CN107778267A - A kind of synthetic method of morpholine derivative - Google Patents
A kind of synthetic method of morpholine derivative Download PDFInfo
- Publication number
- CN107778267A CN107778267A CN201610753632.4A CN201610753632A CN107778267A CN 107778267 A CN107778267 A CN 107778267A CN 201610753632 A CN201610753632 A CN 201610753632A CN 107778267 A CN107778267 A CN 107778267A
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- CN
- China
- Prior art keywords
- reaction synthesis
- synthesis compound
- morpholine
- tetrahydrofuran
- acylation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KAORJRKQURUVES-UHFFFAOYSA-N FCc1ccc(CCNCCCN2CCOCC2)cc1 Chemical compound FCc1ccc(CCNCCCN2CCOCC2)cc1 KAORJRKQURUVES-UHFFFAOYSA-N 0.000 description 1
- ZLNXQPVWCKHXSF-UHFFFAOYSA-N Fc1ccc(CNCCN2C=COCC2)cc1 Chemical compound Fc1ccc(CNCCN2C=COCC2)cc1 ZLNXQPVWCKHXSF-UHFFFAOYSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N NCc(cc1)ccc1F Chemical compound NCc(cc1)ccc1F IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- KNOOZPRRCORIDE-UHFFFAOYSA-N O=C(CCl)NCc(cc1)ccc1F Chemical compound O=C(CCl)NCc(cc1)ccc1F KNOOZPRRCORIDE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to organic synthesis field; the special standby synthetic method for being related to a kind of morpholine ethamine of morpholine derivative i.e. N (4 luorobenzyl) 2; using 4 fluorin benzyl amines as initiation material; target product is obtained by acylation, nucleophilic displacement of fluorine, reduction, the compound can enrich organic synthesis molecular building block.
Description
Technical field
The invention belongs to organic synthesis field, and a kind of morpholine derivative more particularly to is N- (4- luorobenzyls) -2- morpholines
Ethamine synthetic method.
Technical background
Compound N-(4- luorobenzyls) -2- morpholine ethamine, structural formula are：
This compound N-(4- luorobenzyls) -2- morpholines ethamine and the derivative of correlation have in pharmaceutical chemistry and organic synthesis
It is widely used.The synthesis of N- (4- luorobenzyls) -2- morpholine ethamine is more difficult at present.Therefore, it is necessary to which to develop a raw material easy
, it is easy to operate, react easily controllable, the suitable synthetic method of overall yield.
The content of the invention
It is former by starting of 4- fluorin benzyl amines the invention discloses a kind of method of synthesis N- (4- luorobenzyls) -2- morpholine ethamine
Material, target product 5 is obtained by acylation, nucleophilic, reduction, hydrochloric acid salt, under synthetic route：
In a preferred embodiment, the reagent used in described acylation reaction synthesis compound 2 is selected from chloracetyl
Chlorine；Alkali used in described necleophilic reaction synthesis compound 3 is selected from potassium carbonate；Described reduction substitution reaction synthesis compound 4
Reducing agent used used is selected from lithium aluminium hydride.
In a preferred embodiment, the solvent used in described acylation reaction synthesis compound 2 is selected from dichloromethane
Alkane；Solvent used in described necleophilic reaction synthesis compound 3 is selected from DMF；Described reduction substitution reaction
Solvent used in synthesis compound 4 is selected from tetrahydrofuran.
Beneficial effects of the present invention：Provide a kind of quick, side of efficiently synthesizing of N- (4- luorobenzyls) -2- morpholine ethamine
Method.
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 chloro- N- acetamidos of 2-) -4- fluorobenzene methylamines
12g 4- fluorin benzyl amines are added in 120ml dichloromethane, are cooled to 0 DEG C, chloracetyl chloride is added dropwise, are stirred 3 hours,
Add water to be extracted, liquid separation, drying, concentration, the isolated 14g of residue upper prop (the chloro- N- acetamidos of 2-) -4- fluorobenzene first
Amine.
(2) synthesis of (2- morpholine-N- acetamidos) -4- fluorobenzene methylamines
14g (the chloro- N- acetamidos of 2-) -4- fluorobenzene methylamines are added in 110ml DMFs, added
6g potassium carbonate and 8g morpholines, reheat backflow overnight, be cooled to room temperature, concentrate, add water and dichloromethane, extract liquid separation,
Organic phase is collected, liquid separation, drying, concentration, silica gel post separation obtains 17g (2- morpholine-N- acetamidos) -4- fluorobenzene first on residue
Amine.
(3) synthesis of N- (4- luorobenzyls) -2- morpholine ethamine
17g (2- morpholine-N- acetamidos) -4- methyl benzene methanamines are added in 150ml tetrahydrofurans, are cooled to 0 DEG C,
Be slowly added to 6.5g Lithium Aluminium Hydrides, 0 DEG C is stirred 6 hours, adds water, filtering, filtrate concentration, obtain 12g N- (4- luorobenzyls)-
2- morpholine ethamine.
Embodiment 2：
(1) synthesis of (the chloro- N- acetamidos of 2-) -4- fluorobenzene methylamines
10g 4- fluorin benzyl amines are added in 120ml tetrahydrofurans, are cooled to 5 DEG C, chloracetyl chloride is added dropwise, are stirred 4 hours,
Add water to be extracted, liquid separation, drying, concentration, the isolated 11g of residue upper prop (the chloro- N- acetamidos of 2-) -4- fluorobenzene first
Amine.
(2) synthesis of (2- morpholine-N- acetamidos) -4- fluorobenzene methylamines
11g (the chloro- N- acetamidos of 2-) -4- fluorobenzene methylamines are added in 100ml toluene, add 5.7g triethylamines and
6.3g morpholines, reheat backflow overnight, be cooled to room temperature, concentrate, add water and ethyl acetate, extract liquid separation, collect organic
Phase, liquid separation, drying, concentration, silica gel post separation obtains 12.9g (2- morpholine-N- acetamidos) -4- fluorobenzene methylamines on residue.
(3) synthesis of N- (4- luorobenzyls) -2- morpholine ethamine
12.9g (2- morpholine-N- acetamidos) -4- fluorobenzene methylamines are added in 140ml ether, are cooled to 0 DEG C, slowly
Add 5.4g Lithium Aluminium Hydrides, 0 DEG C stir 4.5 hours, add water, filtering, filtrate concentration, obtain 11.2g N- (4- luorobenzyls)-
2- morpholine ethamine.
Claims (3)
1. the method for one kind synthesis N- (4- luorobenzyls) -2- morpholine ethamine, using 4- fluorin benzyl amines as initiation material, by acylation, parent
Core, reduction obtain target product 4, and synthetic route is as follows：
2. according to the method for claim 1, it is characterised in that the reagent used in described acylation reaction synthesis compound 2
Selected from chloracetyl chloride；Alkali used in described necleophilic reaction synthesis compound 3 be selected from potassium carbonate, sodium hydride, triethylamine, pyridine,
In one kind, preferably potassium carbonate；Reducing agent used used in described reduction substitution reaction synthesis compound 4 is selected from boron hydrogen
Change one kind in sodium, potassium borohydride, lithium aluminium hydride, preferably lithium aluminium hydride.
3. according to the method for claim 1, it is characterised in that the solvent used in described acylation reaction synthesis compound 2
One kind in dichloromethane, tetrahydrofuran, dioxane, preferably dichloromethane；Described necleophilic reaction synthesis chemical combination
The one kind of solvent in dioxane, DMF, toluene used in thing 3, preferably N, N- dimethyl formyls
Amine；Solvent used in described reduction substitution reaction synthesis compound 4 is selected from ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, dioxy
One kind in six rings, preferably tetrahydrofuran.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610753632.4A CN107778267A (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of morpholine derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610753632.4A CN107778267A (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of morpholine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107778267A true CN107778267A (en) | 2018-03-09 |
Family
ID=61441164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610753632.4A Withdrawn CN107778267A (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of morpholine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107778267A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854188A (en) * | 2015-12-08 | 2017-06-16 | 湖南华腾制药有限公司 | A kind of preparation method of morpholine derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230853A (en) * | 2014-08-18 | 2014-12-24 | 湖南华腾制药有限公司 | Preparation method of (p-methylphenyl) methylamine-N-morpholinoethyl hydrochloride |
-
2016
- 2016-08-29 CN CN201610753632.4A patent/CN107778267A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230853A (en) * | 2014-08-18 | 2014-12-24 | 湖南华腾制药有限公司 | Preparation method of (p-methylphenyl) methylamine-N-morpholinoethyl hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854188A (en) * | 2015-12-08 | 2017-06-16 | 湖南华腾制药有限公司 | A kind of preparation method of morpholine derivative |
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Application publication date: 20180309 |