CN104478911A - Method for preparing 3-trifluoromethyl pyrrole boric acid - Google Patents
Method for preparing 3-trifluoromethyl pyrrole boric acid Download PDFInfo
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- CN104478911A CN104478911A CN201410795879.3A CN201410795879A CN104478911A CN 104478911 A CN104478911 A CN 104478911A CN 201410795879 A CN201410795879 A CN 201410795879A CN 104478911 A CN104478911 A CN 104478911A
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- trifluoromethyl
- trifluoromethyl pyrpole
- boric acid
- methyl
- pyrpole
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- 238000000034 method Methods 0.000 title claims abstract description 24
- AMZRLVNLRZMETD-UHFFFAOYSA-N boric acid 3-(trifluoromethyl)-1H-pyrrole Chemical compound B(O)(O)O.FC(C1=CNC=C1)(F)F AMZRLVNLRZMETD-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000004327 boric acid Substances 0.000 claims abstract description 34
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000002994 raw material Substances 0.000 claims abstract description 23
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 4
- BOMVFZYVIGUOEV-UHFFFAOYSA-N 3-(trifluoromethyl)-1h-pyrrole Chemical compound FC(F)(F)C=1C=CNC=1 BOMVFZYVIGUOEV-UHFFFAOYSA-N 0.000 claims abstract 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- 239000003960 organic solvent Substances 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000638 solvent extraction Methods 0.000 claims description 16
- -1 boric acid ester Chemical class 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- MPZFNWUSPPJWCF-UHFFFAOYSA-N FC(C(=O)C(=O)C(C(F)(F)F)=O)(F)F Chemical compound FC(C(=O)C(=O)C(C(F)(F)F)=O)(F)F MPZFNWUSPPJWCF-UHFFFAOYSA-N 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 235000015320 potassium carbonate Nutrition 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 5
- 239000005977 Ethylene Substances 0.000 claims description 5
- 229960004424 carbon dioxide Drugs 0.000 claims description 5
- 235000011089 carbon dioxide Nutrition 0.000 claims description 5
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- SRRMARNIMTYPPE-UHFFFAOYSA-N n,n-di(propan-2-yl)propan-2-amine;lithium Chemical compound [Li].CC(C)N(C(C)C)C(C)C SRRMARNIMTYPPE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 3
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 abstract 3
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 230000002902 bimodal effect Effects 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a method for preparing 3-trifluoromethyl pyrrole boric acid, belonging to the technical field of organic chemical synthesis. The method is characterized by comprising the following steps: (I) with trifluoroacetic anhydride as a start raw material, generating 4-ethoxy-3-alkenyl trifluoroacetyl ketone through reaction between the trifluoroacetic anhydride and ethyl vinyl ether; (II) performing heating reflux of 4-ethoxy-3-alkenyl trifluoroacetyl ketone and hydrazine dihydrochloride in an ethanol solution to obtain 3-trifluoromethyl pyrrole; and (III) performing functional group conversion of 3-trifluoromethyl pyrrole to generate 1-methyl-3-trifluoromethyl-5-pyrrole boric acid, N-tert-butyl acyl-3-trifluoromethyl-5-pyrrole boric acid and 1-methyl-3-trifluoromethyl-4-pyrrole boric acid respectively. The method has the beneficial effects that the generated target compound has good purity and stable properties, the method is simple and easy to operate, and the preparation scale is easy to enlarge to realize industrial production.
Description
Technical field
The present invention relates to organic chemical synthesis technical field, specifically a kind of method preparing 3-trifluoromethyl pyrpole boric acid.
Background technology
3-trifluoromethyl pyrpole boric acid is the intermediate of a kind of important synthesis medicine and agricultural chemicals, have the industrial chemicals of wide application prospect, but there be limited evidence currently of has the synthetic method of this compounds of bibliographical information.Innovation of the present invention is from raw material cheap and easy to get, by organic synthesis route reasonable in design, preparation high yield, highly purified midbody compound, then carries out the structural modification of midbody compound, resynthesis target compound, the ultimate aim compound generated, purity is good, is easy to amplify produce, cost is low, easily realizes commercially produced product.
Summary of the invention
The present invention is about a kind of preparation method of 3-trifluoromethyl pyrpole boric acid, by rational syntheti c route, utilize raw material cheap and easy to get, prepare midbody compound, then carry out the structural modification of midbody compound, final synthesising target compound, of the present invention preparation is simple, and the yield of intermediate and target compound is higher, and purity is good, can production be amplified, greatly reduce preparation cost.
A kind of method preparing 3-trifluoromethyl pyrpole boric acid of the present invention, its syntheti c route is as follows:
A kind of method preparing 3-trifluoromethyl pyrpole boric acid of the present invention, the technical scheme of employing is:
One, take trifluoro-acetic anhydride as starting raw material, ether is solvent, under low temperature, with the effect of ethylene ethyl ether at organic bases, adds 1N dilute hydrochloric acid, is separated organic phase, dry, concentrated generation 4-oxyethyl group-3-alkene trifluoroacetyl ketone;
Two, 4-oxyethyl group-3-alkene trifluoroacetyl ketone and hydrazine dihydrochloride reflux in ethanolic soln, cooling, removal of solvent under reduced pressure, adds water dilution, with organic solvent extraction, is separated, dry, concentrates and obtain 3-trifluoromethyl pyrpole;
Three, 3-trifluoromethyl pyrpole is dissolved in dimethyl formamide, adds salt of wormwood, be chilled to 0 DEG C, slowly drip methyl iodide, rise to room temperature, stir 12 hours, to go out reaction with shrend, with organic solvent extraction, be separated, drying, concentrated, underpressure distillation, obtains N-methyl-3-trifluoromethyl pyrpole;
Four, N-methyl-3-trifluoromethyl pyrpole is dissolved in tetrahydrofuran solution, is chilled to-78 DEG C, slowly drips diisopropylamine lithium,-78 DEG C of reactions 2 hours, add triisopropyl boric acid ester, slowly rise to room temperature, react 12 hours, add 1N dilute hydrochloric acid cancellation reaction, then add organic solvent extraction, be separated, drying, concentrated, obtain thick product, use normal hexane rinsing, obtain 1-methyl-3-trifluoromethyl-5-pyrrol boronic acid;
Five, 3-trifluoromethyl pyrpole and tertiary butyl carbonic anhydride are under catalyst action, react 6 hours, add shrend and to go out reaction, with organic solvent extraction, are separated, dry, concentrated, obtain N-tertiary butyl acyl group-3-trifluoromethyl pyrpole;
Six, N-tertiary butyl acyl group-3-trifluoromethyl pyrpole is dissolved in tetrahydrofuran solution, is chilled to-78 DEG C, slowly drips diisopropylamine lithium,-78 DEG C of reactions 2 hours, add trimethyl borate, slowly rise to room temperature, react 12 hours, add saturated ammonium chloride cancellation reaction, then add organic solvent extraction, be separated, drying, concentrated, obtain thick product, use normal hexane rinsing, obtain N-tertiary butyl acyl group-3-trifluoromethyl-5-pyrrol boronic acid;
Seven, be dissolved in acetic acid by 3-trifluoromethyl pyrpole, be chilled to 0 DEG C, slowly add NBS, finish, rise to room temperature, react 12 hours, be poured into water, add organic solvent extraction, be separated, dry, concentrated, recrystallization, obtains the bromo-3-trifluoromethyl pyrpole of 4-;
Eight, bromo-for 4-3-trifluoromethyl pyrpole is dissolved in dimethyl formamide, adds salt of wormwood, be chilled to 0 DEG C, slow dropping methyl iodide, rise to room temperature, stir 12 hours, to go out reaction with shrend, with organic solvent extraction, be separated, dry, concentrated, underpressure distillation, obtains the bromo-1-methyl of 4--3-trifluoromethyl pyrpole;
Nine, the bromo-1-methyl of 4--3-trifluoromethyl pyrpole is dissolved in ether, is chilled to-78 DEG C, slowly drips tert-butyl lithium,-78 DEG C of reactions 2 hours, add triisopropyl boric acid ester, slowly rise to room temperature, react 12 hours, add 1N dilute hydrochloric acid cancellation reaction, then add organic solvent extraction, be separated, drying, concentrated, obtain thick product, use normal hexane rinsing, obtain 1-methyl-3-trifluoromethyl-4-pyrrol boronic acid.
In described step one, low temperature is 0 DEG C, and organic bases is pyridine.
Temperature of reaction in described step 2 is 80 DEG C.
Organic solvent in described step 2 and step 7 is methylene dichloride, step 3, four, five, six, eight and step 9 in organic solvent be ether.
Catalyzer in described step 5 is 4-N, N '-dimethyl pyridine.
Described step 4, six and step 9 in, reaction carries out under inert nitrogen gas.
In described step one, the mol ratio of raw material trifluoro-acetic anhydride and ethylene ethyl ether and pyridine is 1:1.1:1.
In described step 2, the mol ratio of raw material 4-oxyethyl group-3-alkene trifluoroacetyl ketone and hydrazine dihydrochloride is 1:1.
In described step 3, the mol ratio of raw material 3-trifluoromethyl pyrpole and methyl iodide and salt of wormwood is 1:1.5:1.5.
In described step 4, the mol ratio of raw material N-methyl-3-trifluoromethyl pyrpole and diisopropylamine lithium and triisopropyl boric acid ester is 1:1.1:1.05.
In described step 5, the mol ratio of raw material 3-trifluoromethyl pyrpole and tertiary butyl carbonic anhydride and catalyzer is 1:1:0.06.
In described step 6, the mol ratio of raw material N-tertiary butyl acyl group-3-trifluoromethyl pyrpole and diisopropylamine lithium and trimethyl borate is 1:1.1:1.1.
In described step 7, the mol ratio of raw material 3-trifluoromethyl pyrpole and NBS is 1:1.1.
In described step 8, the mol ratio of the bromo-3-trifluoromethyl pyrpole of raw material 4-and methyl iodide and salt of wormwood is 1:1.5:1.2.
In described step 9, the mol ratio of the bromo-1-methyl of raw material 4--3-trifluoromethyl pyrpole and tert-butyl lithium and triisopropyl boric acid ester is 1:2:1.1.
Embodiment
Be clearly and completely described below in conjunction with the technical scheme in the embodiment of the present invention.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Implement 1
The preparation of 4-oxyethyl group-3-alkene trifluoroacetyl ketone:
In 12L reaction flask, add 1620g trifluoro-acetic anhydride (7.71mol) and 6L ether, be chilled to 0 DEG C, slowly drip 611g ethylene ethyl ether (8.49mol) and 610g pyridine (7.71mol), finish, rise to room temperature, stir 12 hours, add 2L 1N dilute hydrochloric acid, be separated organic phase, washing, saturated sodium-chloride is washed, with anhydrous magnesium sulfate drying, concentrated generation 4-oxyethyl group-3-alkene trifluoroacetyl ketone 1200g, yield 92%, 1HNMR (CDCl
3): 1.30ppm, three peaks (3H); 4.02ppm, four peaks (2H); 5.82ppm, bimodal (1H); 7.82ppm, bimodal (1H); 13CNMR (CDCl
3): 14.10ppm, 53.37ppm, 97.80ppm, 117.91ppm, 168.10ppm, 180.43ppm.
Implement 2
The preparation of 3-trifluoromethyl pyrpole:
817g 4-oxyethyl group-3-alkene trifluoroacetyl ketone (4.86mol) and 510.16g hydrazine dihydrochloride (4.86mol) are dissolved in 2L dehydrated alcohol, reflux 12 hours, be chilled to room temperature, removal of solvent under reduced pressure, add water dilution, with dichloromethane extraction, be separated, dry, concentrate and obtain 3-trifluoromethyl pyrpole 450g, yield 68%, 1H NMR (CDCl
3): 6.71ppm, bimodal (1H); 7.76ppm, bimodal (1H); 13CNMR (CDCl
3): 103.82ppm, 123.06ppm, 130.36ppm, 142.70ppm.
Implement 3
The preparation of N-methyl-3-trifluoromethyl pyrpole:
In 5L reaction flask, 450g 3-trifluoromethyl pyrpole (3.29mol) is dissolved in 2L dimethyl formamide, adds 682.61g salt of wormwood (4.94mol), coldly cause 0 DEG C, slowly drip 701.03g methyl iodide (4.94mol), rise to room temperature, stir 12 hours, to go out reaction with shrend, by extracted with diethyl ether, be separated, dry, concentrated, underpressure distillation, obtain N-methyl-3-trifluoromethyl pyrpole 385.49g, yield 78%, 1HNMR (CDCl
3): 4.85ppm, unimodal (3H); 6.50ppm, bimodal (1H); 7.35ppm, bimodal (1H); 13CNMR (CDCl
3): 39.19ppm, 104.39ppm, 122.78ppm, 131.46ppm, 142.31ppm.
Implement 4
The preparation of the bromo-3-trifluoromethyl pyrpole of 4-:
542g 3-trifluoromethyl pyrpole (3.97mol) is dissolved in acetic acid, is chilled to 0 DEG C, slowly add 776.45g NBS (4.36mol), finish, rise to room temperature, react 12 hours, be poured into water, add dichloromethane extraction, be separated, dry, concentrated, use normal hexane recrystallization, obtain 4-bromo-3-trifluoromethyl pyrpole 640g, yield 75%, 1H NMR (CDCl
3): 7.78ppm, unimodal; 13CNMR (CDCl
3): 92.30ppm, 122.19ppm, 140.10ppm, 140.84ppm.
Implement 5
The preparation of the bromo-1-methyl of 4--3-trifluoromethyl pyrpole:
Bromo-for 250g 4-3-trifluoromethyl pyrpole (1.16mol) is dissolved in 2L dimethyl formamide, adds 192.87g salt of wormwood (1.40mol), coldly cause 0 DEG C, slow dropping 247.60g methyl iodide (1.74mol), rises to room temperature, stirs 12 hours, to go out reaction with shrend, by extracted with diethyl ether, be separated, dry, concentrated, underpressure distillation, obtains the bromo-1-methyl of 4--3-trifluoromethyl pyrpole 266.32g, yield 57%, GC.98%; 1HNMR (CDCl
3): 3.96ppm, unimodal (3H); 7.42ppm, unimodal (1H).
Implement 6
The preparation of N-tertiary butyl acyl group-3-trifluoromethyl pyrpole:
98g 3-trifluoromethyl pyrpole (0.72mol) is dissolved in 200mL tetrahydrofuran solution, adds 5.26g4-N, N '-dimethyl pyridine (0.043mol); after being chilled to 0 DEG C, slowly dripping 156.49g tertiary butyl carbonic anhydride (0.72mol), rise to room temperature; react 6 hours, add shrend and to go out reaction, by extracted with diethyl ether; be separated; drying, concentrated, obtain N-tertiary butyl acyl group-3-trifluoromethyl pyrpole 160g; yield 94%, 1H NMR (CDCl
3): 1.76ppm, unimodal (9H); 6.62ppm, bimodal (1H); 8.12ppm, bimodal (1H).
Implement 7
The preparation of N-tertiary butyl acyl group-3-trifluoromethyl-5-pyrrol boronic acid:
Under nitrogen protection, 191g N-tertiary butyl acyl group-3-trifluoromethyl pyrpole (0.81mol) is dissolved in 3L tetrahydrofuran solution, be chilled to-78 DEG C, slow dropping 524mL triisopropylamine lithium (0.89mol, 1.7N inTHF),-78 DEG C of reactions 2 hours, add 92.43g trimethyl borate (0.89mol), slowly rise to room temperature, react 12 hours, add saturated ammonium chloride cancellation reaction, add extracted with diethyl ether again, be separated, dry, concentrated, obtain thick product, use normal hexane rinsing, obtain N-tertiary butyl acyl group-3-trifluoromethyl-5-pyrrol boronic acid 163.30g, yield 72%, HPLC.98%, 1H NMR (DMSO-d
6/ D
2o): 1.62ppm, unimodal (9H), 6.96ppm, unimodal (1H).
Implement 8
The preparation of 1-methyl-3-trifluoromethyl-5-pyrrol boronic acid:
Under nitrogen protection, 120gN-methyl-3-trifluoromethyl pyrpole (0.80mol) is dissolved in 1L tetrahydrofuran solution, be chilled to-78 DEG C, slow dropping 518mL diisopropylamine lithium (0.88mol, 1.7N in THF),-78 DEG C of reactions 2 hours, add 157.88g triisopropyl boric acid ester (0.84mol), slowly rise to room temperature, react 12 hours, add 1N dilute hydrochloric acid cancellation reaction, add extracted with diethyl ether again, be separated, dry, concentrated, obtain thick product, use normal hexane rinsing, obtain 1-methyl-3-trifluoromethyl-5-pyrrol boronic acid 81g, yield 52%, GC.98%, 1H NMR (DMSO-d
6/ D
2o): 4.10ppm, unimodal (3H), 7.09ppm, unimodal (1H).
Implement 9
The preparation of 1-methyl-3-trifluoromethyl-4-pyrrol boronic acid:
Under nitrogen protection, the bromo-1-methyl of 80g4--3-trifluoromethyl pyrpole (0.35mol) is dissolved in 500mL ether, be chilled to-78 DEG C, slow dropping 411mL tert-butyl lithium (0.70mol, 1.7N in hexanes),-78 DEG C of reactions 2 hours, add 72.28g triisopropyl boric acid ester (0.38mol), slowly rise to room temperature, react 12 hours, add 1N dilute hydrochloric acid cancellation reaction, add extracted with diethyl ether again, be separated, dry, concentrated, obtain thick product, use normal hexane rinsing, obtain 1-methyl-3-trifluoromethyl-4-pyrrol boronic acid 52.83g, yield 78%, GC.98%, 1H NMR (DMSO-d
6/ D
2o): 3.89ppm, unimodal (3H), 7.92ppm, unimodal (1H).
The above is preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, and any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (15)
1. prepare the method for 3-trifluoromethyl pyrpole boric acid for one kind, comprise the preparation of 4-oxyethyl group-3-alkene trifluoroacetyl ketone, the preparation of 3-trifluoromethyl pyrpole, the preparation of N-methyl-3-trifluoromethyl pyrpole, the preparation of 1-methyl-3-trifluoromethyl-5-pyrrol boronic acid, the preparation of N-tertiary butyl acyl group-3-trifluoromethyl pyrpole, the preparation of N-tertiary butyl acyl group-3-trifluoromethyl-5-pyrrol boronic acid, the preparation of the bromo-3-trifluoromethyl pyrpole of 4-, the preparation of the bromo-1-methyl of 4--3-trifluoromethyl pyrpole and the preparation of 1-methyl-3-trifluoromethyl-4-pyrrol boronic acid; It is characterized in that:
1. the preparation of 4-oxyethyl group-3-alkene trifluoroacetyl ketone: take trifluoro-acetic anhydride as starting raw material, under low temperature, with ethylene ethyl ether in organic bases effect, adds 1N dilute hydrochloric acid, is separated organic phase, dry, concentrated generation 4-oxyethyl group-3-alkene trifluoroacetyl ketone;
2. the preparation of 3-trifluoromethyl pyrrole: 4-oxyethyl group-3-alkene trifluoroacetyl ketone and hydrazine dihydrochloride reflux in ethanolic soln, cooling, removal of solvent under reduced pressure, adds water dilution, with organic solvent extraction, is separated, dry, concentrates and obtain 3-trifluoromethyl pyrpole;
3. the preparation of N-methyl-3-trifluoromethyl pyrpole: be dissolved in dimethyl formamide by 3-trifluoromethyl pyrpole, add salt of wormwood, coldly causes 0 DEG C, slow dropping methyl iodide, rise to room temperature, stir 12 hours, to go out reaction with shrend, with organic solvent extraction, be separated, dry, concentrated, underpressure distillation, obtains N-methyl-3-trifluoromethyl pyrpole;
4. the preparation of 1-methyl-3-trifluoromethyl-5-pyrrol boronic acid: N-methyl-3-trifluoromethyl pyrpole is dissolved in tetrahydrofuran solution, is chilled to-78 DEG C, slowly drips diisopropylamine lithium,-78 DEG C of reactions 2 hours, add triisopropyl boric acid ester, slowly rise to room temperature, react 12 hours, add 1N dilute hydrochloric acid cancellation reaction, then add organic solvent extraction, be separated, drying, concentrated, obtain thick product, use normal hexane rinsing, obtain 1-methyl-3-trifluoromethyl-5-pyrrol boronic acid;
5. the preparation of N-tertiary butyl acyl group-3-trifluoromethyl pyrpole: 3-trifluoromethyl pyrpole and tertiary butyl carbonic anhydride, under catalyst action, react 6 hours, adds shrend and to go out reaction, with organic solvent extraction, be separated, dry, concentrated, obtain N-tertiary butyl acyl group-3-trifluoromethyl pyrpole;
6. the preparation of N-tertiary butyl acyl group-3-trifluoromethyl-5-pyrrol boronic acid: N-tertiary butyl acyl group-3-trifluoromethyl pyrpole is dissolved in tetrahydrofuran solution, be chilled to-78 DEG C, slow dropping diisopropylamine lithium,-78 DEG C of reactions 2 hours, add trimethyl borate, slowly rise to room temperature, react 12 hours, add saturated ammonium chloride cancellation reaction, then add organic solvent extraction, be separated, drying, concentrated, obtain thick product, use normal hexane rinsing, obtain N-tertiary butyl acyl group-3-trifluoromethyl-5-pyrrol boronic acid;
7. the preparation of the bromo-3-trifluoromethyl pyrpole of 4-: 3-trifluoromethyl pyrpole is dissolved in acetic acid, is chilled to 0 DEG C, slowly adds NBS, finish, rise to room temperature, react 12 hours, be poured into water, add organic solvent extraction, be separated, drying, concentrated, recrystallization, obtains the bromo-3-trifluoromethyl pyrpole of 4-;
8. the preparation of 4-bromo-1-methyl-3-trifluoromethyl pyrpole: be dissolved in dimethyl formamide by bromo-for 4-3-trifluoromethyl pyrpole, add salt of wormwood, coldly causes 0 DEG C, slow dropping methyl iodide, rise to room temperature, stir 12 hours, to go out reaction with shrend, with organic solvent extraction, be separated, dry, concentrated, underpressure distillation, obtains the bromo-1-methyl of 4--3-trifluoromethyl pyrpole;
9. 1-methyl-3-trifluoromethyl-4-pyrrol boronic acid: the bromo-1-methyl of 4--3-trifluoromethyl pyrpole is dissolved in ether, is chilled to-78 DEG C, slowly drips tert-butyl lithium,-78 DEG C of reactions 2 hours, add triisopropyl boric acid ester, slowly rise to room temperature, react 12 hours, add 1N dilute hydrochloric acid cancellation reaction, then add organic solvent extraction, be separated, drying, concentrated, obtain thick product, use normal hexane rinsing, obtain 1-methyl-3-trifluoromethyl-4-pyrrol boronic acid.
2. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 1. in low temperature be 0 DEG C; Described step 2. in temperature of reaction be 80 DEG C.
3. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 1. in organic bases be pyridine.
4. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 2. with step 7. in organic solvent be methylene dichloride; In described step 3., 4., 5., 6., 8. with step 9. in organic solvent be ether.
5. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 5. in catalyzer be 4-N, N '-dimethyl pyridine.
6. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 4., 6. with step 9. in reaction carry out under inert nitrogen gas.
7. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 1. in raw material trifluoro-acetic anhydride and the mol ratio of ethylene ethyl ether and pyridine be 1:1.1:1.
8. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 2. in raw material 4-oxyethyl group-3-alkene trifluoroacetyl ketone and the mol ratio of hydrazine dihydrochloride be 1:1.
9. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 3. in raw material 3-trifluoromethyl pyrpole and the mol ratio of methyl iodide and salt of wormwood be 1:1.5:1.5.
10. a kind of method preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 4. in raw material N-methyl-3-trifluoromethyl pyrpole and the mol ratio of triisopropylamine lithium and triisopropyl boric acid ester be 1:1.1:1.05.
11. a kind of methods preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 5. in raw material 3-trifluoromethyl pyrpole and the mol ratio of tertiary butyl carbonic anhydride and catalyzer be 1:1:0.06.
12. a kind of methods preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 6. in raw material N-tertiary butyl acyl group-3-trifluoromethyl pyrpole and the mol ratio of diisopropylamine lithium and trimethyl borate be 1:1.1:1.1.
13. a kind of methods preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 7. in raw material 3-trifluoromethyl pyrpole and the mol ratio of NBS be 1:1.1.
14. a kind of methods preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 8. in the bromo-3-trifluoromethyl pyrpole of raw material 4-and the mol ratio of methyl iodide and salt of wormwood be 1:1.5:1.2.
15. a kind of methods preparing 3-trifluoromethyl pyrpole boric acid as claimed in claim 1, is characterized in that: described step 9. in the bromo-1-methyl of raw material 4--3-trifluoromethyl pyrpole and the mol ratio of tert-butyl lithium and triisopropyl boric acid ester be 1:2:1.1.
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