CN107286076A - A kind of preparation method of piperidines - Google Patents
A kind of preparation method of piperidines Download PDFInfo
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- CN107286076A CN107286076A CN201610207517.7A CN201610207517A CN107286076A CN 107286076 A CN107286076 A CN 107286076A CN 201610207517 A CN201610207517 A CN 201610207517A CN 107286076 A CN107286076 A CN 107286076A
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- 0 *N1CCC(COc(cc2)c(CN)cc2Cl)CC1 Chemical compound *N1CCC(COc(cc2)c(CN)cc2Cl)CC1 0.000 description 2
- XWQDMIXVAYAZGB-UHFFFAOYSA-N N#Cc1cc(Cl)ccc1O Chemical compound N#Cc1cc(Cl)ccc1O XWQDMIXVAYAZGB-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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of piperidines 4 ((2 (amino methyl) 4 bromobenzene epoxide) methyl) piperidinyl-1 t-butyl formate, using the hydroxy benzaldehyde of 5 chlorine 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 preparation method of piperidines 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates.
Technical background
Compound 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates, structural formula is：
This compound 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates and the derivative of correlation have extensive use in pharmaceutical chemistry and organic synthesis.The synthesis of current 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates is more difficult.It is easy to get accordingly, it would be desirable to develop a raw material, it is easy to operate, react easily controllable, the suitable synthetic method of overall yield.
The content of the invention
The invention discloses a kind of preparation method of piperidines 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates, using 5- chlorine-2-hydroxyls benzaldehyde as initiation material, target product 5 is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction, synthesis step is as follows：
(1) using 5- chlorine-2-hydroxyls benzaldehyde 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；Reagent used in described etherification reaction prepare compound 4 is selected from 4- (hydroxymethyl) piperidines -1- t-butyl formates；Catalyst used in described catalytic hydrogenation reaction prepare compound 5 is selected from palladium carbon.
In a preferred embodiment, the solvent used in described oximation reaction prepare compound 2 is selected from ethanol；Solvent used in described elimination reaction prepare compound 3 is selected from acetic anhydride；Solvent used in described etherification reaction prepare compound 4 is 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；Temperature used in described elimination reaction prepare compound 3 is the reflux temperature of solvent；Temperature used in described etherification reaction prepare compound 4 is room temperature；Temperature used in described catalytic hydrogenation reaction prepare compound 5 is room temperature.
The present invention relates to a kind of preparation method of the preparation method of piperidines 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -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 that present invention is further limited.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 5- chlorine-2-hydroxyls benzaldoxime
30g 5- chlorine-2-hydroxyl benzaldehydes are added in 270ml ethanol, 17g hydroxylamine hydrochlorides is added dropwise to, is stirred overnight at room temperature, are cooled down, water and ethyl acetate is added, extraction point liquid is collected organic phase, dried, and concentration obtains 23g 5- chlorine-2-hydroxyl benzaldoximes.
(2) synthesis of 5- chlorine-2-hydroxyls benzonitrile
23g 5- chlorine-2-hydroxyl benzaldoximes are added in 190ml acetic anhydride, stirring 2 hours is heated to reflux, concentration pours into residue in frozen water, ethyl acetate extraction point liquid is added, collects organic phase, dry, concentration crosses post separation and obtains 16g5- chlorine-2-hydroxyl benzonitriles.
(3) synthesis of 4- ((the chloro- 2- cyano-benzene oxygens of 4-) methyl) piperidines -1- t-butyl formates
15g 5- chlorine-2-hydroxyl benzonitriles 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, silica gel post separation obtains 17g 4- ((the chloro- 2- cyano-benzene oxygens of 4-) methyl) piperidines -1- t-butyl formates on concentration, residue.
(4) synthesis of 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates
17g 5- (1- benzyls -1,2,3,6- tetrahydropyridine -4- bases) -2- methylpyrimidines are added in 170ml methanol, add the palladium carbons of 1g 10%, logical hydrogen, it is stirred at room temperature 24 hours, filters, collects filtrate, concentration, obtains 7g 4- ((2- (amino methyl) -4- chlorophenoxies) methyl) piperidines -1- t-butyl formates.
Claims (6)
1. a kind of preparation of piperidines 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates
Method, using 5- chlorine-2-hydroxyls benzaldehyde as initiation material, mesh is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction
Product 5 is marked, synthetic route is as follows,
2. method according to claim 1, it is characterized in that described 4 steps reaction is,
(1) using 5- chlorine-2-hydroxyls benzaldehyde 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. according to claim 1-2 method, it is characterised in that the reagent used in described oximation reaction prepare compound 2 is selected from
Hydroxylamine hydrochloride；One kind in acetic anhydride, POCl3 of reagent used in described elimination reaction prepare compound 3 or
Two kinds of mixture；Reagent used in described etherification reaction prepare compound 4 is selected from 4- (hydroxymethyl) piperidines -1-
T-butyl formate；Catalyst used in described catalytic hydrogenation reaction prepare compound 5 is selected from palladium carbon, palladium dydroxide, thunder
One or more of mixtures in one or more of mixtures in Buddhist nun's nickel.
4. according to claim 1-2 method, 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,
One kind in dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid
Or several mixtures；Solvent used in described elimination reaction prepare compound 3 be selected from methanol, ethanol, normal propyl alcohol,
Isopropanol, acetic anhydride, POCl3, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, two
One or more of mixtures in toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, water；Institute
The solvent used in etherification reaction prepare compound 4 stated be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran,
Dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- dimethyl
One or more of mixtures in formamide, DMAC N,N' dimethyl acetamide, acetonitrile, POCl3；Described catalysis adds
Solvent used in hydrogen reaction prepare compound 5 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxy six
Ring, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide,
One or more of mixtures in DMAC N,N' dimethyl acetamide, acetic acid, water.
5. according to claim 1-2 method, 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 of 0 DEG C~solvent
Temperature；Temperature used in described etherification reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described catalysis adds
Temperature used in hydrogen reaction prepare compound 5 is the reflux temperature of 0 DEG C~solvent.
6. according to claim 1-2 method, 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；Described etherification reaction
Temperature used in prepare compound 4 is room temperature；Temperature used in described catalytic hydrogenation reaction prepare compound 5 is room temperature.
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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: 20171024 |
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