CN108610309A - A kind of preparation method of piperidine derivative - Google Patents
A kind of preparation method of piperidine derivative Download PDFInfo
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- CN108610309A CN108610309A CN201611148201.1A CN201611148201A CN108610309A CN 108610309 A CN108610309 A CN 108610309A CN 201611148201 A CN201611148201 A CN 201611148201A CN 108610309 A CN108610309 A CN 108610309A
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- 0 *N1CCC(COc(ccc(C(F)(F)F)c2)c2C#N)CC1 Chemical compound *N1CCC(COc(ccc(C(F)(F)F)c2)c2C#N)CC1 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
Abstract
The invention discloses a kind of preparation methods of 4 ((2 (amino methyl) 4 4-trifluoromethylphenopendant) methyl) piperidinyl-1 t-butyl formate of piperidine derivative, using 5 trifluoromethyl, 2 hydroxy benzaldehyde 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) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates preparation method.
Technical background
Compound 4- ((2- (amino methyl) -4- 4-trifluoromethylphenopendants) methyl) piperidines -1- t-butyl formates, structural formula
For：
This compound 4- ((2- (amino methyl) -4- 4-trifluoromethylphenopendants) methyl) piperidines -1- t-butyl formates and phase
The derivative of pass has extensive use in pharmaceutical chemistry and organic synthesis.4- ((2- (amino methyl) -4- trifluoromethyls at present
Phenoxy group) methyl) piperidines -1- t-butyl formates synthesis it is more difficult.Therefore, it is necessary to develop a raw material to be easy to get, operation side
Just, easily controllable, the suitable synthetic method of overall yield is reacted.
Invention content
The invention discloses a kind of piperidine derivative 4- ((2- (amino methyl) -4- 4-trifluoromethylphenopendants) methyl) piperazines
The preparation method of pyridine -1- t-butyl formates, using 5- trifluoromethyls-Benzaldehyde,2-hydroxy as starting material, by oximate, elimination,
Etherificate, catalytic hydrogenation reaction obtain target product 5, and synthesis step is as follows：
(1) using 5- trifluoromethyls-Benzaldehyde,2-hydroxy 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) -4- chlorophenoxies) methyl) piperidines -1- formic acid
The preparation method of the preparation method of the tert-butyl ester is reported currently without other Patents documents.
The present invention is further described by the following embodiment, these descriptions are not to make the content of present invention into one
The restriction of step.It should be understood by those skilled in the art that equivalent replacement made by technical characteristic of the invention, or change accordingly
Into still falling within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 5- trifluoromethyls-Benzaldehyde,2-hydroxy oxime
30g 5- trifluoromethyls-Benzaldehyde,2-hydroxy is added in 270ml ethyl alcohol, 17g hydroxylamine hydrochlorides, room temperature are added dropwise to
It is stirred overnight, it is cooling, water and ethyl acetate is added, extracts liquid separation, collects organic phase, dry, concentration obtains 23g 5- fluoroforms
Base-Benzaldehyde,2-hydroxy oxime.
(2) synthesis of 5- trifluoromethyls -2- hydroxy benzonitriles
23g 5- trifluoromethyls-Benzaldehyde,2-hydroxy oxime is added in 190ml acetic anhydride, stirring 2 hours is heated to reflux,
Concentration, residue is poured into ice water, and ethyl acetate is added and extracts liquid separation, collects organic phase, and dry, concentration is crossed post separation and obtained
To 16g 5- trifluoromethyl -2- hydroxy benzonitriles.
(3) synthesis of 4- ((4- trifluoromethyl -2- cyano-benzene oxygens) methyl) piperidines -1- t-butyl formates
15g 5- trifluoromethyl -2- hydroxy benzonitriles are added in 180ml tetrahydrofurans, 19g 4- (hydroxyls are sequentially added
Ylmethyl) piperidines -1- t-butyl formates, 42g triphenylphosphines, 35g diisopropyl azodiformates are stirred at room temperature 24 hours, dense
It contracts, silica gel post separation obtains 17g 4- ((4- trifluoromethyl -2- cyano-benzene oxygens) methyl) tertiary fourth of piperidines -1- formic acid on residue
Ester.
(4) synthesis of 4- ((2- (amino methyl) -4- 4-trifluoromethylphenopendants) methyl) piperidines -1- t-butyl formates
17g 5- (1- benzyls -1,2,3,6- tetrahydropyridine -4- bases) -2- methylpyrimidines are added in 170ml methanol, are added
Enter 10% palladium carbons of 1g, lead to hydrogen, be stirred at room temperature 24 hours, filter, collect filtrate, concentration obtains 7g 4- ((2- (amino first
Base) -4- 4-trifluoromethylphenopendants) methyl) piperidines -1- t-butyl formates.
Claims (6)
1. a kind of piperidine derivative 4- ((2- (amino methyl) -4- 4-trifluoromethylphenopendants) methyl) piperidines -1- t-butyl formates
Preparation method, it is anti-by oximate, elimination, etherificate, catalytic hydrogenation using 5- trifluoromethyls-Benzaldehyde,2-hydroxy as starting material
Target product 5 should be obtained, synthetic route is as follows,
2. the method according to claim 1, it is characterized in that the 4 steps reaction is,
(1) using 5- trifluoromethyls-Benzaldehyde,2-hydroxy 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-
It is the reflux temperature of 0 DEG C~solvent to answer the temperature used in prepare compound 5.
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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| CN201611148201.1A CN108610309A (en) | 2016-12-13 | 2016-12-13 | A kind of preparation method of piperidine derivative |
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| CN201611148201.1A CN108610309A (en) | 2016-12-13 | 2016-12-13 | 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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- 2016-12-13 CN CN201611148201.1A patent/CN108610309A/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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Application publication date: 20181002 |