparative example provides a preparation method: step 1 is the same as example 1, and step 2 is basically the same as example 1, except that: the ethyl magnesium bromide was replaced with the same molar amount of sodium borohydride. As a result, it was found that the reaction yield was as low as 40%, the reaction was incomplete and a large amount of by-products were produced.
Therefore, the Grignard reagent or the organic lithium reagent reacts with 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole at first, then water is added for removing reaction, and the Grignard reagent or the organic lithium reagent and the molar equivalent thereof are controlled, so that the halogen removal of 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole at a specific position can be realized, and a high-purity target product is obtained with high yield. The reagents of comparative examples 2 to 3 cannot be used for the synthesis of the target product of the present invention.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (12)
1. A preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole is characterized in that: the preparation method comprises the following steps: 1) Reacting a compound of formula III
With a fluorinated alkylating reagent in a solvent under the alkaline condition to generate the compound shown in the formula II
In the formula III, X is selected from Br or I; 2) Reacting a compound of formula II
Reacting with a dehalogenation reagent in an organic solvent under the atmosphere of inert gas to generate an intermediate state shown in a formula IV
And then reacting the intermediate state shown in the formula IV in the presence of water to generate the compound shown in the formula I
；
The fluorinated alkylating reagent is selected from one or the combination of two of ethyl difluorobromoacetate and sodium difluorochloroacetate;
the dehalogenation reagent is selected from a Grignard reagent or an organic lithium reagent; the Grignard reagent is R-Mg-Br, the organic lithium reagent is R-Li, wherein R is C1-6 alkyl; in the formula I, the formula II and the formula IV, X is selected from Br or I, and in the formula IV, Y is selected from MgBr or Li; the molar ratio of the Grignard reagent to the compound represented by the formula II is 1 to 1.5:1.
2. the process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the dehalogenation reagent is a Grignard reagent; and/or the molar ratio of the dehalogenation reagent to the compound shown in the formula II is 1-1.2: 1; and/or, in the formula I, the formula II and the formula IV, X is Br.
3. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the Grignard reagent is selected from methyl magnesium bromide or ethyl magnesium bromide; the organolithium reagent is selected from the group consisting of methyl lithium, butyl lithium, sec-butyl lithium, iso-butyl lithium and tert-butyl lithium.
4. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the organic solvent is one or the combination of two of tetrahydrofuran and diethyl ether; and/or the volume mass ratio of the organic solvent to the compound shown in the formula II is 5-20 ml:1g of a compound; and/or, when the dehalogenation reagent is a Grignard reagent, the temperature of the reaction for generating the intermediate state shown in the formula IV is-5 ℃ and the time is 1-2 hours, and when the dehalogenation reagent is an organic lithium reagent, the temperature of the reaction for generating the intermediate state shown in the formula IV is-60-30 ℃ and the time is 1-2 hours.
5. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: when the dehalogenation reagent is a Grignard reagent, dissolving the compound shown in the formula II in the organic solvent under the atmosphere of inert gas, cooling the organic solvent to-5 ℃, dropwise adding the Grignard reagent into the organic solvent, and reacting for 1-2 hours at-5 ℃; when the dehalogenation reagent is an organic lithium reagent, dissolving the compound shown in the formula II in the organic solvent under the atmosphere of inert gas, cooling the organic solvent to-60 to-30 ℃, dropwise adding the organic lithium reagent into the organic solvent, and reacting for 1-2 hours at-60 to-30 ℃.
6. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: when the dehalogenation reagent is a Grignard reagent, the temperature of the reaction for generating the compound shown in the formula I is-5~5 ℃, and the time is 10-30 minutes, and when the dehalogenation reagent is an organic lithium reagent, the temperature of the reaction for generating the compound shown in the formula I is-60-30 ℃, and the time is 10-30 minutes; and/or, the intermediate state shown in the formula IV is reacted in the presence of water to generate the compound shown in the formula I: and adding water for reaction and layering to obtain an organic phase and a water phase, and drying, filtering, concentrating and carrying out column chromatography on the organic phase to obtain the compound shown in the formula I.
7. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the solvent is one or the combination of two of tetrahydrofuran and acetonitrile; and/or the volume mass ratio of the solvent to the compound shown in the formula III is 5-10 ml:1g of a compound; and/or the temperature of the fluoroalkylation reaction is 35-70 ℃ and the time is 12-18 hours.
8. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the alkaline condition is formed by adding one or two bases selected from sodium hydroxide and potassium carbonate; and/or, in the formula III, X is Br.
9. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 8, wherein: the molar ratio of the base to the compound represented by the formula III is 2 to 5:1; and/or the molar ratio of the fluoroalkylating agent to the compound of formula III is 1.2 to 3:1.
10. the process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the step of producing the compound represented by formula II comprises: dissolving the compound shown in the formula III in a solvent, adding alkali, heating to 35-70 ℃, adding the fluorinated alkylation reagent, and carrying out fluorinated alkylation reaction for 12-18 hours.
11. A preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole is characterized in that: the preparation method comprises the following steps: a compound of formula III
With a fluorinated alkylating reagent in a solvent under the alkaline condition to generate the compound shown in the formula II
In the formula III, X is selected from Br or I, and the fluorinated alkylating reagent is selected from one or a combination of two of ethyl difluorobromoacetate and sodium difluorochloroacetate; then under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-5 ℃, dripping the Grignard reagent into the organic solvent, reacting for 1-5 hours at-5 ℃, then adding water, and layering the system to obtain the compound shown in formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; in the formula I and the formula II, X is selected from Br or I, the Grignard reagent is R-Mg-Br, wherein R is C1-6 alkyl, and the molar ratio of the Grignard reagent to the compound shown in the formula II is 1-1.5: 1.
12. a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole is characterized in that: the preparation method comprises the following steps: a compound of formula III
With a fluorinated alkylating agent in a solvent under the alkaline condition to generate a compound shown in a formula II
In the formula III, X is selected from Br or I, and the fluorinated alkylating reagent is selected from one or the combination of two of ethyl difluorobromoacetate and sodium difluorochloroacetate; then under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-60-30 deg.C, and mixing the organic solvent with the solventDropwise adding a lithium reagent into an organic solvent, reacting for 1-5 hours at-60 to-30 ℃, then adding water, and layering the system to obtain a compound shown as a formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; in the formula I and the formula II, X is selected from Br or I, and the organic lithium reagent is R-Li, wherein R is C1-6 alkyl; the mol ratio of the organic lithium reagent to the compound shown in the formula II is 1-1.5: 1.
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