CN102757401A - Preparation method and application of 4-trifluoroacetyl-7-oxo-1, 4-oxgyen nitrogen and high hydrogen hybrid - Google Patents
Preparation method and application of 4-trifluoroacetyl-7-oxo-1, 4-oxgyen nitrogen and high hydrogen hybrid Download PDFInfo
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- CN102757401A CN102757401A CN2012102160951A CN201210216095A CN102757401A CN 102757401 A CN102757401 A CN 102757401A CN 2012102160951 A CN2012102160951 A CN 2012102160951A CN 201210216095 A CN201210216095 A CN 201210216095A CN 102757401 A CN102757401 A CN 102757401A
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Abstract
The invention discloses a preparation method of 4-trifluoroacetyl-7-oxo-1, 4-oxgyen nitrogen and high hydrogen hybrid and an application of the 4-trifluoroacetyl-7-oxo-1, 4-oxgyen nitrogen and high hydrogen hybrid. The preparation method comprises the following steps of: (1) dissolving 1 mol of hydrochloric piperidone serving as the raw material into a solvent, adding 4-dimethylaminopyridine accounting for 0.05 to 5wt% of the raw material, adding 2 to 3 mols of triethylamine, and dropwise adding 1.5 to 2.5 mols of trifluoroacetic anhydride at 0 to 10 DEG C to react, and then cooling, and filtering to obtain a filtrate for later use; and (2) dissolving 1.0 to 2.5 mols of oxidant into the solvent, and dropwise adding into the filtrate prepared in the step (1) at 0 to 10 DEG C to react for 6 to 48 hours, thus obtaining the 4-trifluoroacetyl-7-oxo-1, 4-oxgyen nitrogen and high hydrogen hybrid. According to the preparation method of the 4-trifluoroacetyl-7-oxo-1, 4-oxgyen nitrogen and high hydrogen hybrid, a continuous material feeding method is adopted to form a novel structural hybrid which has yield up to 60%; the prepared monomer serves as the raw material to prepare a functionalized aliphatic polyester in a synthesizing way; the aliphatic polyester has high biocompatibility and high biodegradability, and the aliphatic polyester is applied to targeting drug carrier and tissue engineering, and also can serve as the sensitive material for an ion-elective electrode.
Description
Technical field
The present invention relates to organic chemistry filed; Relate in particular to a kind of 4-trifluoroacetyl group-7-oxo-1, the novel preparation method and the application of the high hydrogen of 4-oxygen nitrogen assorted
.
Background technology
The curative effect that improves cancer therapy drug is the target that cancer therapy drug is studied with reducing spinoff; Effectively solution mainly adopts biodegradable material load cancer therapy drug at present; With pH mediation delivery of drug, improve the utilization ratio of medicine effectively, and significantly reduce the anti-medicine resistance of tumour patient.
Degradable type macromolecular material has important science and using value at everyway such as industrial, agriculture, medical, civilian, and especially the research of biodegradation type medical macromolecular materials becomes hot issue in the current polymer science field.Yet this type biodegradable material exists defective, but hydrophobicity, inappropriate degraded side group, in polymer chain, lacks the skeleton of functionalization.Bio-medical technology now more and more requires plyability, the variety of bio-medical material; In the past during the decade; The polyester and the polycarbonate of side groups such as containing hydroxyl, carboxyl, amino and tetrahydrobenzene have been reported; The polymkeric substance of these functionalization has improved its hydrophobicity and biological degradability on the one hand, has also promoted the reactivity with medicine on the other hand.
Protonated polymkeric substance is the weakly alkaline polymkeric substance of basic groups such as band amido, pyridine or imidazolyl or the slightly acidic polymkeric substance of band hydroxy-acid group.When pH changed, the ionization state of this base polymer changed, and caused their solvabilities in water to change.These polymkeric substance are water insoluble under alkalescence and neutrallty condition, and under acidic conditions, owing to the protonated positive charge that has takes place basic group, make polymkeric substance water-soluble.These weakly alkaline polymkeric substance never are dissolved into dissolved to be changed mutually, and pH all can change through their hydrophobic substituent group of adjustment.Cyclic monomer synthetic significant in practice that contains the trifluoroacetic anhydride side group; It is through the deprotection of ring-opening copolymerization and trifluoroacetic anhydride; The hydrophobicity and the biological degradability of polymkeric substance are improved; Reach the purpose that takes place to change mutually with pH, be applicable to the conveying of cancer therapy drug, have a wide range of applications in targeted drug, organizational project.
Summary of the invention
The purpose of this invention is to provide a kind of new compound 4-trifluoroacetyl group-7-oxo-1, the preparation method of the high hydrogen of 4-oxygen nitrogen assorted
.
4-trifluoroacetyl group-7-oxo-1, the structural formula of the high hydrogen of 4-oxygen nitrogen assorted
is following:
4-trifluoroacetyl group-7-oxo-1, the preparing method's of the high hydrogen of 4-oxygen nitrogen assorted
step is following:
(1) is that raw material is dissolved in the solvent with 1 mole piperidine hydrochloride ketone, adds raw material weight per-cent and be 0.05～5% 4-Dimethylamino pyridine, add 2～3 moles triethylamine again; Drip acylating agent at 0～10 ℃, reacted 3～6 hours, put into the refrigerator cooling; Filter, discard deposition, it is for use to filtrate; Acylating agent is a trifluoroacetic anhydride, and the mol ratio of trifluoroacetic anhydride and piperidine hydrochloride ketone is 1.5: 1～2.5: 1;
(2) 1.0～2.5 moles oxygenant is dissolved in the solvent; At 0～10 ℃; Be added drop-wise in the above-mentioned filtrating; Reaction times is 6～48 hours, makes 4-trifluoroacetyl group 7-oxo-1, and assorted
productive rate of the high hydrogen of 4-oxygen nitrogen can reach 60%.Wherein: oxygenant is 3-chloroperoxybenzoic acid or hydrogen peroxide, and oxygenant and piperidine hydrochloride ketone mol ratio are 1.0: 1～2.5: 1.
4-trifluoroacetyl group-7-oxo-1; The high hydrogen of 4-oxygen nitrogen assorted
is used for the multifunction aliphatic polyester of synthesising biological consistency and biodegradability; Be used for target medicine carrier and organizational project, as the sensitive material of ion specific electrode.
The present invention adopts the continuous charging method to synthesize novel assorted
productive rate of structure up to 60%; With the monomer for preparing is raw material; But synthetic aliphatic polyester with functionalization of excellent biological compatibility and biodegradability; Be used for target medicine carrier and organizational project, also can be used as the sensitive material of ion specific electrode.
Description of drawings
Accompanying drawing is 4-trifluoroacetyl group-7-oxo-1, and the high hydrogen of 4-oxygen nitrogen is assorted
1H-NMR (CDCl
3) collection of illustrative plates.
Embodiment
4-trifluoroacetyl group-7-oxo-1, the structural formula of the high hydrogen of 4-oxygen nitrogen assorted
is following:
4-trifluoroacetyl group-7-oxo-1, the preparing method's of the high hydrogen of 4-oxygen nitrogen assorted
step is following:
(1) is that raw material is dissolved in the solvent with 1 mole piperidine hydrochloride ketone, adds raw material weight per-cent and be 0.05～5% 4-Dimethylamino pyridine, add 2～3 moles triethylamine again; Drip acylating agent at 0～10 ℃, reacted 3～6 hours, put into the refrigerator cooling; Filter, discard deposition, it is for use to filtrate; Acylating agent is a trifluoroacetic anhydride, and the mol ratio of trifluoroacetic anhydride and piperidine hydrochloride ketone is 1.5: 1～2.5: 1;
(2) 1.0～2.5 moles oxygenant is dissolved in the solvent; At 0～10 ℃; Be added drop-wise in the above-mentioned filtrating; Reaction times is 6～48 hours, makes 4-trifluoroacetyl group 7-oxo-1, and assorted
productive rate of the high hydrogen of 4-oxygen nitrogen can reach 60%.Wherein: oxygenant is 3-chloroperoxybenzoic acid or hydrogen peroxide, and oxygenant and piperidine hydrochloride ketone mol ratio are 1.0: 1～2.5: 1.
4-trifluoroacetyl group-7-oxo-1; The high hydrogen of 4-oxygen nitrogen assorted
is used for the multifunction aliphatic polyester of synthesising biological consistency and biodegradability; Be used for target medicine carrier and organizational project, as the sensitive material of ion specific electrode.
Take by weighing 5.00g (0.0325mol) 4-piperidone (PID) in the round-bottomed flask of a 250mL; Add 50mL methylene dichloride and 13.6mL (0.0975mol) triethylamine successively; Add 4-Dimethylamino pyridine 25mg; Stirring and dissolving 1h, then 0 ℃ with magnetic agitation under will be dissolved with 11.4mL (0.0809mol) trifluoroacetic anhydride methylene dichloride 35mL solution slowly be added dropwise in the above-mentioned round-bottomed flask with constant pressure funnel.Drip off the back and continue to keep 30min down, stir 2.5h under the room temperature at 0 ℃.Stopped reaction places refrigerator, after half a hour, filters, and discards solid, and it is for use to filtrate.Take by weighing 3-chloro peroxide acid (CPBA) 5.3g (0.0230) in the round-bottomed flask of a 250mL, add the 25mL methylene dichloride then, stirring and dissolving 0.5h, then 0 ℃ with magnetic agitation under above-mentioned filtrating slowly is added dropwise in the above-mentioned round-bottomed flask.After stirring 1h under the room temperature, the 10mL dichloromethane solution that will be dissolved with 2.2g (0.0095mol) 3-chloro peroxide acid is added dropwise in the reaction flask, continues reaction 4.5h.Stopped reaction, solution with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, are used anhydrous magnesium sulfate drying successively.Filter; Rotary evaporation gained solution; Get faint yellow crystallization, adopt normal hexane and ETHYLE ACETATE mixed solvent recrystallization, obtain the white plates crystallization: 4-trifluoroacetyl group-7-oxo-1; Assorted
vacuum-drying of the high hydrogen of 4-oxygen nitrogen is to constant weight, and productive rate is 45%.
1H-NMR(CDCl
3)2.9
2(-COCH
2-)，3.70～4.10(CH
2CH
2N-)，4.36(-OCH
2，2H)。
Take by weighing 5.00g (0.0325mol) 4-piperidone (PID) in the round-bottomed flask of a 250mL; Add 50mL methylene dichloride and 9.1mL (0.065mol) triethylamine successively; Add 4-Dimethylamino pyridine 250mg; Stirring and dissolving 1h, then 0 ℃ with magnetic agitation under will be dissolved with 6.9mL (0.0488mol) trifluoroacetic anhydride methylene dichloride 20mL solution slowly be added dropwise in the above-mentioned round-bottomed flask with constant pressure funnel.Drip off the back and continue to keep 30min down, stir 5.5h under the room temperature at 0 ℃.Stopped reaction places refrigerator, after half a hour, filters, and discards solid, and it is for use to filtrate.Take by weighing 3-chloro peroxide acid (CPBA) 13.1g (0.0569mol) in the round-bottomed flask of a 250mL, add the 60mL methylene dichloride then, stirring and dissolving 0.5h, then 0 ℃ with magnetic agitation under above-mentioned filtrating slowly is added dropwise in the above-mentioned round-bottomed flask.After stirring 24h under the room temperature, the 25mL dichloromethane solution that will be dissolved with 5.6g (0.0243mol) 3-chloro peroxide acid is added dropwise in the reaction flask, continues reaction 24h.Stopped reaction, solution with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, are used anhydrous magnesium sulfate drying successively.Filter; Rotary evaporation gained solution; Get faint yellow crystallization, adopt normal hexane and ETHYLE ACETATE mixed solvent recrystallization, obtain the white plates crystallization: 4-trifluoroacetyl group-7-oxo-1; Assorted
vacuum-drying of the high hydrogen of 4-oxygen nitrogen is to constant weight, and productive rate is 38%.
Embodiment 3
Take by weighing 5.00g (0.0325mol) 4-piperidone (PID) in the round-bottomed flask of a 250mL; Add 50mL methylene dichloride and 13.6mL (0.0975mol) triethylamine successively; Add 4-Dimethylamino pyridine 50mg; Stirring and dissolving 1h, then 0 ℃ with magnetic agitation under will be dissolved with 6.9mL (0.0488mol) trifluoroacetic anhydride methylene dichloride 20mL solution slowly be added dropwise in the above-mentioned round-bottomed flask with constant pressure funnel.Drip off the back and continue to keep 30min down, stir 5.5h under the room temperature at 0 ℃.Stopped reaction places refrigerator, after half a hour, filters, and discards solid, and it is for use to filtrate.Take by weighing 3-chloro peroxide acid (CPBA) 9.0g (0.0391mol) in the round-bottomed flask of a 250mL, add the 45mL methylene dichloride then, stirring and dissolving 0.5h, then 0 ℃ with magnetic agitation under above-mentioned filtrating slowly is added dropwise in the above-mentioned round-bottomed flask.After stirring 24h under the room temperature, the 20mL dichloromethane solution that will be dissolved with 4.0g (0.0174mol) 3-chloro peroxide acid is added dropwise in the reaction flask, continues reaction 24h.Stopped reaction, solution with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, are used anhydrous magnesium sulfate drying successively.Filter; Rotary evaporation gained solution; Get faint yellow crystallization, adopt normal hexane and ETHYLE ACETATE mixed solvent recrystallization, obtain the white plates crystallization: 4-trifluoroacetyl group-7-oxo-1; Assorted
vacuum-drying of the high hydrogen of 4-oxygen nitrogen is to constant weight, and productive rate is 60%.
Embodiment 4
Use and embodiment 3 identical operations; Difference is the disposable adding 13g of added 3-chloro peroxide acid; Obtain 4-trifluoroacetyl group-7-oxo-1, the productive rate of the high hydrogen of 4-oxygen nitrogen assorted
is 46%.
Use and embodiment 3 identical operations; Difference is that added solvent is a chloroform; Obtain 4-trifluoroacetyl group-7-oxo-1, the productive rate of the high hydrogen of 4-oxygen nitrogen assorted
is 52%.
Embodiment 6
Take by weighing 5.00g (0.0325mol) 4-piperidone (PID) in the round-bottomed flask of a 250mL; Add 50mL methylene dichloride and 13.6mL (0.0975mol) triethylamine successively; Add 4-Dimethylamino pyridine 50mg; Stirring and dissolving 1h, then 0 ℃ with magnetic agitation under will be dissolved with 6.9mL (0.0488mol) trifluoroacetic anhydride methylene dichloride 20mL solution slowly be added dropwise in the above-mentioned round-bottomed flask with constant pressure funnel.Drip off the back and continue to keep 30min down, stir 5.5h under the room temperature at 0 ℃.Stopped reaction places refrigerator, after half a hour, filters; Discard solid, filtrating with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, is used anhydrous magnesium sulfate drying successively, filters; Rotary evaporation gained solution gets faint yellow crystallization, and vacuum-drying is mixed with solution then.Take by weighing 3-chloro peroxide acid (CPBA) 9.0g (0.0391mol) in the round-bottomed flask of a 250mL; Add the 45mL methylene dichloride then; Stirring and dissolving 0.5h, then 0 ℃ with magnetic agitation under above-mentioned obtain solution slowly is added dropwise in the dichloromethane solution that contains the 3-chloro peroxide acid.After stirring 24h under the room temperature, the 20mL dichloromethane solution that will be dissolved with 4.0g (0.0174mol) 3-chloro peroxide acid is added dropwise in the reaction flask, continues reaction 24h.Stopped reaction, solution with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, are used anhydrous magnesium sulfate drying successively.Filter; Rotary evaporation gained solution; Get faint yellow crystallization, adopt normal hexane and ETHYLE ACETATE mixed solvent recrystallization, obtain the white plates crystallization: 4-trifluoroacetyl group-7-oxo-1; Assorted
vacuum-drying of the high hydrogen of 4-oxygen nitrogen is to constant weight, and productive rate is 36%.
Claims (3)
1. 4-trifluoroacetyl group-7-oxo-1, the high hydrogen of 4-oxygen nitrogen assorted
is characterized in that its structural formula is following:
。
2. 4-trifluoroacetyl group-7-oxo-1 according to claim 1; The preparation method of the high hydrogen of 4-oxygen nitrogen assorted
is characterized in that its step is following:
(1) is that raw material is dissolved in the solvent with 1 mole piperidine hydrochloride ketone, adds raw material weight per-cent and be 0.05～5% 4-Dimethylamino pyridine, add 2～3 moles triethylamine again; Drip acylating agent at 0～10 ℃, reacted 3～6 hours, put into the refrigerator cooling; Filter, discard deposition, it is for use to filtrate; Acylating agent is a trifluoroacetic anhydride, and the mol ratio of trifluoroacetic anhydride and piperidine hydrochloride ketone is 1.5: 1～2.5: 1;
(2) 1.0～2.5 moles oxygenant is dissolved in the solvent; At 0～10 ℃; Be added drop-wise in the above-mentioned filtrating; Reaction times is 6～48 hours, makes 4-trifluoroacetyl group 7-oxo-1, and assorted
productive rate of the high hydrogen of 4-oxygen nitrogen can reach 60%.Wherein: oxygenant is 3-chloroperoxybenzoic acid or hydrogen peroxide, and oxygenant and piperidine hydrochloride ketone mol ratio are 1.0: 1～2.5: 1.
3. 4-trifluoroacetyl group-7-oxo-1 according to claim 1; The application of the high hydrogen of 4-oxygen nitrogen assorted
; It is characterized in that being used for the multifunction aliphatic polyester of synthesising biological consistency and biodegradability; Be used for target medicine carrier and organizational project, as the sensitive material of ion specific electrode.
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|---|---|---|---|
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|---|---|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009039461A2 (en) * | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
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- 2012-06-20 CN CN2012102160951A patent/CN102757401A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009039461A2 (en) * | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
Non-Patent Citations (2)
| Title |
|---|
| 《Macromolecules》 20000607 Mikael Trollsas et al Hydrophilic Aliphatic Polyesters: Design, Synthesis, and Ring-Opening Polymerization of Functional Cyclic Esters 4619-4627 2 第33卷, 第13期 * |
| MIKAEL TROLLSAS ET AL.: "Hydrophilic Aliphatic Polyesters: Design, Synthesis, and Ring-Opening Polymerization of Functional Cyclic Esters", 《MACROMOLECULES》 * |
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Application publication date: 20121031 |