CN115385852A - Efficient synthesis method of 2-amino-4-trifluoromethylpyridine - Google Patents
Efficient synthesis method of 2-amino-4-trifluoromethylpyridine Download PDFInfo
- Publication number
- CN115385852A CN115385852A CN202211077430.4A CN202211077430A CN115385852A CN 115385852 A CN115385852 A CN 115385852A CN 202211077430 A CN202211077430 A CN 202211077430A CN 115385852 A CN115385852 A CN 115385852A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethylpyridine
- reaction
- trifluoro
- ethoxy
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- RWGBXAQMUBGGKQ-UHFFFAOYSA-N 4-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=CC(C(F)(F)F)=CC=N1 RWGBXAQMUBGGKQ-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims abstract description 45
- YKYIFUROKBDHCY-UHFFFAOYSA-N 4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical compound CCOC=CC(=O)C(F)(F)F YKYIFUROKBDHCY-UHFFFAOYSA-N 0.000 claims abstract description 34
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 claims abstract description 32
- IKHLLNMSMFVTLP-UHFFFAOYSA-N 4-(trifluoromethyl)-1h-pyridin-2-one Chemical compound OC1=CC(C(F)(F)F)=CC=N1 IKHLLNMSMFVTLP-UHFFFAOYSA-N 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 230000002140 halogenating effect Effects 0.000 claims abstract description 20
- 238000005583 trifluoroacetylation reaction Methods 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 106
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 31
- 239000003153 chemical reaction reagent Substances 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 26
- 230000002194 synthesizing effect Effects 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- 238000005406 washing Methods 0.000 claims description 23
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 238000005576 amination reaction Methods 0.000 claims description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 7
- 239000005457 ice water Substances 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 235000002639 sodium chloride Nutrition 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000007710 freezing Methods 0.000 claims description 4
- 230000008014 freezing Effects 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000013067 intermediate product Substances 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- GBNPVXZNWBWNEN-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=NC(Cl)=C1 GBNPVXZNWBWNEN-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005658 halogenation reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- QXCOHSRHFCHCHN-UHFFFAOYSA-N 2-chloropyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(Cl)=C1 QXCOHSRHFCHCHN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- -1 trifluoromethylpyridine compound Chemical class 0.000 description 2
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical compound FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a high-efficiency synthesis method of 2-amino-4-trifluoromethylpyridine, which comprises the following steps: s1, obtaining 4-ethoxy-1,1,1-trifluoro-3-buten-2-one by performing trifluoroacetylation on vinyl ethyl ether serving as a starting material; s2, cyclizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone obtained in the S1 with chloroacetonitrile to obtain 2-hydroxy-4-trifluoromethylpyridine; s3, halogenating the 2-hydroxy-4-trifluoromethylpyridine obtained in the S2 through 2-hydroxy to obtain 2-halo-4-trifluoromethylpyridine; and S4, aminating the 2-halogen-4-trifluoromethylpyridine obtained in the S3 by using the 2-halogen to obtain the 2-amino-4-trifluoromethylpyridine. The invention has simple synthetic route, insensitivity to water and oxygen, low cost and suitability for large-scale production.
Description
Technical Field
The invention relates to the field of drug synthesis processes, in particular to a high-efficiency synthesis method of 2-amino-4-trifluoromethylpyridine.
Background
The 2-amino-4-trifluoromethylpyridine is used as an intermediate for medicine synthesis, the trifluoromethylpyridine compound and the derivative thereof have higher biological activity due to the special electronic effect, and other functional groups can be further introduced into the 5-position of the molecule, so that various heterocyclic compounds can be designed from the 2-amino-4-trifluoromethylpyridine. At present, only few methods can prepare trifluoromethyl pyridine derivatives, for example, 2-chloroisonicotinic acid is used as a raw material, 4-formic acid of the 2-chloroisonicotinic acid is fluorinated through sulfur tetrafluoride and hydrogen fluoride, and then 2-chloro-amination is carried out on the 4-formic acid to obtain 2-amino-4-trifluoromethyl pyridine.
Disclosure of Invention
Aiming at the problems, the invention provides a high-efficiency synthesis method of 2-amino-4-trifluoromethylpyridine, which has simple synthesis route and low cost and is suitable for large-scale production.
The technical scheme adopted by the invention for solving the technical problems is as follows: a high-efficiency synthesis method of 2-amino-4-trifluoromethylpyridine comprises the following steps:
s1, obtaining 4-ethoxy-1,1,1-trifluoro-3-buten-2-one by performing trifluoroacetylation on vinyl ethyl ether serving as a starting material;
s2, cyclizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone obtained in the S1 and chloroacetonitrile to obtain 2-hydroxy-4-trifluoromethyl pyridine;
s3, halogenating the 2-hydroxy-4-trifluoromethylpyridine obtained in the S2 through 2-hydroxy to obtain 2-halo-4-trifluoromethylpyridine;
and S4, aminating the 2-halogen-4-trifluoromethyl pyridine obtained in the S3 to obtain the 2-amino-4-trifluoromethyl pyridine.
Preferably, the specific steps of synthesizing 4-ethoxy-1,1,1-trifluoro-3-buten-2-one in the step S1 are as follows:
reacting the vinyl ethyl ether with trifluoroacetylation, wherein a trifluoroacetylation reagent in the reaction process is trifluoroacetic anhydride, trifluoroacetyl chloride or trifluoroacetic acid, a reaction solvent used for preparing 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone through reaction is dichloromethane, chloroform, toluene or ethyl ether, an acid binding agent adopts pyridine, triethylamine, ethylenediamine or dimethylaminopyridine, the molar ratio of the vinyl ethyl ether to the trifluoroacetylation reagent is 1:1-1.5, the reaction temperature is-20 ℃ to room temperature, the trifluoroacetylation reagent is slowly dripped into a vinyl ethyl ether solution, after the reaction is finished, water is added for quenching, an aqueous layer is extracted through an extracting agent, an organic phase is combined, water is used for washing, anhydrous magnesium sulfate is used for drying, the solvent is evaporated under reduced pressure, and column chromatography separation and purification are carried out, and the extracting agent is dichloromethane, chloroform or ethyl acetate;
the reaction formula for synthesizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone is as follows
Preferably, in the step S2, the 4-ethoxy-1,1,1-trifluoro-3-buten-2-one obtained in the step S1 and chloroacetonitrile are subjected to ring closing reaction, tetrahydrofuran is used as a solvent under the action of zinc powder and trimethylchlorosilane to produce an intermediate product of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and chloroacetonitrile, and the ring closing reaction is carried out through nucleophilic substitution reaction under the action of concentrated acid, the molar ratio of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to chloroacetonitrile is 1:1 to 1.5,4-ethoxy-1,1,1-trifluoro-3-buten-2-one to zinc powder is 1:1 to 3,4-ethoxy-1,1,1-trifluoro-3-buten-2-one to trimethylchlorosilane is 1;
the reaction formula for synthesizing the 2-hydroxy-4-trifluoromethylpyridine is as follows
Preferably, the specific steps of synthesizing 2-hydroxy-4-trifluoromethylpyridine in the step S2 are as follows:
adding zinc powder into a reaction bottle, adding trimethyl silicon chloride into the reaction bottle at room temperature by taking tetrahydrofuran as a solvent, reacting for 20-120min, adding chloroacetonitrile into a constant-pressure dropping funnel, adding tetrahydrofuran into the constant-pressure dropping funnel to mix with chloroacetonitrile, dropwise adding one tenth of chloroacetonitrile solution into the reaction bottle, then adding 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone into the constant-pressure dropping funnel to mix with chloroacetonitrile, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone and chloroacetonitrile into the reaction bottle, cooling to room temperature after the reaction is finished, filtering out unreacted zinc powder, removing tetrahydrofuran under reduced pressure, adding glacial acetic acid under vigorous stirring, heating and refluxing for 2-6h, cooling to room temperature, dropwise adding ammonia water into an ice water bath to adjust the pH to 7-8, extracting with ethyl acetate, washing with saturated common salt, drying, distilling off the ethyl acetate under reduced pressure, and separating and purifying by column chromatography.
Preferably, the specific steps of synthesizing 2-hydroxy-4-trifluoromethylpyridine in the step S2 are as follows:
adding tetrahydrofuran into a reaction bottle, adding zinc powder under stirring, adding trimethyl silicon chloride at room temperature, reacting for 20-120min, heating and refluxing for 10-30min, adding chloroacetonitrile into a constant-pressure dropping funnel, adding tetrahydrofuran into the constant-pressure dropping funnel to be mixed with the chloroacetonitrile, adding 4-ethoxy-1,1,1-trifluoro-3-butene-2-one into the constant-pressure dropping funnel to be mixed with the chloroacetonitrile, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one and the chloroacetonitrile into the reaction bottle, continuing stirring for 10-30min after the reaction is finished, cooling to room temperature, slowly dropwise adding HCl, stirring for 10-24h, filtering out unreacted zinc powder, standing and layering the filtrate, extracting dichloromethane, combining organic phases, carrying out saturated salt column chromatography, washing with anhydrous magnesium sulfate, drying under reduced pressure, distilling off dichloromethane, separating and purifying.
Preferably, the specific steps for synthesizing 2-halo-4-trifluoromethylpyridine in the step S3 are as follows:
adding the 2-hydroxy-4-trifluoromethylpyridine obtained in the step S2 into a reaction bottle, adding a halogenating reagent to perform a halogenating reaction to halogenate 2-hydroxy, wherein the halogenating reagent is phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide or thionyl chloride, the molar ratio of the 2-hydroxy-4-trifluoromethylpyridine to the halogenating reagent is 1:1-5, the solvent used in the halogenating reaction is DMF or acetonitrile, the reaction temperature is from room temperature to reflux, the reaction time is 1-24h, after the reaction is finished, adding water to quench, extracting a water layer by using an extracting agent, combining organic phases, washing the organic phases by using saturated sodium carbonate to remove acid, washing by using saturated saline solution, drying by using anhydrous magnesium sulfate, evaporating the solvent to obtain a light yellow liquid, and the extracting agent is dichloromethane, chloroform or ethyl acetate;
the reaction formula for synthesizing the 2-halogen-4-trifluoromethyl pyridine is as follows
Preferably, in the step S4, the 2-halo-4-trifluoromethylpyridine is reacted with an amination reagent to aminate the halogen at the 2-position, the amination reagent is ammonia, hydrazine hydrate or sodium amide, the reaction molar ratio of the 2-halo-4-trifluoromethylpyridine to the amination reagent is 1:1-30, and the solvent used for the reaction is toluene or tetrahydrofuran;
the reaction formula for synthesizing the 2-amino-4-trifluoromethylpyridine is as follows
Preferably, the specific steps for synthesizing 2-amino-4-trifluoromethylpyridine in the step S4 are as follows:
adding sodium amide into a reaction bottle under the protection of nitrogen, adding tetrahydrofuran or toluene, adding the 2-halogen-4-trifluoromethylpyridine obtained in the step S3, stirring at room temperature for 10-24h, dropwise adding methanol to quench the reaction, stirring at room temperature for 20-60min, removing the solvent under reduced pressure, adding water to dissolve the solid, extracting with methyl tert-butyl ether, drying, filtering, removing the solvent under reduced pressure, and performing column chromatography separation and purification.
Preferably, the specific steps for synthesizing 2-amino-4-trifluoromethylpyridine in the step S4 are as follows:
adding the 2-halogen-4-trifluoromethyl pyridine obtained in the step S3 into a reaction bottle, adding hydrazine hydrate, heating and refluxing for 1-12h, extracting with diethyl ether, washing with saturated saline solution, spin-drying the solvent, putting the obtained liquid into a refrigerator for freezing and solidifying, taking a solid precipitate, adding the solid into the reaction bottle, sequentially adding methanol, raney Ni washed with methanol, refluxing for 2-10h under the protection of nitrogen, filtering by using a sand core funnel, extracting with diethyl ether, washing with ammonia water, washing with saturated saline solution, drying, filtering, spin-drying the solvent, and separating and purifying by using column chromatography.
Preferably, the specific steps for synthesizing 2-amino-4-trifluoromethylpyridine in the step S4 are as follows:
and (4) adding the 2-halogen-4-trifluoromethyl pyridine obtained in the step (S3) into a reaction bottle, adding ammonia water, and reacting at high temperature and high pressure for 2-12h.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention has simple synthetic route and reaction conditions, is not sensitive to water and oxygen, has easily obtained selected raw materials such as vinyl ethyl ether, trifluoroacetic anhydride, chloroacetonitrile and the like, has low cost and environmental protection, and is suitable for large-scale production;
2. the invention has more types of selected halogenating reagents, easily obtained raw materials and higher halogenating reaction yield which can reach 85 percent;
3. the invention selects the sodium amide as the amination reagent, and has high reaction activity, short reaction time and high yield.
Drawings
FIG. 1 is a NMR spectrum of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of 2-chloro-4-trifluoromethylpyridine according to the present invention;
FIG. 3 is a NMR spectrum of 2-amino-4- (trifluoromethyl) pyridine of the present invention.
Detailed Description
The invention will now be described in detail with reference to fig. 1-3, wherein the exemplary embodiments and descriptions of the invention are provided to illustrate the invention, but not to limit the invention.
A high-efficiency synthesis method of 2-amino-4-trifluoromethylpyridine comprises the following steps: s1, performing trifluoroacetylation on vinyl ethyl ether serving as a starting material to obtain 4-ethoxy-1,1,1-trifluoro-3-butene-2-one; s2, cyclizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone obtained in the S1 with chloroacetonitrile to obtain 2-hydroxy-4-trifluoromethylpyridine; s3, halogenating the 2-hydroxy-4-trifluoromethylpyridine obtained in the S2 through 2-hydroxy to obtain 2-halo-4-trifluoromethylpyridine; and S4, aminating the 2-halogen-4-trifluoromethylpyridine obtained in the S3 by using the 2-halogen to obtain the 2-amino-4-trifluoromethylpyridine. The method comprises the following specific steps:
synthesis of S1, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one:
reacting vinyl ethyl ether with trifluoroacetylation, wherein a trifluoroacetylation reagent in the reaction process is trifluoroacetic anhydride, trifluoroacetyl chloride or trifluoroacetic acid, preferably trifluoroacetic anhydride, a reaction solvent used for preparing 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone by the reaction is dichloromethane, chloroform, toluene or diethyl ether, preferably chloroform, an acid binding agent is pyridine, triethylamine, ethylenediamine or dimethylaminopyridine, preferably pyridine, and the molar ratio of vinyl ethyl ether to trifluoroacetylation reagent is 1:1-1.5, preferably 1:1, after the reaction is finished, adopting dichloromethane, chloroform or ethyl acetate as an extracting agent.
Adding vinyl ether into a reaction bottle, sequentially adding acid-binding agent pyridine and chloroform, placing the reaction bottle in an ice-water bath, enabling the temperature of a reaction solution to be lower than 15 ℃ to obtain a vinyl ether solution, adding trifluoroacetic anhydride into a constant-pressure dropping funnel, adding chloroform into the constant-pressure dropping funnel to be mixed with the trifluoroacetic anhydride, slowly dropping the chloroform solution of the trifluoroacetic anhydride into the reaction bottle to react with the vinyl ether solution, controlling the dropping speed, and controlling the temperature of the reaction solution to be not higher than 25 ℃ after dropping within 1.5 h. Continuing to react for 30min-12h after the dropwise adding is finished, preferably 30min, adding water to quench the reaction, continuing to stir for 10-20min, extracting a water layer by dichloromethane, combining organic phases, washing with water for three times, drying by anhydrous magnesium sulfate, evaporating the dichloromethane solvent under reduced pressure, separating and purifying by column chromatography, and synthesizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone by the following reaction formula
Synthesis of S2, 2-hydroxy-4- (trifluoromethyl) pyridine:
carrying out a ring closing reaction on the 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and chloroacetonitrile obtained in the step S1, under the action of zinc powder and trimethylchlorosilane, taking tetrahydrofuran as a solvent, carrying out ring closing on the 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and chloroacetonitrile production intermediate products, and under the action of concentrated acid, carrying out a nucleophilic substitution reaction, wherein the molar ratio of the 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to the chloroacetonitrile is 1:1-1.5, preferably 1, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to the zinc powder is 1:1-3, preferably 1, the molar ratio of the 4-ethoxy-5725 zxft-trifluoro-3-buten-2-one to the trimethylchlorosilane is 1, preferably 1, 2-ethoxy-5725 zxft-3525-trifluoro-3-buten-2-one to the molar ratio of hydrochloric acid is 1, preferably 1, 0.2-ethoxy-0.2-0.32, and preferably the molar ratio of nitric acid to 1, 1.2-ethoxy-342-2-sulfuric acid; the reaction formula for synthesizing 2-hydroxy-4-trifluoromethyl pyridine is as follows
Specific operation (a): adding zinc powder into a reaction bottle, taking tetrahydrofuran as a solvent, adding trimethyl silicon chloride into the reaction bottle at room temperature, reacting for 20-60min, adding chloroacetonitrile into a constant-pressure dropping funnel, adding tetrahydrofuran into the constant-pressure dropping funnel to mix with the chloroacetonitrile, dropwise adding one tenth of chloroacetonitrile solution into the reaction bottle, after dropwise addition is completed within 5-30min, adding 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone into the constant-pressure dropping funnel to mix with the chloroacetonitrile, slightly boiling, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one and the chloroacetonitrile into the reaction bottle, after completion of the reaction, cooling to room temperature after the reaction is completed, filtering out unreacted zinc powder, removing tetrahydrofuran under reduced pressure, adding glacial acetic acid under vigorous stirring, adding concentrated sulfuric acid, heating and refluxing for 2-6h, preferably for 2h, cooling to room temperature, adding ammonia water under ice water bath to adjust the pH to 7-8, extracting ethyl acetate, drying saturated salt, performing column chromatography and separating;
specific operation (b): adding tetrahydrofuran into a reaction bottle, adding zinc powder under stirring, adding trimethyl silicon chloride at room temperature, reacting for 20-60min, heating and refluxing for 10-30min, adding chloroacetonitrile into a constant-pressure dropping funnel, adding tetrahydrofuran into the constant-pressure dropping funnel to be mixed with the chloroacetonitrile, adding 4-ethoxy-1,1,1-trifluoro-3-butene-2-one into the constant-pressure dropping funnel to be mixed with the chloroacetonitrile, controlling the temperature of a reaction solution to be below 45 ℃, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one and the chloroacetonitrile into the reaction bottle, after 2-6h dropwise adding, continuing to stir for 15-30min after the reaction is finished, cooling to room temperature, slowly adding 2 times of single amount of HCl, stirring for 10-24h, filtering out unreacted zinc powder, standing and layering a filtrate, extracting dichloromethane, combining organic phases, washing with saturated salt water, drying with anhydrous magnesium sulfate, decompressing and distilling off the dichloromethane, separating and purifying.
S3, synthesis of 2-halo-4-trifluoromethylpyridine:
adding the 2-hydroxy-4-trifluoromethylpyridine obtained in the step S2 into a reaction bottle, adding a halogenating reagent to perform halogenation reaction to halogenate 2-hydroxy, wherein the halogenating reagent is phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide or thionyl chloride, preferably phosphorus oxychloride, the molar ratio of the 2-hydroxy-4-trifluoromethylpyridine to the halogenating reagent is 1:1-5, preferably 1.5, the solvent used in the halogenation reaction is DMF or acetonitrile, the reaction temperature is from room temperature to reflux, the reflux is heated for 1-5h, preferably 2h, the reaction is completed, the reaction is poured into ice water to be quenched and cooled to room temperature, the water layer is extracted by dichloromethane, chloroform or ethyl acetate and other extracting agents, the dichloromethane is preferably used, the organic phase is washed by saturated sodium carbonate to remove acid, then is washed by saturated sodium chloride, anhydrous light yellow magnesium sulfate is dried, the solvent is evaporated to obtain a 2-halo-4-trifluoromethylpyridine synthetic reaction formula as follows
S4, synthesis of 2-amino-4-trifluoromethylpyridine:
reacting the 2-halogen-4-trifluoromethylpyridine obtained in the step S3 with an amination reagent to aminate 2-halogen, wherein the amination reagent is ammonia water, hydrazine hydrate or sodium amide, preferably sodium amide, the reaction molar ratio of the 2-halogen-4-trifluoromethylpyridine to the amination reagent is 1:1-30, preferably 1:5, and the solvent used in the reaction is toluene or tetrahydrofuran; the reaction formula for synthesizing 2-amino-4-trifluoromethyl pyridine is as follows
Specific operation (a): adding sodium amide into a reaction bottle under the protection of nitrogen, adding tetrahydrofuran or toluene, preferably tetrahydrofuran, adding the 2-halogen-4-trifluoromethylpyridine obtained in the step S3, stirring at room temperature for 10-24h, dropwise adding methanol to quench the reaction, stirring at room temperature for 20-60min, removing the solvent under reduced pressure, adding water to dissolve the solid, extracting with methyl tert-butyl ether, drying, filtering, removing the solvent under reduced pressure, and performing column chromatography separation and purification;
specific operation (b): adding the 2-halogen-4-trifluoromethyl pyridine obtained in the step S3 into a reaction bottle, then adding hydrazine hydrate, heating and refluxing for 1-12h, extracting with diethyl ether, washing with saturated saline solution, spin-drying the solvent, putting the obtained liquid into a refrigerator for freezing and curing, taking a solid precipitate, adding the solid into the reaction bottle, sequentially adding methanol, raney Ni washed with methanol, refluxing for 2-10h under the protection of nitrogen, filtering with a sand core funnel, extracting with diethyl ether, washing with ammonia water, washing with saturated saline solution, drying, filtering, spin-drying the solvent, and separating and purifying by column chromatography;
specific operation (c): and (4) adding the 2-halogen-4-trifluoromethyl pyridine obtained in the step (S3) into a reaction bottle, adding ammonia water, and reacting at high temperature and high pressure for 2-12h, preferably 6h.
The 2-halo-4-trifluoromethylpyridine in the invention is 2-chloro-4-trifluoromethylpyridine.
Example 1
Synthesis of S1, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one:
adding 72g of ethyl vinyl ether into a 1L round-bottom flask, adding 86ml of pyridine, adding 240ml of chloroform, cooling the feed liquid to below 15 ℃ through an ice-water bath, adding trifluoroacetic anhydride into a constant-pressure dropping funnel, adding 120ml of chloroform into the constant-pressure dropping funnel for dissolving, slowly dropwise adding a chloroform solution of the trifluoroacetic anhydride into the round-bottom flask, controlling the reaction temperature to be not more than 25 ℃, continuing to stir for 30min after 1.5h of dropwise addition, detecting the gas phase until the raw material is unchanged, adding water for quenching reaction, stirring for 10min, standing for layering, extracting organic phase by dichloromethane, combining the organic phases, washing with water for three times, drying with anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, controlling the external temperature to be less than 45 ℃, obtaining a crude product 131.4g, yield 78%, gas phase purity 95.9%, nuclear magnetic purity more than 95%, and nuclear magnetic resonance hydrogen spectrogram of the obtained 4-ethoxy-1,1,1-trifluoro-3-butene-2-one is shown in figure 1, and the specific meteorological detection conditions and nuclear magnetic conditions are as follows,
gas phase detection conditions:
a gas chromatograph: shimadzu GC-2010; a detector: FID,230 ℃; carrier gas: n2; the flow rate of H2 is 40ml/min; air flow rate: :400mL/min; and (3) chromatographic column: rtx-1,0.25mm × 30m,0.25 μm; column temperature: keeping the temperature at 40 ℃ for 1 minute, heating to 220 ℃ at the heating rate of 10 ℃/min and keeping the temperature for 1 minute; a sample inlet: 230 ℃, flow rate: 2mL/min, split ratio: 50; retention time of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one: 4.14min; ethyl vinyl ether retention time: 1.50min; trifluoroacetic anhydride retention time: 1.31min; pyridine retention time: 2.93min; chloroform retention time: 1.88min.
Nuclear magnetic conditions:
Bruker 300MHz，CDCl3。
s2, synthesis of 2-hydroxy-4-trifluoromethylpyridine:
adding 13.6g of zinc powder into a round-bottom flask, adding 100ml of THF, adding 5g of trimethyl silicon chloride, stirring for reaction for 20min, adding 9g of chloroacetonitrile into a constant-pressure dropping funnel, adding 20ml of THF into the constant-pressure dropping funnel, dropwise adding one tenth of a chloroacetonitrile THF solution into the reaction flask, completing dropwise addition for 5min, adding 19g of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one into the constant-pressure dropping funnel to mix with the chloroacetonitrile, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and the chloroacetonitrile into the reaction flask, releasing heat during the reaction, enabling the dropping speed to be too fast to cause reflux, deepening the color of the reaction solution, completing 30min dropping, cooling to room temperature, filtering out unreacted zinc powder, removing THF from the reaction solution under reduced pressure, adding glacial acetic acid under stirring to generate a large amount of precipitate, adding concentrated sulfuric acid, heating for reflux for 2h, cooling to room temperature, adding ammonia water bath, extracting pH7-8, extracting with ethyl acetate, filtering out saturated salt, drying under reduced pressure, removing magnesium sulfate, separating and separating to obtain a crude product.
Chromatographic conditions are as follows:
liquid chromatograph: SHIMADZU SPD-10A; mobile phase: H2O CH3CN = 40; a chromatographic column: intersil ODS-3 (4.6 mm I.D.x 250mm,5micro meter, GL sciences, ltd.); flow rate: 0.8ml/min; column temperature: room temperature; a detector: an Ultraviolet absorption photometer, wavelenth 210nm; retention time: 2.6min.
Synthesis of S3, 2-chloro-4-trifluoromethylpyridine
Repeating the step S2, synthesizing 2-hydroxy-4-trifluoromethylpyridine in multiple batches, adding 28.4g of 2-hydroxy-4-trifluoromethylpyridine into a round-bottom flask, adding 40ml of phosphorus oxychloride, heating and refluxing for 1-2h, basically eliminating HPLC (high performance liquid chromatography) measuring principle, cooling, pouring into ice, extracting dichloromethane, combining organic phases, washing with saturated sodium bicarbonate to remove acid, washing with saturated saline solution, drying with anhydrous magnesium sulfate, evaporating dichloromethane at normal pressure, distilling with a water pump under reduced pressure, cooling with ice water to obtain a product, obtaining 18.1g of light yellow liquid with yield of 60%, obtaining a nuclear magnetic resonance hydrogen spectrogram of the obtained 2-chloro-4-trifluoromethylpyridine by reaction as shown in figure 2, wherein the specific meteorological detection conditions and nuclear magnetic conditions are as follows,
gas phase detection conditions:
gas chromatograph: shimadzu GC-2010; a detector: FID,230 ℃; carrier gas: n2; the flow rate of H2 is 40mL/min; air flow rate: 400mL/min; a chromatographic column: rtx-1, 0.25mm. Times.30m, 0.25. Mu.m; column temperature: keeping the temperature at 40 ℃ for 1min, heating to 220 ℃ at the heating rate of 10 ℃/min and keeping the temperature for 1min; a sample inlet: 230 ℃; flow rate: 2mL/min; the split ratio is as follows: 50; 2-chloro-4- (trifluoromethyl) pyridine retention time: 4.4min.
Nuclear magnetic conditions:
Bruker 300MHz，CDCl3。
s4, synthesis of 2-amino-4-trifluoromethylpyridine:
adding 5.4g of 2-chloro-4-trifluoromethylpyridine into a round-bottom flask, adding 36ml of hydrazine hydrate, heating and refluxing for 4h, detecting the disappearance of raw materials by HPLC, adding diethyl ether into the reaction solution for extraction twice (100 ml), combining organic layers, washing with saturated saline, spin-drying, placing in a refrigerator for freezing and curing, separating out solids with the yield of 83 percent, and obtaining a nuclear magnetic resonance hydrogen spectrogram of the 2-amino-4-trifluoromethylpyridine obtained by the reaction as shown in figure 3, wherein the specific liquid chromatography conditions and the nuclear magnetic conditions are as follows,
liquid chromatography conditions:
a liquid chromatograph: SHAMDZU SPD-10A; mobile phase: h2o, ch3cn = 40; a chromatographic column: intersil ODS-3 (4.6 mm I.D.X 250mm,5micro meter, GL sciences, ltd.); the flow rate is 1.0ml/min; column temperature: room temperature; a detector: ultraviolet absorption photometer, wavelenth:210nm.
Nuclear magnetic conditions:
Bruker 300MHz，DMSO。
the invention has simple synthetic route and reaction conditions, is not sensitive to water and oxygen, has easily obtained selected raw materials such as vinyl ethyl ether, trifluoroacetic anhydride, chloroacetonitrile and the like, has low cost and environmental protection, and is suitable for large-scale production; secondly, the types of halogenating reagents are more, the raw materials are easy to obtain, and the yield of halogenation reaction is higher and can reach 85%; and finally, the sodium amide is used as an amination reagent, so that the reaction activity is high, the reaction time is short, the yield is high, and the synthetic method has important significance in preparing the 2-amino-4-trifluoromethylpyridine compound.
The technical solutions provided by the embodiments of the present invention are described in detail above, and the principles and embodiments of the present invention are explained herein by using specific examples, and the descriptions of the embodiments are only used to help understanding the principles of the embodiments of the present invention; meanwhile, for a person skilled in the art, according to the embodiments of the present invention, the specific implementation manners and the application ranges may be changed, and in conclusion, the content of the present specification should not be construed as limiting the invention.
Claims (10)
1. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine is characterized by comprising the following steps:
s1, obtaining 4-ethoxy-1,1,1-trifluoro-3-buten-2-one by performing trifluoroacetylation on vinyl ethyl ether serving as a starting material;
s2, cyclizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone obtained in the S1 with chloroacetonitrile to obtain 2-hydroxy-4-trifluoromethylpyridine;
s3, halogenating the 2-hydroxy-4-trifluoromethylpyridine obtained in the S2 through 2-hydroxy to obtain 2-halo-4-trifluoromethylpyridine;
and S4, aminating the 2-halogen-4-trifluoromethylpyridine obtained in the S3 by using the 2-halogen to obtain the 2-amino-4-trifluoromethylpyridine.
2. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 1, wherein: the specific steps for synthesizing 4-ethoxy-1,1,1-trifluoro-3-buten-2-one in the step S1 are as follows:
reacting the vinyl ethyl ether with trifluoroacetylation, wherein a trifluoroacetylation reagent in the reaction process is trifluoroacetic anhydride, trifluoroacetyl chloride or trifluoroacetic acid, a reaction solvent used for preparing 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone through reaction is dichloromethane, chloroform, toluene or ethyl ether, an acid binding agent adopts pyridine, triethylamine, ethylenediamine or dimethylaminopyridine, the molar ratio of the vinyl ethyl ether to the trifluoroacetylation reagent is 1:1-1.5, the reaction temperature is-20 ℃ to room temperature, the trifluoroacetylation reagent is slowly dripped into a vinyl ethyl ether solution, after the reaction is finished, water is added for quenching, an aqueous layer is extracted through an extracting agent, an organic phase is combined, water is used for washing, anhydrous magnesium sulfate is used for drying, the solvent is evaporated under reduced pressure, and column chromatography separation and purification are carried out, and the extracting agent is dichloromethane, chloroform or ethyl acetate;
the reaction formula for synthesizing the 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone is as follows
3. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 1, wherein: in the step S2, the 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and chloroacetonitrile obtained in the step S1 are subjected to a ring closing reaction, tetrahydrofuran is used as a solvent under the action of zinc powder and trimethylchlorosilane, an intermediate product is produced from 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and chloroacetonitrile, and ring closing is performed through nucleophilic substitution reaction under the action of concentrated acid, wherein the molar ratio of the 4-ethoxy-1,1,1-trifluoro-3-buten-2-one to the chloroacetonitrile is 1:1-1.5,4-ethoxy-1,1,1-trifluoro-3-buten-2-one to the zinc powder is 1:1-3,4-ethoxy-1,1,1-trifluoro-3-buten-2-one to the trimethylchlorosilane is 3525-3,4-ethoxy-3856-trifluoro-3-buten-2-one to the molar ratio of 1.5 zxft 5-trifluoro-3-buten-2-ketone to 5283 + 1-hydrochloric acid, and the molar ratio of hydrochloric acid is 1.5-5283 + 5-ethoxy-trifluoro-5-trifluoro-buten-5329;
the reaction formula for synthesizing the 2-hydroxy-4-trifluoromethylpyridine is as follows
4. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 3, wherein: the specific steps of synthesizing 2-hydroxy-4-trifluoromethylpyridine in the step S2 are as follows:
adding zinc powder into a reaction bottle, adding trimethyl silicon chloride into the reaction bottle at room temperature by taking tetrahydrofuran as a solvent, reacting for 20-120min, adding chloroacetonitrile into a constant-pressure dropping funnel, adding tetrahydrofuran into the constant-pressure dropping funnel, mixing the tetrahydrofuran with chloroacetonitrile, dropwise adding one tenth of chloroacetonitrile solution into the reaction bottle, then adding 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone into the constant-pressure dropping funnel, mixing the chloroethonitrile with the same, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-butene-2-ketone and chloroacetonitrile into the reaction bottle, cooling to room temperature after the reaction is finished, filtering out unreacted zinc powder, removing tetrahydrofuran under reduced pressure, adding glacial acetic acid under vigorous stirring, adding concentrated acid, heating and refluxing for 2-6h, cooling to room temperature, dropwise adding ammonia water into an ice water bath to adjust the pH to 7-8, extracting with ethyl acetate, washing with saturated salt, drying, distilling off ethyl acetate under reduced pressure, and separating and purifying by column chromatography.
5. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 3, wherein: the specific steps of synthesizing 2-hydroxy-4-trifluoromethylpyridine in the step S2 are as follows:
adding tetrahydrofuran into a reaction bottle, adding zinc powder under stirring, adding trimethyl silicon chloride at room temperature, reacting for 20-120min, heating and refluxing for 10-30min, adding chloroacetonitrile into a constant-pressure dropping funnel, adding tetrahydrofuran into the constant-pressure dropping funnel to be mixed with the chloroacetonitrile, adding 4-ethoxy-1,1,1-trifluoro-3-butene-2-one into the constant-pressure dropping funnel to be mixed with the chloroacetonitrile, dropwise adding a mixed solution of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one and the chloroacetonitrile into the reaction bottle, continuing stirring for 10-30min after the reaction is finished, cooling to room temperature, slowly dropwise adding HCl, stirring for 10-24h, filtering out unreacted zinc powder, standing and layering the filtrate, extracting dichloromethane, combining organic phases, carrying out saturated salt column chromatography, washing with anhydrous magnesium sulfate, drying under reduced pressure, distilling off dichloromethane, separating and purifying.
6. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 1, wherein: the specific steps for synthesizing the 2-halogen-4-trifluoromethyl pyridine in the step S3 are as follows:
adding the 2-hydroxy-4-trifluoromethylpyridine obtained in the step S2 into a reaction bottle, adding a halogenating reagent to perform a halogenating reaction to halogenate 2-position hydroxy, wherein the halogenating reagent is phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide or thionyl chloride, the molar ratio of the 2-hydroxy-4-trifluoromethylpyridine to the halogenating reagent is 1:1-5, the solvent used in the halogenating reaction is DMF or acetonitrile, the reaction temperature is from room temperature to reflux, the reaction time is 1-24h, after the reaction is finished, water is added for quenching, an aqueous layer is extracted by an extracting agent, an organic phase is combined, the organic phase is washed by saturated sodium carbonate to remove acid, then is washed by saturated salt water, and is dried by anhydrous magnesium sulfate to evaporate the solvent to obtain a light yellow liquid, and the extracting agent is dichloromethane, chloroform or ethyl acetate;
the reaction formula for synthesizing the 2-halogen-4-trifluoromethyl pyridine is as follows
7. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 1, wherein: in the step S4, 2-halogen-4-trifluoromethylpyridine reacts with an amination reagent to aminate 2-halogen, the amination reagent is ammonia water, hydrazine hydrate or sodium amide, the reaction molar ratio of the 2-halogen-4-trifluoromethylpyridine to the amination reagent is 1:1-30, and a solvent used for the reaction is toluene or tetrahydrofuran;
the reaction formula for synthesizing the 2-amino-4-trifluoromethylpyridine is as follows
8. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 7, wherein: the specific steps for synthesizing the 2-amino-4-trifluoromethylpyridine in the step S4 are as follows:
adding sodium amide into a reaction bottle under the protection of nitrogen, adding tetrahydrofuran or toluene, adding the 2-halogen-4-trifluoromethylpyridine obtained in the step S3, stirring at room temperature for 10-24h, dropwise adding methanol to quench the reaction, stirring at room temperature for 20-60min, removing the solvent under reduced pressure, adding water to dissolve the solid, extracting with methyl tert-butyl ether, drying, filtering, removing the solvent under reduced pressure, and performing column chromatography separation and purification.
9. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 7, wherein: the specific steps for synthesizing the 2-amino-4-trifluoromethylpyridine in the step S4 are as follows:
adding the 2-halogen-4-trifluoromethyl pyridine obtained in the step S3 into a reaction bottle, adding hydrazine hydrate, heating and refluxing for 1-12h, extracting with diethyl ether, washing with saturated saline solution, spin-drying the solvent, putting the obtained liquid into a refrigerator for freezing and solidifying, taking a solid precipitate, adding the solid into the reaction bottle, sequentially adding methanol, raney Ni washed with methanol, refluxing for 2-10h under the protection of nitrogen, filtering by using a sand core funnel, extracting with diethyl ether, washing with ammonia water, washing with saturated saline solution, drying, filtering, spin-drying the solvent, and separating and purifying by using column chromatography.
10. The efficient synthesis method of 2-amino-4-trifluoromethylpyridine according to claim 7, wherein: the specific steps for synthesizing the 2-amino-4-trifluoromethylpyridine in the step S4 are as follows:
and (4) adding the 2-halogen-4-trifluoromethyl pyridine obtained in the step (S3) into a reaction bottle, adding ammonia water, and reacting at high temperature and high pressure for 2-12h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211077430.4A CN115385852A (en) | 2022-09-05 | 2022-09-05 | Efficient synthesis method of 2-amino-4-trifluoromethylpyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211077430.4A CN115385852A (en) | 2022-09-05 | 2022-09-05 | Efficient synthesis method of 2-amino-4-trifluoromethylpyridine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115385852A true CN115385852A (en) | 2022-11-25 |
Family
ID=84124166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211077430.4A Pending CN115385852A (en) | 2022-09-05 | 2022-09-05 | Efficient synthesis method of 2-amino-4-trifluoromethylpyridine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115385852A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1263094A (en) * | 1999-12-29 | 2000-08-16 | 中国科学院上海有机化学研究所 | Method for synthesizing 4-trifluoromethyl pyridine compound |
| CN101709051A (en) * | 2009-11-24 | 2010-05-19 | 南京第一农药集团有限公司 | Preparation method of 2-amino-3-chloro-5-(trifluoromethyl) pyridine |
| CN102099036A (en) * | 2008-06-03 | 2011-06-15 | 英特芒尼公司 | Compounds and methods for treating inflammatory and fibrotic disorders |
| CN102712593A (en) * | 2010-01-21 | 2012-10-03 | 石原产业株式会社 | Method for producing 2-amino-4-(trifluoromethyl)pyridine |
| CN104072347A (en) * | 2014-06-30 | 2014-10-01 | 湖南海利化工股份有限公司 | Preparation method for 4- alkoxy-1,1,1- trifluoro-3- butane-2-ketone |
| CN109232402A (en) * | 2018-10-09 | 2019-01-18 | 五邑大学 | A kind of preparation method for the nitrogenous hexa-member heterocycle class compound that 2- amino replaces |
-
2022
- 2022-09-05 CN CN202211077430.4A patent/CN115385852A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1263094A (en) * | 1999-12-29 | 2000-08-16 | 中国科学院上海有机化学研究所 | Method for synthesizing 4-trifluoromethyl pyridine compound |
| CN102099036A (en) * | 2008-06-03 | 2011-06-15 | 英特芒尼公司 | Compounds and methods for treating inflammatory and fibrotic disorders |
| CN101709051A (en) * | 2009-11-24 | 2010-05-19 | 南京第一农药集团有限公司 | Preparation method of 2-amino-3-chloro-5-(trifluoromethyl) pyridine |
| CN102712593A (en) * | 2010-01-21 | 2012-10-03 | 石原产业株式会社 | Method for producing 2-amino-4-(trifluoromethyl)pyridine |
| CN104072347A (en) * | 2014-06-30 | 2014-10-01 | 湖南海利化工股份有限公司 | Preparation method for 4- alkoxy-1,1,1- trifluoro-3- butane-2-ketone |
| CN109232402A (en) * | 2018-10-09 | 2019-01-18 | 五邑大学 | A kind of preparation method for the nitrogenous hexa-member heterocycle class compound that 2- amino replaces |
Non-Patent Citations (2)
| Title |
|---|
| A.D. DUNN: "Nucleophilic displacement in 2-chloro(tri¯uoromethyl)pyridines with amines and ammonia", 《JOURNAL OF FLUORINE CHEMISTRY》, pages 153 - 157 * |
| BIAO JIANG等: "Convenient Approaches to 4-Trifluoromethylpyridine", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, pages 531 - 534 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105294653B (en) | The preparation technology of Vonoprazan fumarate | |
| CN106883216A (en) | A kind of uncommon preparation method for Buddhist nun difficult to understand | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN104478820B (en) | A kind of preparation method of Rivaroxaban intermediate | |
| CN114437031B (en) | Synthesis method of 6-methyl nicotine | |
| CN103880830B (en) | Synthesis method of azilsartan | |
| CN109956901B (en) | Preparation method of isoquinolone compound | |
| CN104892614B (en) | A kind of synthetic method of 6H iso-indoles simultaneously ketone derivatives of [2,1 α] indoles 6 | |
| CN115385852A (en) | Efficient synthesis method of 2-amino-4-trifluoromethylpyridine | |
| CN106146447B (en) | A method of preparing 4- amido imide coumarin derivative | |
| CN111320548A (en) | Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate | |
| CN105237337B (en) | The synthetic method of new 5 [10 (9 carboxyl anthryl)] M-phthalic acid | |
| CN105555748B (en) | A kind of cumene amphyl and preparation method thereof | |
| CN111848546B (en) | 2- (aminomethyl) thiazole-5-nitrile and synthesis method thereof | |
| CN108299384A (en) | Trifluoromethylthio transfering reagent compound and its synthetic method | |
| CN111269094B (en) | Preparation method of 2-bromo-1, 3-dimethoxybenzene | |
| CN109574860B (en) | Method for preparing vilanterol | |
| CN106279114B (en) | A kind of synthetic method of Taladegib | |
| CN111333528B (en) | Synthesis method of multi-configuration O-phenyl-serine compound | |
| CN107151197B (en) | Preparation method of 9-bromophenanthrene | |
| CN112110824B (en) | Method for preparing 2-bromo-5-fluoroaniline | |
| CN116730898A (en) | Synthesis method of L-tryptophanol | |
| CN114751836B (en) | Synthesis method and intermediate of 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline | |
| CN110903245B (en) | Key intermediate for synthesizing 1-alkyl-2-trifluoromethyl-5-amino-1H-imidazole and preparation method thereof | |
| CN106866350A (en) | A kind of preparation method of the bromine fluorenes of high-purity 2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |