CN103145607B - Preparation process of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride - Google Patents
Preparation process of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride Download PDFInfo
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- CN103145607B CN103145607B CN201310077393.1A CN201310077393A CN103145607B CN 103145607 B CN103145607 B CN 103145607B CN 201310077393 A CN201310077393 A CN 201310077393A CN 103145607 B CN103145607 B CN 103145607B
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- phenyl
- tetrahydropyridine hydrochloride
- carboxylic acid
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- butyl ester
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- -1 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride Chemical class 0.000 title claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000005516 engineering process Methods 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 16
- 238000000605 extraction Methods 0.000 claims description 11
- 239000007789 gas Substances 0.000 claims description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 11
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000007935 neutral effect Effects 0.000 claims description 9
- HAKSOKWVNPZVNM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine;hydrochloride Chemical compound Cl.C1CNC=CC1 HAKSOKWVNPZVNM-UHFFFAOYSA-N 0.000 claims description 6
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- SCTHWHFWPIYEOT-UHFFFAOYSA-N tert-butyl 2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1C1=CC=CC=C1 SCTHWHFWPIYEOT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 19
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000007818 Grignard reagent Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000010907 mechanical stirring Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 230000005311 nuclear magnetism Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- 238000011109 contamination Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- PBWQGUWSIBXMSG-UHFFFAOYSA-N tert-butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(O)C1=CC=CC=C1 PBWQGUWSIBXMSG-UHFFFAOYSA-N 0.000 description 3
- VEVVDEKVFXXXGT-UHFFFAOYSA-N 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine;hydrochloride Chemical compound Cl.C1=CC(Br)=CC=C1C1=CCNCC1 VEVVDEKVFXXXGT-UHFFFAOYSA-N 0.000 description 2
- SXOMHACGFSJBIO-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine Chemical compound C1=CC(Cl)=CC=C1C1=CCNCC1 SXOMHACGFSJBIO-UHFFFAOYSA-N 0.000 description 2
- CTTBTYWBXXWBMU-UHFFFAOYSA-N 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine;hydrochloride Chemical compound Cl.C1=CC(F)=CC=C1C1=CCNCC1 CTTBTYWBXXWBMU-UHFFFAOYSA-N 0.000 description 2
- CINKHTHKJZDIBT-UHFFFAOYSA-N Cl.NCC1=CC=C(C=C1)C=1CCNCC1 Chemical compound Cl.NCC1=CC=C(C=C1)C=1CCNCC1 CINKHTHKJZDIBT-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- POGWXTJNUCZEPR-UHFFFAOYSA-N 4-phenyl-1,2,3,6-tetrahydropyridin-1-ium;chloride Chemical compound Cl.C1NCCC(C=2C=CC=CC=2)=C1 POGWXTJNUCZEPR-UHFFFAOYSA-N 0.000 description 1
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- RBWRWAUAVRMBAC-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=[C-]C=C1 RBWRWAUAVRMBAC-UHFFFAOYSA-M 0.000 description 1
- BVUQKCCKUOSAEV-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=[C-]C=C1 BVUQKCCKUOSAEV-UHFFFAOYSA-M 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation process of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride. The process comprises the following steps of: reacting N-tert-butyloxycarboryl-4-piperidone with a substituted phenyl Grignard reagent to prepare tert-butyl 4-hydroxy-4-monosubstituted phenyl piperidine-1-carboxylate; and then, acidizing by hydrochloric acid, removing Boc, salifying, dehydrating in molecules, cooling and filtering to obtain the target product 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride. The preparation method is reasonable in line, high in yield, high in purity, simple and easily-available in raw materials, low in cost and suitable for industrial massive production.
Description
Technical field
The invention belongs to synthetic organic chemical art, relate to a kind of preparation technology of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride.
Background technology
4-substituted-phenyl-1,2,3,6-tetrahydropyridine hydrochloride is a kind of important medicine and pesticide intermediate, and be widely used in medicine and agricultural chemicals production, have larger industrial prospect and social benefit, its chemical structural formula is as follows:
Wherein R represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxyl group.
The method of current bibliographical information synthesis 4-substituted-phenyl-1,2,3,6-tetrahydropyridine hydrochloride mainly contains two kinds.Adopt N-benzyl-4-piperidone and phenyl-magnesium-bromide reaction, then slough benzyl by methylsulphonic acid, then change into hydrochloride and obtain target compound (Bioorg. Med. Chem. Lett., 22 (2012), 2560.).This synthetic method shortcoming is that reactions steps is long, and total recovery is lower than 50.0%, and aftertreatment produces a large amount of waste water.Such as, adopt phenylo boric acid and N-tertbutyloxycarbonyl-4-trifluoromethanesulfonic acid base-1,2,3,6 tetrahydropyridines are raw material, through suzuki linked reaction, the intermediate product obtained sloughs tertbutyloxycarbonyl under hydrochloric acid effect, obtains 4-substituted-phenyl-1 after salify, 2,3,6-tetrahydropyridine hydrochloride (Bioorg. Med. Chem. Lett., 13 (2003) 3951.).The shortcoming of this synthetic method is that starting raw material is expensive, and uses expensive catalyzer, easily causes heavy metal contamination.
Summary of the invention
Present invention, avoiding the shortcoming of above two kinds of methods, raw material is cheap and easy to get, and synthetic route is simple, and total recovery, up to more than 80.0%, is avoided causing severe contamination to environment.Its reaction process is as follows:
The object of this invention is to provide a kind of preparation technology of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride.
Realizing the technical scheme that the object of the invention takes is: a kind of preparation technology of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride, comprises the following steps:
1) preparation of 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester:
N-tertbutyloxycarbonyl-4-piperidone is dissolved in tetrahydrofuran (THF), cool to-5 ~ 15 DEG C, be added dropwise to R substituted-phenyl magnesium bromide, stir 3 ~ 8 hours at 10 ~ 15 DEG C, after having reacted, add hydrochloric acid to pH value for neutral, extraction, organic phase is replaced as Virahol, obtains the aqueous isopropanol of 4-hydroxyl-4-R Phenylpiperidine-1-carboxylic acid tert-butyl ester;
2) 4-monosubstituted phenyl-1,2, the preparation of 3,6-tetrahydropyridine hydrochloride:
At the aqueous isopropanol of 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester, pass into hydrogen chloride gas, stir and heat up, 75 ~ 82 DEG C of reactions 1 ~ 10 hour, after having reacted, be cooled to 10 ~ 20 DEG C, stir 1 ~ 5 hour, filter, obtain target product.
R substituted-phenyl described in step 1 is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group.
The concentration of hydrochloric acid that cancellation technique described in step 1 adopts is 1.0 ~ 12.0mol/L, and described extraction adopts ethyl acetate, 2-methyltetrahydrofuran, t-butyl methyl ether or toluene.
Mol ratio 1.2 ~ the 1.5:1 of the N-tertbutyloxycarbonyl-4-piperidone described in step 1 and R substituted-phenyl magnesium bromide.
Mol ratio 3.0 ~ the 5.0:1 of the 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester described in step 2 and hydrogen chloride gas.
Compared with prior art, present invention, avoiding the shortcoming of prior art two kinds of methods, raw material is cheap and easy to get, and synthetic route is simple, and total recovery, up to more than 80.0%, is avoided causing severe contamination to environment.
Embodiment
Embodiment 1.
The preparation technology of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxy-4-phenyl piperidine-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 2.2 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to-5 ~ 0 DEG C, drip the solution that 3.0 Kg phenyl-magnesium-bromides are dissolved in 5.0 L tetrahydrofuran (THF)s, stir 3 hours at-5 ~ 0 DEG C, HPLC analyzes display without raw material, the hydrochloric acid dripping 1.0mol/L below 30 DEG C is about 18.0L, be neutral to pH, add 5.0 L ethyl acetate, extraction, separatory, organic phase is threaded to 3.0 L, add 7.0 L Virahols, organic phase is threaded to 5.0 L, obtain the aqueous isopropanol of 4-hydroxy-4-phenyl piperidine-1-carboxylic acid tert-butyl ester.
2) 4-phenyl-1,2, the preparation of 3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxy-4-phenyl piperidine-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 2.0 kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 10 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 2 hours, filter, obtain faint yellow solid, yield 85.2%, purity 99.6%, nuclear-magnetism H composes and identifies that structure is correct.
Embodiment 2.
The preparation technology of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxyl-4-(4-fluorophenyl)-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 2.0 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 0 ~ 5 DEG C, drip the solution that 2.6 Kg 4-flourophenyl magnesium bromide are dissolved in 4.0 L tetrahydrofuran (THF)s, stir 5 hours at 0 ~ 5 DEG C, HPLC analyzes display without raw material, hydrochloric acid about 8.0 L of 3.0 mol/L is dripped below 30 DEG C, be neutral to pH, add 5.0 L 2-methyltetrahydrofurans, extraction, separatory, organic phase is threaded to 3.0 L, add 7.0 L Virahols, organic phase is threaded to 6.0 L, obtain the aqueous isopropanol of 4-hydroxyl-4-(4-fluorophenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) preparation of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxyl-4-(4-fluorophenyl) piperidines-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 1.1 kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 8 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 2 hours, filter, obtain faint yellow solid, yield 88.5%, purity 99.6%, nuclear-magnetism H composes and identifies that structure is correct.
Embodiment 3.
The preparation technology of 4-(4-chloro-phenyl-)-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxyl-4-(4-chloro-phenyl-)-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 2.0 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 0 ~ 5 DEG C, drip the solution that 3.0 Kg 4-chlorophenylmagnesium bromide are dissolved in 6.0 L tetrahydrofuran (THF)s, stir 7 hours at 0 ~ 5 DEG C, HPLC analyzes display without raw material, hydrochloric acid about 4 L of 6.0 mol/L is dripped below 30 DEG C, be neutral to pH, add 5.0 L ethyl acetate, extraction, separatory, organic phase is threaded to 2.0 L, add 8.0 L Virahols, organic phase is threaded to 6.0 L, obtain the aqueous isopropanol of 4-hydroxyl-4-(4-chloro-phenyl-) piperidines-1-carboxylic acid tert-butyl ester.
2) preparation of 4-(4-chloro-phenyl-)-1,2,3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxyl-4-(4-chloro-phenyl-) piperidines-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 1.5 kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 7 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 2 hours, filter, obtain faint yellow solid, yield 89.0%, purity 99.3%, nuclear-magnetism H composes and identifies that structure is correct.
Embodiment 4.
The preparation technology of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxyl-4-(4-bromophenyl)-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 1.8 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 10 ~ 15 DEG C, drip the solution that 3.5 Kg 4-flourophenyl magnesium bromide are dissolved in 6.0 L tetrahydrofuran (THF)s, stir 6 hours at 10 ~ 15 DEG C, HPLC analyzes display without raw material, hydrochloric acid about 5.0 L of 4.0 mol/L is dripped below 30 DEG C, be neutral to pH, add 5.0 L ethyl acetate, extraction, separatory, organic phase is threaded to 3.0 L, add 9.0 L Virahols, organic phase is threaded to 5.0 L, obtain the aqueous isopropanol of 4-hydroxyl-4-(4-bromophenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) preparation of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxyl-4-(4-bromophenyl) piperidines-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 1.3 kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 3 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 2 hours, filter, obtain faint yellow solid, yield 81.6%, purity 99.2%, nuclear-magnetism H composes and identifies that structure is correct.
Embodiment 5.
The preparation technology of 4-(4-aminomethyl phenyl)-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxyl-4-(4-aminomethyl phenyl)-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 2.0 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 5 ~ 10 DEG C, drip the solution that 2.7 Kg 4-methylphenyl magnesium bromide are dissolved in 5.0 L tetrahydrofuran (THF)s, stir 8 hours at 5 ~ 10 DEG C, HPLC analyzes display without raw material, hydrochloric acid about 12.0 L of 2.0 mol/L is dripped below 30 DEG C, be neutral to pH, add 5.0 L t-butyl methyl ether, extraction, separatory, organic phase is threaded to 2.0 L, add 7.0 L Virahols, organic phase is threaded to 6.0 L, obtain the aqueous isopropanol of 4-hydroxyl-4-(4-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) preparation of 4-(4-aminomethyl phenyl)-1,2,3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxyl-4-(4-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 1.8kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 5 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 2 hours, filter, obtain faint yellow solid, yield 85.3%, purity 99.8%, nuclear-magnetism H composes and identifies that structure is correct.
Embodiment 6.
The preparation technology of 4-(4-trifluoromethyl)-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxyl-4-(4-trifluoromethyl)-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 1.9 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 10 ~ 15 DEG C, drip the solution that 3.0 Kg 4-trifluoromethyl magnesium bromides are dissolved in 5.0 L tetrahydrofuran (THF)s, stir 4 hours at 10 ~ 15 DEG C, HPLC analyzes display without raw material, hydrochloric acid about 11.0 L of 2.0 mol/L is dripped below 30 DEG C, be neutral to pH, add 6.0 L toluene, extraction, separatory, organic phase is threaded to 2.0 L, add 7.0 L Virahols, organic phase is threaded to 5.0 L, obtain the aqueous isopropanol of 4-hydroxyl-4-(4-trifluoromethyl) piperidines-1-carboxylic acid tert-butyl ester.
2) preparation of 4-(4-trifluoromethyl)-1,2,3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxyl-4-(4-trifluoromethyl) piperidines-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 1.7 kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 6 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 3 hours, filter, obtain faint yellow solid, yield 80.5%, purity 99.0%, nuclear-magnetism H composes and identifies that structure is correct.
Embodiment 7.
The preparation technology of 4-(4-p-methoxy-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride
1) preparation of 4-hydroxyl-4-(4-p-methoxy-phenyl)-1-carboxylic acid tert-butyl ester
In the reaction flask of 30.0 L, be equipped with mechanical stirring, nitrogen protection, constant pressure funnel device, add 2.1 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to-5 ~ 0 DEG C, drip the solution that 3.3 Kg 4-methoxyphenyl-magnesium bromide are dissolved in 4.0 L tetrahydrofuran (THF)s, stir 8 hours at-5 ~ 0 DEG C, HPLC analyzes display without raw material, hydrochloric acid about 1.2 L of 12.0 mol/L is dripped below 30 DEG C, be neutral to pH, add 5.5 L ethyl acetate, extraction, separatory, organic phase is threaded to 2.0 L, add 9.0 L Virahols, organic phase is threaded to 5.0 L, obtain the aqueous isopropanol of 4-hydroxyl-4-(4-p-methoxy-phenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) preparation of 4-(4-p-methoxy-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride
In the reaction flask of 30.0 L, add the aqueous isopropanol of above-mentioned 4-hydroxyl-4-(4-p-methoxy-phenyl) piperidines-1-carboxylic acid tert-butyl ester.Be cooled to 10 ~ 20 DEG C, pass into 1.2 kg hydrogen chloride gas, be warming up to 75 ~ 82 DEG C of reactions 2 hours, HPLC analyzes display without raw material, be cooled to 10 ~ 20 DEG C, stir 1 hour, filter, obtain faint yellow solid, yield 85.0%, purity 99.5%, nuclear-magnetism H composes and identifies that structure is correct.
Claims (4)
1. the preparation technology of 4-monosubstituted phenyl-1,2,3, a 6-tetrahydropyridine hydrochloride, is characterized in that described technique comprises the following steps:
1) preparation of 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester:
N-tertbutyloxycarbonyl-4-piperidone is dissolved in tetrahydrofuran (THF), cool to-5 ~ 15 DEG C, be added dropwise to R substituted-phenyl magnesium bromide, stir 3 ~ 8 hours, after having reacted at 10 ~ 15 DEG C, add hydrochloric acid to pH value for neutral, extraction, is replaced as Virahol by organic phase, obtains the aqueous isopropanol of 4-hydroxyl-4-R Phenylpiperidine-1-carboxylic acid tert-butyl ester, wherein, the R of R substituted-phenyl is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group;
2) 4-monosubstituted phenyl-1,2, the preparation of 3,6-tetrahydropyridine hydrochloride:
At the aqueous isopropanol of 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester, pass into hydrogen chloride gas, stir and heat up, 75 ~ 82 DEG C of reactions 1 ~ 10 hour, after having reacted, be cooled to 10 ~ 20 DEG C, stir 1 ~ 5 hour, filter, obtain target product.
2. 4-monosubstituted phenyl-1 according to claim 1,2,3, the preparation technology of 6-tetrahydropyridine hydrochloride, it is characterized in that the concentration of hydrochloric acid that the cancellation technique described in step 1 adopts is 1.0 ~ 12.0mol/L, described extraction adopts ethyl acetate, 2-methyltetrahydrofuran, t-butyl methyl ether or toluene.
3. the preparation technology of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride according to claim 1, is characterized in that the mol ratio 1.2 ~ 1.5:1 of the N-tertbutyloxycarbonyl-4-piperidone described in step 1 and R substituted-phenyl magnesium bromide.
4. the preparation technology of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride according to claim 1, is characterized in that the mol ratio 3.0 ~ 5.0:1 of the 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester described in step 2 and hydrogen chloride gas.
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| Medicinal Chemistry Letters》.2012,第22卷第2560-2564. * |
| Richard J. Conway,等."Synthesis and SAR study of 4-arylpiperidines and 4-aryl-1,2,3,6-tetrahydropyridines as 5-HT2C agonists".《Bioorganic & * |
| 李敬芬,等."叔丁氧羰基化".《药物合成反应》.2010,第77页. * |
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