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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- 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
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- 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
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- 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 |
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| CN201611074598.4A CN108117510A (en) | 2016-11-29 | 2016-11-29 | A kind of preparation method of piperidine derivative |
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| CN201611074598.4A CN108117510A (en) | 2016-11-29 | 2016-11-29 | A kind of preparation method of piperidine derivative |
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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
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| 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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