CN107778216A - A kind of preparation method of fluorine substituted piperidine derivative - Google Patents
A kind of preparation method of fluorine substituted piperidine derivative Download PDFInfo
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- CN107778216A CN107778216A CN201610772011.0A CN201610772011A CN107778216A CN 107778216 A CN107778216 A CN 107778216A CN 201610772011 A CN201610772011 A CN 201610772011A CN 107778216 A CN107778216 A CN 107778216A
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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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- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of preparation method of fluorine substituted piperidine derivative 4 ((2 (amino methyl) 4 fluorophenoxy) methyl) piperidinyl-1 t-butyl formate, using the hydroxy benzaldehyde of 5 fluorine 2 as initiation material, target product is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction, the compound 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 fluorine substituted piperidine derivative 4-
The preparation method of ((2- (amino methyl) -4- fluorophenoxies) methyl) piperidines -1- t-butyl formates.
Technical background
Fluorine substituted piperidine derivative 4- ((2- (amino methyl) -4- fluorophenoxies) methyl) piperidines -1- t-butyl formates, knot
Structure formula is：
This compound 4- ((2- (amino methyl) -4- fluorophenoxies) methyl) piperidines -1- t-butyl formates and correlation spread out
Biology has extensive use in pharmaceutical chemistry and organic synthesis.4- ((2- (amino methyl) -4- fluorophenoxies) methyl) at present
The synthesis of piperidines -1- t-butyl formates is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, easy to operate, reaction is easy to control
System, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses a kind of fluorine substituted piperidine derivative 4- ((2- (amino methyl) -4- fluorophenoxies) methyl) piperazine
The preparation method of pyridine -1- t-butyl formates, using the fluoro- Benzaldehyde,2-hydroxies of 5- as initiation material, by oximate, elimination, it is etherified, urges
Change hydrogenation reaction and obtain target product 5, synthesis step is as follows：
(1) using the fluoro- Benzaldehyde,2-hydroxies of 5- as initiation 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 described oximation reaction prepare compound 2 is selected from hydroxylamine hydrochloride；
Reagent used in described elimination reaction prepare compound 3 is selected from acetic anhydride；Used in described etherification reaction prepare compound 4
Reagent is selected from 4- (hydroxymethyl) piperidines -1- t-butyl formates；Catalysis used in described catalytic hydrogenation reaction prepare compound 5
Agent is selected from palladium carbon.
In a preferred embodiment, the solvent used in described oximation reaction prepare compound 2 is selected from ethanol；It is described
Elimination reaction prepare compound 3 used in solvent be selected from acetic anhydride；Solvent used in described etherification reaction prepare compound 4
Selected from tetrahydrofuran；Solvent used in described catalytic hydrogenation reaction prepare compound 5 is selected from methanol.
In a preferred embodiment, the reaction temperature used in described 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；The described institute of etherification reaction prepare compound 4
Temperature is room temperature；Temperature used in described catalytic hydrogenation reaction prepare compound 5 is room temperature.
The present invention relates to a kind of fluorine substituted piperidine derivative 4- ((2- (amino methyl) -4- fluorophenoxies) methyl) piperidines -
The preparation method of the preparation method of 1- t-butyl formates, reported currently without other Patents documents.
The present invention is further described by the following embodiment, and 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 to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of the fluoro- Benzaldehyde,2-hydroxy oximes of 5-
The fluoro- Benzaldehyde,2-hydroxies of 30g 5- are added in 270ml ethanol, 17g hydroxylamine hydrochlorides is added dropwise to, was stirred at room temperature
At night, cooling, water and ethyl acetate are added, extract liquid separation, collect organic phase, dried, concentration, obtain the fluoro- 2- hydroxy benzenes of 23g 5-
Formaldoxime.
(2) synthesis of the fluoro- 2- hydroxy benzonitriles of 5-
The fluoro- Benzaldehyde,2-hydroxy oximes of 23g 5- are added in 190ml acetic anhydride, are heated to reflux stirring 2 hours, are concentrated,
Residue is poured into frozen water, ethyl acetate extraction liquid separation is added, collects organic phase, dry, concentration, cross post separation and obtain
The fluoro- 2- hydroxy benzonitriles of 16g5-.
(3) synthesis of 4- ((the fluoro- 2- cyano-benzene oxygens of 4-) methyl) piperidines -1- t-butyl formates
The fluoro- 2- hydroxy benzonitriles of 15g 5- are added in 180ml tetrahydrofurans, sequentially add 19g 4- (hydroxymethyl)
Piperidines -1- t-butyl formates, 42g triphenylphosphines, 35g diisopropyl azodiformates, it is stirred at room temperature 24 hours, concentrates, it is remaining
Silica gel post separation obtains 17g 4- ((the fluoro- 2- cyano-benzene oxygens of 4-) methyl) piperidines -1- t-butyl formates on thing.
(4) synthesis of 4- ((2- (amino methyl) -4- fluorophenoxies) methyl) piperidines -1- t-butyl formates
17g 5- (1- benzyls -1,2,3,6- tetrahydropyridine -4- bases) -2- methylpyrimidines are added in 170ml methanol, added
Enter the palladium carbons of 1g 10%, lead to hydrogen, be stirred at room temperature 24 hours, filter, collect filtrate, concentration, obtain 7g 4- ((2- (amino first
Base) -4- fluorophenoxies) methyl) piperidines -1- t-butyl formates.
Claims (6)
- A kind of 1. fluorine substituted piperidine derivative 4- ((2- (amino methyl) -4- fluorophenoxies) methyl) piperidines -1- t-butyl formates Preparation method, using the fluoro- Benzaldehyde,2-hydroxies of 5- as initiation material, obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction Target product 5, synthetic route is as follows,
- 2. method according to claim 1, it is characterized in that described 4 steps reaction is,(1) using the fluoro- Benzaldehyde,2-hydroxies of 5- as initiation 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. method according to claim 1, it is characterised in that the reagent used in described oximation reaction prepare compound 2 is selected from Hydroxylamine hydrochloride；Reagent used in described elimination reaction prepare compound 3 is selected from one or both of acetic anhydride, POCl3 Mixture；Reagent used in described 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 described catalytic hydrogenation reaction prepare compound 5 Or one or more of mixtures in several mixtures.
- 4. method according to claim 1, it is characterised in that the solvent used in described oximation reaction prepare compound 2 is selected from Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N, One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid； Solvent used in described elimination reaction prepare compound 3 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, acetic anhydride, trichlorine oxygen Phosphorus, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- bis- One or more of mixtures in methylacetamide, acetonitrile, water；Solvent used in described etherification reaction prepare compound 4 Selected from methanol, ethanol, 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, POCl3 Or several mixture；Solvent used in described catalytic hydrogenation reaction prepare compound 5 is selected from methanol, ethanol, normal propyl alcohol, different Propyl alcohol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- One or more of mixtures in dimethylformamide, DMAC N,N' dimethyl acetamide, acetic acid, water.
- 5. method according to claim 1, it is characterised in that the reaction temperature used in described oximation reaction prepare compound 2 It is the reflux temperature of 0 DEG C~solvent；Temperature used in described elimination reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent Degree；Temperature used in described etherification reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described catalytic hydrogenation is anti- Answer the reflux temperature that the temperature used in prepare compound 5 is 0 DEG C~solvent.
- 6. method according to claim 1, it is characterised in that the reaction temperature used in described oximation reaction prepare compound 2 It is room temperature；Temperature used in described elimination reaction prepare compound 3 is the reflux temperature of solvent；It is prepared by described etherification reaction Temperature used in compound 4 is room temperature；Temperature used in described catalytic hydrogenation reaction prepare compound 5 is room temperature.
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| CN201610772011.0A CN107778216A (en) | 2016-08-30 | 2016-08-30 | A kind of preparation method of fluorine substituted 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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| 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: 20180309 |