CN108117510A - A kind of preparation method of piperidine derivative - Google Patents
A kind of preparation method of piperidine derivative Download PDFInfo
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- CN108117510A CN108117510A CN201611074598.4A CN201611074598A CN108117510A CN 108117510 A CN108117510 A CN 108117510A CN 201611074598 A CN201611074598 A CN 201611074598A CN 108117510 A CN108117510 A CN 108117510A
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- 150000003053 piperidines Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000003379 elimination reaction Methods 0.000 claims abstract description 12
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 11
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 230000008030 elimination Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 238000006146 oximation reaction Methods 0.000 claims description 9
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000006266 etherification reaction Methods 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- 229940125898 compound 5 Drugs 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- XBXHCBLBYQEYTI-UHFFFAOYSA-N piperidin-4-ylmethanol Chemical class OCC1CCNCC1 XBXHCBLBYQEYTI-UHFFFAOYSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 9
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims 8
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 6
- 238000000034 method Methods 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 229940113088 dimethylacetamide Drugs 0.000 claims 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 1
- 229910000564 Raney nickel Inorganic materials 0.000 claims 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 abstract description 2
- -1 (2 (amino methyl) 5 methylphenoxy) methyl Chemical group 0.000 abstract 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000000926 separation method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- CZPVNHFNUGIMFW-UHFFFAOYSA-N 2-(hydroxyiminomethyl)-5-methylphenol Chemical class CC1=CC=C(C=NO)C(O)=C1 CZPVNHFNUGIMFW-UHFFFAOYSA-N 0.000 description 1
- JODRRPJMQDFCBJ-UHFFFAOYSA-N 2-Hydroxy-4-methylbenzaldehyde Chemical class CC1=CC=C(C=O)C(O)=C1 JODRRPJMQDFCBJ-UHFFFAOYSA-N 0.000 description 1
- AXLGFBZDAYQYSV-UHFFFAOYSA-N CC(C)(C)OC(N1CCC(COc2c(CN)ccc(C)c2)CC1)=O Chemical compound CC(C)(C)OC(N1CCC(COc2c(CN)ccc(C)c2)CC1)=O AXLGFBZDAYQYSV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of preparation methods of piperidine derivative 4 ((2 (amino methyl) 5 methylphenoxy) methyl) piperidinyl-1 t-butyl formate, using 2 hydroxyl, 4 tolyl aldehyde as starting material, target product is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction, which is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of piperidine derivative 4- ((2-
(amino methyl) -5- methylphenoxies) methyl) piperidines -1- t-butyl formates preparation method.
Technical background
Piperidine derivative 4- ((2- (amino methyl) -5- methylphenoxies) methyl) piperidines -1- t-butyl formates, structural formula
For：
This compound 4- ((2- (amino methyl) -5- methylphenoxies) methyl) piperidines -1- t-butyl formates and relevant
Derivative has extensive use in pharmaceutical chemistry and organic synthesis.4- ((2- (amino methyl) -5- methylphenoxies) first at present
Base) piperidines -1- t-butyl formates synthesis it is more difficult.Easy to operate therefore, it is necessary to develop a raw material to be easy to get, reaction is easy
In control, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses a kind of piperidine derivative 4- ((2- (amino methyl) -5- methylphenoxies) methyl) piperidines -1-
The preparation method of t-butyl formate, using 2- hydroxy-4-methyls benzaldehyde as starting material, by oximate, elimination, etherificate, catalysis
Hydrogenation reaction obtains target product 5, and synthesis step is as follows：
(1) using 2- hydroxy-4-methyls benzaldehyde as starting material, 2 are obtained by oximation reaction；
(2) elimination reaction is carried out 2, obtains 3；
(3) 3 progress etherification reactions are obtained 4；
(4) 4 progress catalytic hydrogenation reactions are obtained 5；
In a preferred embodiment, the reagent used in the oximation reaction prepare compound 2 is selected from hydroxylamine hydrochloride；
Reagent used in the elimination reaction prepare compound 3 is selected from acetic anhydride；Used in the etherification reaction prepare compound 4
Reagent is selected from 4- (hydroxymethyl) piperidines -1- t-butyl formates；Catalysis used in the catalytic hydrogenation reaction prepare compound 5
Agent is selected from palladium carbon.
In a preferred embodiment, the solvent used in the oximation reaction prepare compound 2 is selected from ethyl alcohol；It is described
Elimination reaction prepare compound 3 used in solvent be selected from acetic anhydride；Solvent used in the etherification reaction prepare compound 4
Selected from tetrahydrofuran；Solvent used in the catalytic hydrogenation reaction prepare compound 5 is selected from methanol.
In a preferred embodiment, the reaction temperature used in the oximation reaction prepare compound 2 is room temperature；Institute
The temperature used in elimination reaction prepare compound 3 stated is the reflux temperature of solvent；4 institute of etherification reaction prepare compound
Temperature is room temperature；Temperature used in the catalytic hydrogenation reaction prepare compound 5 is room temperature.
The present invention relates to a kind of piperidine derivative 4- ((2- (amino methyl) -5- methylphenoxies) methyl) piperidines -1- first
The preparation method of the preparation method of tert-butyl acrylate is reported currently without other Patents documents.
The present invention is further described by the following embodiment, these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made of technical characteristic to the present invention or changing accordingly
Into still falling within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 2- hydroxy-4-methyls benzaldoxime
30g 2- hydroxy-4-methyl benzaldehydes are added in 270ml ethyl alcohol, 17g hydroxylamine hydrochlorides is added dropwise to, is stirred at room temperature
Overnight, cooling adds in water and ethyl acetate, extracts liquid separation, collects organic phase, dry, and concentration obtains 23g 2- hydroxyl -4- first
Benzaldehyde oxime.
(2) synthesis of 2- hydroxy-4-methyls benzonitrile
23g 2- hydroxy-4-methyl benzaldoximes are added in 190ml acetic anhydride, be heated to reflux stirring 2 it is small when, it is dense
Contracting, residue is poured into ice water, is added in ethyl acetate extraction liquid separation, is collected organic phase, and dry, concentration is crossed post separation and obtained
16g 2- hydroxy-4-methyl benzonitriles.
(3) synthesis of 4- ((2- cyano -5- methylphenoxies) methyl) piperidines -1- t-butyl formates
15g 2- hydroxy-4-methyl benzonitriles are added in 180ml tetrahydrofurans, sequentially add 19g 4- (hydroxyl first
Base) piperidines -1- t-butyl formates, 42g triphenylphosphines, 35g diisopropyl azodiformates, be stirred at room temperature 24 it is small when, concentrate, remain
Silica gel post separation obtains 17g 4- ((2- cyano -5- methylphenoxies) methyl) piperidines -1- t-butyl formates on excess.
(4) synthesis of 4- ((2- (amino methyl) -5- methylphenoxies) methyl) piperidines -1- t-butyl formates
17g 4- ((2- cyano -5- methylphenoxies) methyl) piperidines -1- t-butyl formates are added to 170ml methanol
In, add in 10% palladium carbons of 1g, lead to hydrogen, be stirred at room temperature 24 it is small when, filtering, collect filtrate, concentration, obtain 7g 4- ((2- (ammonia
Ylmethyl) -5- methylphenoxies) methyl) piperidines -1- t-butyl formates.
Claims (6)
1. a kind of system of piperidine derivative 4- ((2- (amino methyl) -5- methylphenoxies) methyl) piperidines -1- t-butyl formates
Using 2- hydroxy-4-methyls benzaldehyde as starting material, mesh is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction for Preparation Method
Product 5 is marked, synthetic route is as follows,
2. the method according to claim 1, it is characterized in that the 4 steps reaction is,
(1) using 2- hydroxy-4-methyls benzaldehyde as starting material, 2 are obtained by oximation reaction；
(2) elimination reaction is carried out 2, obtains 3；
(3) 3 progress etherification reactions are obtained 4；
(4) 4 progress catalytic hydrogenation reactions are obtained 5；
3. the method according to claim 1, which is characterized in that the reagent used in the oximation reaction prepare compound 2 is selected from
Hydroxylamine hydrochloride；Reagent used in the elimination reaction prepare compound 3 is selected from one or both of acetic anhydride, phosphorus oxychloride
Mixture；Reagent used in the etherification reaction prepare compound 4 is selected from the tertiary fourth of 4- (hydroxymethyl) piperidines -1- formic acid
Ester；The one kind of catalyst in palladium carbon, palladium dydroxide, Raney's nickel used in the catalytic hydrogenation reaction prepare compound 5
Or the mixture of one or more of several mixture.
4. the method according to claim 1, which is characterized in that the solvent used in the oximation reaction prepare compound 2 is selected from
Methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
The mixture of one or more of dinethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid；
Solvent used in the elimination reaction prepare compound 3 is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetic anhydride, trichlorine oxygen
Phosphorus, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- bis-
The mixture of one or more of methylacetamide, acetonitrile, water；Solvent used in the etherification reaction prepare compound 4
Selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, adjacent diformazan
One kind in benzene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, phosphorus oxychloride
Or several mixture；Solvent used in the catalytic hydrogenation reaction prepare compound 5 is selected from methanol, ethyl alcohol, normal propyl alcohol, different
Propyl alcohol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N-
The mixture of one or more of dimethylformamide, DMAC N,N' dimethyl acetamide, acetic acid, water.
5. the method according to claim 1, which is characterized in that the reaction temperature used in the oximation reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in the elimination reaction prepare compound 3 is the reflux temperature of 0 DEG C~solvent
Degree；Temperature used in the etherification reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；The catalytic hydrogenation is anti-
Answer the reflux temperature that the temperature used in prepare compound 5 is 0 DEG C~solvent.
6. the method according to claim 1, which is characterized in that the reaction temperature used in the oximation reaction prepare compound 2
It is room temperature；Temperature used in the elimination reaction prepare compound 3 is the reflux temperature of solvent；It is prepared by the etherification reaction
Temperature used in compound 4 is room temperature；Temperature used in the catalytic hydrogenation reaction prepare compound 5 is room temperature.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611074598.4A CN108117510A (en) | 2016-11-29 | 2016-11-29 | A kind of preparation method of piperidine derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611074598.4A CN108117510A (en) | 2016-11-29 | 2016-11-29 | A kind of preparation method of piperidine derivative |
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| CN108117510A true CN108117510A (en) | 2018-06-05 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103930416A (en) * | 2011-09-09 | 2014-07-16 | 默克专利股份公司 | Benzonitrile derivatives as kinase inhibitors |
-
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- 2016-11-29 CN CN201611074598.4A patent/CN108117510A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103930416A (en) * | 2011-09-09 | 2014-07-16 | 默克专利股份公司 | Benzonitrile derivatives as kinase inhibitors |
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