CN106854174A - A kind of preparation method of 4 substituted piperidine derivatives - Google Patents
A kind of preparation method of 4 substituted piperidine derivatives Download PDFInfo
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- CN106854174A CN106854174A CN201510899842.XA CN201510899842A CN106854174A CN 106854174 A CN106854174 A CN 106854174A CN 201510899842 A CN201510899842 A CN 201510899842A CN 106854174 A CN106854174 A CN 106854174A
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- YSDJVLAQRCCLPB-WTKPLQERSA-N Oc(c(/C=N\O)c1)ccc1Br Chemical compound Oc(c(/C=N\O)c1)ccc1Br YSDJVLAQRCCLPB-WTKPLQERSA-N 0.000 description 1
Classifications
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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
Abstract
The invention discloses a kind of 4 preparation methods of substituted pyridine compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates, with the bromo- Benzaldehyde,2-hydroxies of 5- 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 4 preparation methods of substituted pyridine compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates.
Technical background
4 substituted pyridine compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates, structural formula is：
The derivative of this compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates and correlation has extensive use in pharmaceutical chemistry and organic synthesis.The synthesis of current 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates is more difficult.Accordingly, it would be desirable to develop a raw material be easy to get, 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 4 preparation methods of substituted pyridine compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates, with the bromo- Benzaldehyde,2-hydroxies of 5- as initiation material, target product 5 is obtained by oximate, elimination, etherificate, catalytic hydrogenation reaction.Synthesis step is as follows：
(1) with the bromo- Benzaldehyde,2-hydroxies of 5- as initiation material, 2 are obtained by oximation reaction；
(2) elimination reaction is carried out 2, obtains 3；
(3) carry out etherification reaction 3 and obtain 4；
(4) carry out catalytic hydrogenation reaction 4 and obtain 5；
One preferred embodiment in, reagent used by described oximation reaction prepare compound 2 is selected from hydroxylamine hydrochloride；Reagent used by described elimination reaction prepare compound 3 is selected from acetic anhydride；Reagent used by described etherification reaction prepare compound 4 is selected from 4- (hydroxymethyl) piperidines -1- t-butyl formates；Catalyst used by described catalytic hydrogenation reaction prepare compound 5 is selected from palladium carbon.
One preferred embodiment in, solvent used by described oximation reaction prepare compound 2 is selected from ethanol；Solvent used by described elimination reaction prepare compound 3 is selected from acetic anhydride；Solvent used by described etherification reaction prepare compound 4 is selected from tetrahydrofuran；Solvent used by described catalytic hydrogenation reaction prepare compound 5 is selected from methyl alcohol.
One preferred embodiment in, the reaction temperature used by described oximation reaction prepare compound 2 is room temperature；Temperature used by described elimination reaction prepare compound 3 is the reflux temperature of solvent；Temperature used by described etherification reaction prepare compound 4 is room temperature；Temperature used by described catalytic hydrogenation reaction prepare compound 5 is room temperature.
The present invention relates to a kind of 4 preparation methods of the preparation method of substituted pyridine compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates, currently without other Patents documents report.
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 made to technical characteristic of the invention, or be correspondingly improved, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of the bromo- Benzaldehyde,2-hydroxy oximes of 5-
The bromo- Benzaldehyde,2-hydroxies of 30g 5- are added in 270ml ethanol, 17g hydroxylamine hydrochlorides are added dropwise to, is stirred overnight at room temperature, cooled down, add water and ethyl acetate, extraction point liquid to collect organic phase, dry, concentration obtains the bromo- Benzaldehyde,2-hydroxy oximes of 23g 5-.
(2) synthesis of the bromo- 2- hydroxy benzonitriles of 5-
The bromo- Benzaldehyde,2-hydroxy oximes of 23g 5- are added in 190ml acetic anhydride, stirring 2 hours, concentration is heated to reflux, residue is poured into frozen water, ethyl acetate extraction point liquid is added, organic phase is collected, dry, concentration, cross post separation and obtain the bromo- 2- hydroxy benzonitriles of 16g 5-.
(3) synthesis of 4- ((the bromo- 2- cyano-benzene oxygens of 4-) methyl) piperidines -1- t-butyl formates
The bromo- 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, concentration, silica gel post separation obtains 17g 4- ((the bromo- 2- cyano-benzene oxygens of 4-) methyl) piperidines -1- t-butyl formates on residue.
(4) synthesis of 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates
17g 5- (1- benzyls -1,2,3,6- tetrahydropyridine -4- bases) -2- methylpyrimidines are added in 170ml methyl alcohol, 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- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates.
Claims (6)
1. a kind of 4 substituted pyridine compound 4- ((2- (amino methyl) -4- bromobenzenes epoxide) methyl) piperidines -1- t-butyl formates
Preparation method, with the bromo- Benzaldehyde,2-hydroxies of 5- as initiation material, by oximate, elimination, etherificate, catalytic hydrogenation reaction
Target product 5 is obtained, synthetic route is as follows,
2. method according to claim 1, it is characterized by described 4 steps reaction is,
(1) with the bromo- Benzaldehyde,2-hydroxies of 5- as initiation material, 2 are obtained by oximation reaction；
(2) elimination reaction is carried out 2, obtains 3；
(3) carry out etherification reaction 3 and obtain 4；
(4) carry out catalytic hydrogenation reaction 4 and obtain 5；
3. method according to claim 1, it is characterised in that the reagent used by described oximation reaction prepare compound 2 is selected from salt
Sour azanol；Reagent used by described elimination reaction prepare compound 3 is selected from the one kind or two in acetic anhydride, POCl3
The mixture planted；Reagent used by described etherification reaction prepare compound 4 is selected from 4- (hydroxymethyl) piperidines -1- formic acid
The tert-butyl ester；Catalyst used by described catalytic hydrogenation reaction prepare compound 5 is selected from palladium carbon, palladium dydroxide, Raney's nickel
In the mixture of one or more in the mixture of one or more.
4. method according to claim 1, it is characterised in that the solvent used by described oximation reaction prepare compound 2 is selected from first
Alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, two
One kind in toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile, acetic acid or
Several mixtures；Solvent used by described elimination reaction prepare compound 3 is selected from methyl alcohol, ethanol, normal propyl alcohol, different
Propyl alcohol, acetic anhydride, POCl3, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, a diformazan
The mixture of one or more in benzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, water；It is described
Etherification reaction prepare compound 4 used by solvent be selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, two
The ring of oxygen six, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- dimethyl methyls
The mixture of one or more in acid amides, DMAC N,N' dimethyl acetamide, acetonitrile, POCl3；Described catalytic hydrogenation
Reaction prepare compound 5 used by solvent be selected from methyl alcohol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane,
Dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N-
The mixture of one or more in dimethylacetylamide, acetic acid, water.
5. method according to claim 1, it is characterised in that the reaction temperature used by described oximation reaction prepare compound 2 is
The reflux temperature of 0 DEG C~solvent；Temperature used by described elimination reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used by described etherification reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described catalytic hydrogenation
Temperature used by reaction prepare compound 5 is the reflux temperature of 0 DEG C~solvent.
6. method according to claim 1, it is characterised in that the reaction temperature used by described oximation reaction prepare compound 2 is
Room temperature；Temperature used by described elimination reaction prepare compound 3 is the reflux temperature of solvent；Described etherification reaction system
Temperature used by standby compound 4 is room temperature；Temperature used by described catalytic hydrogenation reaction prepare compound 5 is room temperature.
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| CN201510899842.XA CN106854174A (en) | 2015-12-08 | 2015-12-08 | A kind of preparation method of 4 substituted piperidine derivatives |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136111A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN103930416A (en) * | 2011-09-09 | 2014-07-16 | 默克专利股份公司 | Benzonitrile derivatives as kinase inhibitors |
| CN104520300A (en) * | 2012-06-04 | 2015-04-15 | 第一三共株式会社 | Imidazo[1,2-b]pyridazine derivative as kinase inhibitor |
-
2015
- 2015-12-08 CN CN201510899842.XA patent/CN106854174A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012136111A1 (en) * | 2011-04-02 | 2012-10-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Phenylpropionic acid compound, preparation method therefor and medicinal use thereof |
| CN103930416A (en) * | 2011-09-09 | 2014-07-16 | 默克专利股份公司 | Benzonitrile derivatives as kinase inhibitors |
| CN104520300A (en) * | 2012-06-04 | 2015-04-15 | 第一三共株式会社 | Imidazo[1,2-b]pyridazine derivative as kinase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| 姚其正等: "《药物合成反应》", 30 September 2012 * |
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