CN103145607A - 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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- CN103145607A CN103145607A CN2013100773931A CN201310077393A CN103145607A CN 103145607 A CN103145607 A CN 103145607A CN 2013100773931 A CN2013100773931 A CN 2013100773931A CN 201310077393 A CN201310077393 A CN 201310077393A CN 103145607 A CN103145607 A CN 103145607A
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- phenyl
- tetrahydropyridine hydrochloride
- carboxylic acid
- butyl ester
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- -1 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride Chemical class 0.000 title claims abstract description 15
- 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
- HAKSOKWVNPZVNM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine;hydrochloride Chemical compound Cl.C1CNC=CC1 HAKSOKWVNPZVNM-UHFFFAOYSA-N 0.000 claims description 27
- 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
- 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 17
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 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 9
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 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
- 230000007935 neutral effect Effects 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
- 238000001228 spectrum Methods 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
- QYBFFRXNNFXREA-UHFFFAOYSA-M FC1=CC=C([Mg]Br)C=C1 Chemical class FC1=CC=C([Mg]Br)C=C1 QYBFFRXNNFXREA-UHFFFAOYSA-M 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 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
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical class 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
- RLMRCLVRMBOBQR-UHFFFAOYSA-M NCC1=CC=C(C=C1)[Mg]Br Chemical class NCC1=CC=C(C=C1)[Mg]Br RLMRCLVRMBOBQR-UHFFFAOYSA-M 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
- 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
- 239000000575 pesticide Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000126 substance Substances 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
Landscapes
- 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 the Synthetic Organic Chemistry field, relate to a kind of 4-monosubstituted phenyl-1,2,3, the preparation technology of 6-tetrahydropyridine hydrochloride.
Background technology
4-substituted-phenyl-1,2,3,6-tetrahydropyridine hydrochloride is a kind of important medicine and pesticide intermediate, is widely used in medicine and agricultural chemicals production, has larger industrial prospect and social benefit, its chemical structural formula is as follows:
Wherein R represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxyl group.
Bibliographical information synthesizes 4-substituted-phenyl-1,2,3 at present, and the method for 6-tetrahydropyridine hydrochloride mainly contains two kinds.Adopt the reaction of N-benzyl-4-piperidone and phenyl-magnesium-bromide, 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.For example, adopt phenylo boric acid and N-tertbutyloxycarbonyl-4-trifluoromethanesulfonic acid base-1,2,3,6 tetrahydropyridines are raw material, through the suzuki linked reaction, the intermediate product that obtains is sloughed tertbutyloxycarbonyl under the 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
The present invention has avoided the shortcoming of above two kinds of methods, and raw material is cheap and easy to get, and synthetic route is simple, and total recovery is avoided environment is caused severe contamination up to more than 80.0%.Its reaction process is as follows:
The purpose of this invention is to provide a kind of 4-monosubstituted phenyl-1,2,3, the preparation technology of 6-tetrahydropyridine hydrochloride.
Realize that the technical scheme that the object of the invention is taked is: a kind of 4-monosubstituted phenyl-1,2,3, the preparation technology of 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 ℃, be added dropwise to R substituted-phenyl magnesium bromide, stirred 3～8 hours at 10～15 ℃, after having reacted, add the hydrochloric acid cancellation to be neutrality, extraction to the pH value, 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-1,2,3, the preparation of 6-tetrahydropyridine hydrochloride:
Aqueous isopropanol at 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester passes into hydrogen chloride gas, stirs to heat up, and 75～82 ℃ of reactions 1～10 hour, after having reacted, is cooled to 10～20 ℃, stirs 1～5 hour, filters, and gets target product.
R substituted-phenyl described in step 1 is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group.
The concentration of hydrochloric acid of the cancellation process using described in step 1 is 1.0 ~ 12.0mol/L, and ethyl acetate, 2-methyltetrahydrofuran, t-butyl methyl ether or toluene are adopted in described extraction.
Mol ratio 1.2 ~ the 1.5:1 of the N-tertbutyloxycarbonyl described in step 1-4-piperidone and R substituted-phenyl magnesium bromide.
Mol ratio 3.0 ~ the 5.0:1 of the 4-hydroxyl described in step 2-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester and hydrogen chloride gas.
Compared with prior art, the present invention has avoided the shortcoming of two kinds of methods of prior art, and raw material is cheap and easy to get, and synthetic route is simple, and total recovery is avoided environment is caused severe contamination up to more than 80.0%.
Embodiment
Embodiment 1.
4-phenyl-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 2.2 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to-5～0 ℃, drip the solution that 3.0 Kg phenyl-magnesium-bromides are dissolved in 5.0 L tetrahydrofuran (THF)s, stirred 3 hours at-5～0 ℃, HPLC analyzes and shows without raw material, at the about 18.0L of the hydrochloric acid that drips 1.0mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxy-4-phenyl piperidine-1-carboxylic acid tert-butyl ester.
2) 4-phenyl-1,2,3, the preparation of 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 ℃, pass into 2.0 kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 10 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 2 hours, filter, obtain faint yellow solid, yield 85.2%, purity 99.6%, nuclear-magnetism H spectrum identifies that structure is correct.
Embodiment 2.
4-(4-fluorophenyl)-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 2.0 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 0～5 ℃, drip the solution that 2.6 Kg 4-fluorophenyl magnesium bromides are dissolved in 4.0 L tetrahydrofuran (THF)s, stirred 5 hours at 0～5 ℃, HPLC analyzes and shows without raw material, at about 8.0 L of the hydrochloric acid that drips 3.0 mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxyl-4-(4-fluorophenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) 4-(4-fluorophenyl)-1,2,3, the preparation of 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 ℃, pass into 1.1 kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 8 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 2 hours, filter, obtain faint yellow solid, yield 88.5%, purity 99.6%, nuclear-magnetism H spectrum identifies that structure is correct.
Embodiment 3.
4-(4-chloro-phenyl-)-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 2.0 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 0～5 ℃, drip the solution that 3.0 Kg 4-chloro-phenyl-magnesium bromides are dissolved in 6.0 L tetrahydrofuran (THF)s, stirred 7 hours at 0～5 ℃, HPLC analyzes and shows without raw material, at about 4 L of the hydrochloric acid that drips 6.0 mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxyl-4-(4-chloro-phenyl-) piperidines-1-carboxylic acid tert-butyl ester.
2) 4-(4-chloro-phenyl-)-1,2,3, the preparation of 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 ℃, pass into 1.5 kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 7 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 2 hours, filter, obtain faint yellow solid, yield 89.0%, purity 99.3%, nuclear-magnetism H spectrum identifies that structure is correct.
Embodiment 4.
4-(4-bromophenyl)-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 1.8 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 10～15 ℃, drip the solution that 3.5 Kg 4-fluorophenyl magnesium bromides are dissolved in 6.0 L tetrahydrofuran (THF)s, stirred 6 hours at 10～15 ℃, HPLC analyzes and shows without raw material, at about 5.0 L of the hydrochloric acid that drips 4.0 mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxyl-4-(4-bromophenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) 4-(4-bromophenyl)-1,2,3, the preparation of 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 ℃, pass into 1.3 kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 3 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 2 hours, filter, obtain faint yellow solid, yield 81.6%, purity 99.2%, nuclear-magnetism H spectrum identifies that structure is correct.
Embodiment 5.
4-(4-aminomethyl phenyl)-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 2.0 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 5～10 ℃, drip the solution that 2.7 Kg 4-aminomethyl phenyl magnesium bromides are dissolved in 5.0 L tetrahydrofuran (THF)s, stirred 8 hours at 5～10 ℃, HPLC analyzes and shows without raw material, at about 12.0 L of the hydrochloric acid that drips 2.0 mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxyl-4-(4-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) 4-(4-aminomethyl phenyl)-1,2,3, the preparation of 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 ℃, pass into the 1.8kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 5 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 2 hours, filter, obtain faint yellow solid, yield 85.3%, purity 99.8%, nuclear-magnetism H spectrum identifies that structure is correct.
Embodiment 6.
4-(4-trifluoromethyl)-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 1.9 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to 10～15 ℃, drip the solution that 3.0 Kg 4-trifluoromethyl magnesium bromides are dissolved in 5.0 L tetrahydrofuran (THF)s, stirred 4 hours at 10～15 ℃, HPLC analyzes and shows without raw material, at about 11.0 L of the hydrochloric acid that drips 2.0 mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxyl-4-(4-trifluoromethyl) piperidines-1-carboxylic acid tert-butyl ester.
2) 4-(4-trifluoromethyl)-1,2,3, the preparation of 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 ℃, pass into 1.7 kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 6 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 3 hours, filter, obtain faint yellow solid, yield 80.5%, purity 99.0%, nuclear-magnetism H spectrum identifies that structure is correct.
Embodiment 7.
4-(4-p-methoxy-phenyl)-1,2,3, the preparation technology of 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, the constant pressure funnel device, add 2.1 kg N-tertbutyloxycarbonyl-4-piperidone, with 6.6 L tetrahydrofuran solvents, cool to-5～0 ℃, drip the solution that 3.3 Kg 4-p-methoxy-phenyl magnesium bromides are dissolved in 4.0 L tetrahydrofuran (THF)s, stirred 8 hours at-5～0 ℃, HPLC analyzes and shows without raw material, at about 1.2 L of the hydrochloric acid that drips 12.0 mol/L below 30 ℃, 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, namely get the aqueous isopropanol of 4-hydroxyl-4-(4-p-methoxy-phenyl) piperidines-1-carboxylic acid tert-butyl ester.
2) 4-(4-p-methoxy-phenyl)-1,2,3, the preparation of 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 ℃, pass into 1.2 kg hydrogen chloride gas, be warming up to 75～82 ℃ of reactions 2 hours, HPLC analyzes and shows without raw material, be cooled to 10～20 ℃, stirred 1 hour, filter, obtain faint yellow solid, yield 85.0%, purity 99.5%, nuclear-magnetism H spectrum identifies that structure is correct.
Claims (5)
1. 4-monosubstituted phenyl-1,2,3, the preparation technology of 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 ℃, be added dropwise to R substituted-phenyl magnesium bromide, stirred 3～8 hours at 10～15 ℃, after having reacted, add the hydrochloric acid cancellation to be neutrality, extraction to the pH value, 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-1,2,3, the preparation of 6-tetrahydropyridine hydrochloride:
Aqueous isopropanol at 4-hydroxyl-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester passes into hydrogen chloride gas, stirs to heat up, and 75～82 ℃ of reactions 1～10 hour, after having reacted, is cooled to 10～20 ℃, stirs 1～5 hour, filters, and gets target product.
2. 4-monosubstituted phenyl-1,2,3 according to claim 1, the preparation technology of 6-tetrahydropyridine hydrochloride is characterized in that the R substituted-phenyl described in step 1 is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group.
3. 4-monosubstituted phenyl-1 according to claim 1,2,3, the preparation technology of 6-tetrahydropyridine hydrochloride, the concentration of hydrochloric acid that it is characterized in that the cancellation process using described in step 1 is 1.0 ~ 12.0mol/L, and ethyl acetate, 2-methyltetrahydrofuran, t-butyl methyl ether or toluene are adopted in described extraction.
4. 4-monosubstituted phenyl-1,2,3 according to claim 1, the preparation technology of 6-tetrahydropyridine hydrochloride is characterized in that the mol ratio 1.2 ~ 1.5:1 of the N-tertbutyloxycarbonyl described in step 1-4-piperidone and R substituted-phenyl magnesium bromide.
5. 4-monosubstituted phenyl-1,2,3 according to claim 1, the preparation technology of 6-tetrahydropyridine hydrochloride is characterized in that the mol ratio 3.0 ~ 5.0:1 of the 4-hydroxyl described in step 2-4-R substituted phenylpiperidines-1-carboxylic acid tert-butyl ester and hydrogen chloride gas.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310077393.1A CN103145607B (en) | 2013-03-12 | 2013-03-12 | Preparation process of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride |
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| CN201310077393.1A CN103145607B (en) | 2013-03-12 | 2013-03-12 | Preparation process of 4-monosubstituted phenyl-1,2,3,6-tetrahydropyridine hydrochloride |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5929663A (en) * | 1982-08-13 | 1984-02-16 | Mitsui Petrochem Ind Ltd | 4-(2,4-dihydroxyphenyl)-3,4-dehydropiperidine compound and its preparation |
| CN101696187A (en) * | 2009-09-30 | 2010-04-21 | 徐州工业职业技术学院 | Synthesizing method of N-substituent-1,2,3,6-tetrahydropyridine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5929663A (en) * | 1982-08-13 | 1984-02-16 | Mitsui Petrochem Ind Ltd | 4-(2,4-dihydroxyphenyl)-3,4-dehydropiperidine compound and its preparation |
| CN101696187A (en) * | 2009-09-30 | 2010-04-21 | 徐州工业职业技术学院 | Synthesizing method of N-substituent-1,2,3,6-tetrahydropyridine |
Non-Patent Citations (2)
| Title |
|---|
| RICHARD J. CONWAY，等: ""Synthesis and SAR study of 4-arylpiperidines and 4-aryl-1,2,3,6-tetrahydropyridines as 5-HT2C agonists"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 李敬芬，等: "《药物合成反应》", 31 August 2010 * |
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