CN116924973A - Preparation method of 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride - Google Patents
Preparation method of 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride Download PDFInfo
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- CN116924973A CN116924973A CN202310933416.8A CN202310933416A CN116924973A CN 116924973 A CN116924973 A CN 116924973A CN 202310933416 A CN202310933416 A CN 202310933416A CN 116924973 A CN116924973 A CN 116924973A
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- trifluoromethylpyridine
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- DIEGHTBYTFRSDU-UHFFFAOYSA-N [3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanamine;hydrochloride Chemical compound Cl.NCC1=NC=C(C(F)(F)F)C=C1Cl DIEGHTBYTFRSDU-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- -1 benzylidene glycine methyl ester Chemical compound 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- GDSROTVTTLUHCO-UHFFFAOYSA-N 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine Chemical compound FC1=NC=C(C(F)(F)F)C=C1Cl GDSROTVTTLUHCO-UHFFFAOYSA-N 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 12
- 239000012312 sodium hydride Substances 0.000 claims abstract description 12
- 238000010992 reflux Methods 0.000 claims abstract description 10
- 239000007789 gas Substances 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 8
- 239000007788 liquid Substances 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002431 hydrogen Chemical class 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000005782 Fluopicolide Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- GBOYJIHYACSLGN-UHFFFAOYSA-N fluopicolide Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CNC(=O)C1=C(Cl)C=CC=C1Cl GBOYJIHYACSLGN-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- ABNQGNFVSFKJGI-UHFFFAOYSA-N 2,3-dichloro-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=C(Cl)C(Cl)=C1 ABNQGNFVSFKJGI-UHFFFAOYSA-N 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- JVQYWHGODHSTAM-UHFFFAOYSA-N [3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanamine Chemical compound NCC1=NC=C(C(F)(F)F)C=C1Cl JVQYWHGODHSTAM-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000817 effect on oomycetes Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- C07D213/61—Halogen atoms or nitro radicals
Abstract
The invention provides a preparation method of 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride, which comprises the following steps: s1: under the protection gas, in an organic solvent A, benzylidene glycine methyl ester reacts with sodium hydride to extract hydrogen, and then reacts with 3-chloro-2-fluoro-5-trifluoromethyl pyridine to obtain a compound I; s2: dissolving the compound I in an organic solvent B, adding the organic solvent B into dilute hydrochloric acid, reacting at a certain temperature to remove benzylidene protection, and carrying out water phase reflux decarboxylation on the reaction completion liquid to obtain the compound II. The invention adopts benzylidene glycine methyl ester to firstly pull hydrogen to form carbanion, and then carries out substitution reaction with 3-chloro-2-fluoro-5-trifluoromethyl pyridine to construct a main carbon skeleton of the product, thus having higher reaction selectivity, high reaction yield and mild reaction conditions.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride.
Background
The fluorine-containing pyridine heterocyclic compounds are paid more and more attention to the design and application of new pesticides, and have the characteristics of long effective period, low toxicity, high drug effect, wide insecticidal spectrum, small dosage, strong metabolic capability and the like. Fluopicolide is a fluoropyridine amide-containing spectrum bactericide which is developed by German Bayer company and has good control effect on oomycete diseases. The fluopicolide can permeate from the surface to the back of the blade, is conducted to the blade tip through the blade base, and mainly reduces the activity of bacteria by inhibiting cell membranes and specific proteins between cells, so that the aim of sterilization is fulfilled. The fluopicolide has the advantages of safety, low toxicity, long lasting period, strong systemic property, good sterilization effect and the like. 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride is a key intermediate for preparing fluoropyridine bactericides, especially fluopicolide, so that the synthesis of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride has important practical significance.
The structural formula of the 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride is as follows:
at present, the method for synthesizing 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride mainly comprises the following steps: 1. cyanide route: 2, 3-dichloro-5-trifluoromethylpyridine or 3-chloro-2-fluoro-5-trifluoromethylpyridine is taken as a raw material to undergo substitution reaction with sodium cyanide or potassium cyanide, and then the substitution reaction is carried out by nickel or palladium carbon hydrogenation reduction to obtain 3-chloro-2-aminomethyl-5-trifluoromethylpyridine, wherein the method has higher yield, but the potassium cyanide or sodium cyanide used belongs to a highly toxic product, the safety risk is high, high-pressure equipment and hydrogen are needed for the hydrogenation reduction in the second step, and the method also belongs to high-risk reaction; 2. nitromethane route: the method takes 2, 3-dichloro-5-trifluoromethylpyridine or 3-chloro-2-fluoro-5-trifluoromethylpyridine as raw materials, then substitutes with nitromethane, and then carries out hydrogenation reduction to obtain 3-chloro-2-aminomethyl-5-trifluoromethylpyridine, wherein the nitromethane used in the method is easy to explosion, the reaction condition is alkaline, and nitromethane is easy to produce an explosive byproduct nitroaldoxime; 3. the glycine ester route, this method takes 2, 3-dichloro-5-trifluoromethylpyridine or 3-chloro-2-fluoro-5-trifluoromethylpyridine as raw materials, take place the substitution with N-diphenylmethylene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine ethyl ester first, then deprotect the base and decarboxylate under the acidic condition to get 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride, N-diphenylmethylene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine ethyl ester that this method uses is expensive and the yield is not high, lead to the whole route cost to rise. (U.S. Pat. No. 5,172B, world patent WO2008118718A, WO2016173998A, WO2004096772A, chinese patent CN106349159A, CN106905231A, CN107286087A, CN111138351A, CN106220555A, CN104557684B, CN109553570A, european patent EP1199305A, EP1422221A, EP 1422220A).
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride, which has the advantages of simple synthetic route and improved reaction selectivity and product yield.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
(1) Under the protection gas, in an organic solvent A, benzylidene glycine methyl ester reacts with sodium hydride to extract hydrogen, and then the benzylidene glycine methyl ester reacts with 3-chloro-2-fluoro-5-trifluoromethylpyridine to generate substitution reaction to obtain N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester shown in a formula I;
(2) Adding a mixed solution of a compound N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester of a formula I and an organic solvent B into dilute hydrochloric acid, reacting at 20 ℃ to remove benzylidene protection, and carrying out water phase reflux decarboxylation on a reaction complete solution to obtain 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride of a formula II; the synthetic route is as follows:
further, in the step (1), sodium hydride is added into a mixed solution of benzylidene glycine methyl ester and an organic solvent A in batches at a temperature of 0-5 ℃ under the protection gas, the mixture is stirred for 10min after the addition, 3-chloro-2-fluoro-5-trifluoromethylpyridine is added dropwise at a temperature of 0-5 ℃, and the mixture is stirred for 1h after the dropwise addition at a temperature of 0-5 ℃. After the HPLC detection reaction is finished, slowly adding the reaction solution into ice water for quenching, extracting by ethyl acetate, washing by water, and concentrating and drying an organic phase to obtain the compound N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester shown in the formula I. By controlling the reaction temperature and the feeding sequence, the occurrence of side reaction is avoided to the greatest extent.
Further, in the step (1), the molar ratio of the raw material 3-chloro-2-fluoro-5-trifluoromethylpyridine, benzylidene glycine methyl ester and sodium hydride is 1: (1.0-2): (1.0-2). In this range, the 3-chloro-2-fluoro-5-trifluoromethylpyridine and benzylidene glycine methyl ester react most completely, and the yield is highest.
Further, in the step (1), the organic solvent a is any one of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, and DMF.
Further, in the step (2), the compound N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester shown in the formula I is dissolved in an organic solvent B, the solution is added into dilute hydrochloric acid, and the system temperature is controlled at 20 ℃ and stirred for 2 hours. Separating liquid after the HPLC detection reaction is finished, heating and refluxing the water phase for 5 hours, cooling to 0-5 ℃ after the HPLC detection reaction is finished, filtering, leaching with cold ethanol, and drying to obtain the compound 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride shown in the formula II.
Further, the molar ratio of the N-benzyl-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester to the dilute hydrochloric acid in the step (2) is 1: (1.5-3).
Further, the organic solvent B in the step (2) is any one of dichloromethane, 1, 2-dichloroethane, chloroform, methyl tertiary butyl ether, benzene, toluene, xylene and chlorobenzene.
Further, the shielding gas is an inert gas, preferably nitrogen.
Compared with the prior art, the preparation method of the 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride has the following advantages:
the preparation method disclosed by the invention takes 3-chloro-2-fluoro-5-trifluoromethyl pyridine and benzylidene glycine methyl ester as main raw materials, and the main carbon skeleton of the product is constructed by substitution after sodium hydride is extracted from hydrogen.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the inventive concepts pertain. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The invention will be described in detail with reference to examples.
The synthetic route of the 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride is as follows:
example 1:
a method for preparing 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride, comprising the steps of:
step (1): the feeding mole ratio of 3-chloro-2-fluoro-5-trifluoromethyl pyridine to benzylidene glycine methyl ester is 1:1.0, adding benzylidene glycine methyl ester (88.8 g,1.0 eq) and tetrahydrofuran (300 mL) into a 2L four-mouth bottle under the protection of nitrogen, stirring and dissolving, cooling to-5-0 ℃, slowly adding sodium hydride (20.0 g,1 eq) in batches, controlling the temperature to 0-5 ℃, stirring for 10min, controlling the temperature to 0-5 ℃, and dropwise adding 3-chloro-2-fluoro-5-trifluoromethylpyridine (100 g,1 eq), and stirring for 1h. After the reaction is detected by HPLC, the reaction solution is slowly added into ice water for quenching, extracted by ethyl acetate, washed by water and concentrated in organic phase to obtain 165.0g of N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester of the compound shown in the formula I, and the yield is: 92.3%.
In the reaction, in order to stabilize the intermediate state of benzylidene glycine methyl ester after being extracted with sodium hydride, the solvent used should be a polar aprotic organic solvent, so tetrahydrofuran can be replaced by diethyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane and DMF.
Step (2): the molar ratio of the compound shown in the formula I to the hydrochloric acid is 1:1.5, adding water (100 mL) and hydrochloric acid (51.2 g,1.5 eq) into a 1L four-mouth bottle, adding a mixed solution of a compound shown in a formula I (100 g,1 eq) and dichloromethane (200 mL) under stirring, stirring for 2h at a temperature of 20 ℃ after the addition, separating liquid after the HPLC detection reaction is finished, transferring the water phase into the 1L four-mouth bottle, stirring and heating to reflux, keeping reflux for 5h, cooling to 0-5 ℃ after the HPLC detection reaction is finished, filtering, leaching with cold ethanol, and drying to obtain 61.4g of a compound shown in a formula II, namely 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride, wherein the yield is as follows: 88.7%.
The organic solvent can be selected from water-insoluble polar organic solvents, and can be replaced by 1, 2-dichloroethane, chloroform, methyl tert-butyl ether, benzene, toluene, xylene, and chlorobenzene.
Example 2:
a method for preparing 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride, comprising the steps of:
step (1): the feeding mole ratio of 3-chloro-2-fluoro-5-trifluoromethyl pyridine to benzylidene glycine methyl ester is 1:1.5, adding benzylidene glycine methyl ester (133.2 g,1.5 eq) and ethylene glycol dimethyl ether (300 mL) into a 2L four-mouth bottle under the protection of nitrogen, stirring and dissolving, cooling to-5-0 ℃, slowly adding sodium hydride (30.0 g,1.5 eq) in batches, controlling the temperature to 0-5 ℃, adding and stirring for 10min, controlling the temperature to 0-5 ℃, and dripping 3-chloro-2-fluoro-5-trifluoromethylpyridine (100 g,1 eq) and stirring for 1h. After the reaction is detected by HPLC, the reaction solution is slowly added into ice water for quenching, extracted by ethyl acetate, washed by water and concentrated in organic phase to obtain 170.7g of N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester as a compound shown in a formula I, and the yield is: 95.5%.
Step (2): the molar ratio of the compound shown in the formula I to the hydrochloric acid is 1:2.0, adding water (100 mL) and hydrochloric acid (68.2 g,2.0 eq) into a 1L four-mouth bottle, adding a mixed solution of a compound shown in a formula I (100 g,1 eq) and chloroform (200 mL) under stirring, stirring for 2h at a temperature of 20 ℃ after the addition, separating liquid after the HPLC detection reaction is finished, transferring the water phase into the 1L four-mouth bottle, stirring and heating to reflux, keeping reflux for 5h, cooling to 0-5 ℃ after the HPLC detection reaction is finished, filtering, leaching with cold ethanol, and drying to obtain 62.9g of a compound shown in a formula II, namely 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride, wherein the yield is as follows: 90.8%.
Example 3:
a method for preparing 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride, comprising the steps of:
step (1): the feeding mole ratio of 3-chloro-2-fluoro-5-trifluoromethyl pyridine to benzylidene glycine methyl ester is 1:2.0, adding benzylidene glycine methyl ester (177.6 g,2.0 eq) and DMF (300 mL) into a 2L four-mouth bottle under the protection of nitrogen, stirring and dissolving, cooling to-5-0 ℃, slowly adding sodium hydride (40.1 g,2.0 eq) in batches, controlling the temperature to 0-5 ℃, stirring for 10min, controlling the temperature to 0-5 ℃ and dropwise adding 3-chloro-2-fluoro-5-trifluoromethylpyridine (100 g,1 eq), and stirring for 1h. After the reaction is detected by HPLC, the reaction solution is slowly added into ice water for quenching, extracted by ethyl acetate, washed by water and concentrated in organic phase to obtain 176.1g of N-benzylidene-2- (3-chloro-5-trifluoromethyl-2-pyridine) glycine methyl ester of the compound shown in the formula I, and the yield is: 98.5%.
Step (2): the molar ratio of the compound shown in the formula I to the hydrochloric acid is 1:3.0, adding water (100 mL) and hydrochloric acid (102.3 g,3.0 eq) into a 1L four-mouth bottle, adding a mixed solution of a compound shown in a formula I (100 g,1 eq) and toluene (200 mL) under stirring, stirring for 2h at a temperature of 20 ℃ after the addition, separating liquid after the HPLC detection reaction is finished, transferring the water phase into the 1L four-mouth bottle, stirring and heating to reflux, keeping reflux for 5h, cooling to 0-5 ℃ after the HPLC detection reaction is finished, filtering, leaching with cold ethanol, and drying to obtain 65.2g of a compound shown in a formula II, namely 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride, wherein the yield is as follows: 94.1%.
The invention adopts benzylidene glycine methyl ester to firstly pull hydrogen to form carbanion, and then carries out substitution reaction with 3-chloro-2-fluoro-5-trifluoromethyl pyridine to construct a main carbon skeleton of the product, thus having higher reaction selectivity, high reaction yield and mild reaction conditions.
The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A preparation method of 3-chloro-2-aminomethyl-5-trifluoromethyl pyridine hydrochloride is characterized by comprising the following steps: the method comprises the following steps:
s1: under the protection gas, in a solvent A, benzylidene glycine methyl ester reacts with sodium hydride to extract hydrogen, and then reacts with 3-chloro-2-fluoro-5-trifluoromethyl pyridine to obtain a compound I;
s2: dissolving a compound I in a solvent B, adding the solvent B into dilute hydrochloric acid, reacting at a certain temperature to remove benzylidene protection, and carrying out reflux decarboxylation on a water phase after the reaction is completed to obtain a compound II;
2. a process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: the molar ratio of the 3-chloro-2-fluoro-5-trifluoromethyl pyridine, the benzylidene glycine methyl ester and the sodium hydride in the step S1 is 1: (1.0-2): (1.0-2).
3. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: in the step S1, sodium hydride is added in a mode of dropwise adding, and the system temperature is controlled to be 0-5 ℃ in a mode of adding 3-chloro-2-fluoro-5-trifluoromethylpyridine in batches.
4. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: the solvent A in the step S1 comprises a polar aprotic organic solvent;
preferably, the solvent A comprises one or more of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane and DMF.
5. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: the compound I in the step S2 is dissolved in a solvent B and added into dilute hydrochloric acid, the protection reaction temperature of the debenzylidene is controlled to be 10-30 ℃, and the decarboxylation reaction temperature is controlled to be 90-100 ℃.
6. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: in the step S2, the solvent B is a polar aprotic organic solvent, and the solvent B includes one or more of dichloromethane, 1, 2-dichloroethane, chloroform, methyl tert-butyl ether, benzene, toluene, xylene, and chlorobenzene.
7. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: in the step S2, the molar ratio of the compound I to the dilute hydrochloric acid is 1: (1.5-3).
8. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: the shielding gas in the step S1 is an inert gas, preferably, the shielding gas is nitrogen.
9. A process for the preparation of 3-chloro-2-aminomethyl-5-trifluoromethylpyridine hydrochloride according to claim 1, wherein: the reaction temperature in the step S2 is 20 ℃.
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