CN104230853B - A kind of preparation method of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride - Google Patents
A kind of preparation method of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride Download PDFInfo
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- CN104230853B CN104230853B CN201410405918.4A CN201410405918A CN104230853B CN 104230853 B CN104230853 B CN 104230853B CN 201410405918 A CN201410405918 A CN 201410405918A CN 104230853 B CN104230853 B CN 104230853B
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- BMTZIHFEIYPIBF-UHFFFAOYSA-N Cc1ccc(CNCCN2CCOCC2)cc1 Chemical compound Cc1ccc(CNCCN2CCOCC2)cc1 BMTZIHFEIYPIBF-UHFFFAOYSA-N 0.000 description 2
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- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses the preparation method of one (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride; with 4-methylbenzylamine for starting raw material; obtain target product through acidylate, nucleophilic, reduction, one-tenth hydrochloride, this compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of preparation method of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride.
Technical background
Compound (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride, structural formula is:
This compound (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride is comparatively difficult at present.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses the method that one prepares (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride, with 4-methylbenzylamine for starting raw material, obtain target product 5 through acidylate, nucleophilic, reduction, one-tenth hydrochloride, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 4-methylbenzylamine for starting raw material, obtain 2 through acylation reaction;
(2) carry out nucleophilic reaction 2 with morpholine, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(3) carry out into hydrochloride 4 and be obtained by reacting target product 5,
One preferred embodiment in, the reagent that described acylation reaction prepares compound 2 used is selected from chloroacetyl chloride; The alkali that described nucleophilic reaction prepares compound 3 used is selected from salt of wormwood; The reductive agent that described reduction reaction prepares compound 4 used is selected from Lithium Aluminium Hydride; The reagent that described salt-forming reaction prepares compound 5 used is selected from hydrogenchloride.
One preferred embodiment in, the solvent that described acylation reaction prepares compound 2 used is selected from methylene dichloride; The solvent that described nucleophilic reaction prepares compound 3 used is selected from tetrahydrofuran (THF); The solvent that described reduction reaction prepares compound 4 used is selected from tetrahydrofuran (THF); Compound 5 solvent selected from methanol used is prepared in described one-tenth hydrochloride reaction.
One preferred embodiment in, it is 0 DEG C that described acylation reaction prepares compound 2 temperature of reaction used; Described nucleophilic reaction prepares the reflux temperature that compound 3 temperature used is solvent; It is 0 DEG C that described reduction reaction prepares compound 4 temperature used; Described one-tenth hydrochloride reaction prepare compound 5 used be room temperature.
The present invention relates to the preparation method of one (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of (the chloro-N-acetamido of 2-)-4-methyl benzene methanamine
15g4-methylbenzylamine is joined in 120ml methylene dichloride, is cooled to 0 DEG C, drip chloroacetyl chloride, stir 2 hours, add water to extract, separatory, drying, concentrated, residuum upper prop is separated and obtains 17g (the chloro-N-acetamido of 2-)-4-methyl benzene methanamine.
(2) synthesis of (2-morpholine-N-acetamido)-4-methyl benzene methanamine
16g (the chloro-N-acetamido of 2-)-4-methyl benzene methanamine and 8.5g morpholine are joined in 150ml tetrahydrofuran (THF), add 6g salt of wormwood, heated overnight at reflux, be cooled to room temperature, concentrated, then add water and methylene dichloride, extraction separatory, collect organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 19g (2-morpholine-N-acetamido)-4-methyl benzene methanamine.
(3) synthesis of (p-methylphenyl) methylamine-N-ethylmorpholine
18g (2-morpholine-N-acetamido)-4-methyl benzene methanamine is joined in 120ml tetrahydrofuran (THF), is cooled to 0 DEG C, slowly adds 6g Lithium Aluminium Hydride, 0 DEG C is stirred 5 hours, adds water, filters, filtrate concentrates, and obtains 13g (p-methylphenyl) methylamine-N-ethylmorpholine.
(4) synthesis of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride
12g (p-methylphenyl) methylamine-N-ethylmorpholine is joined in 100ml methyl alcohol, and logical hydrogenchloride is to saturated, and stirring at room temperature 24 hours, concentrating under reduced pressure obtains 15.6g (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride.
Claims (5)
1. prepare a method for (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride, with 4-methylbenzylamine for starting raw material, obtain target product through acidylate, nucleophilic, reduction, one-tenth hydrochloride, it is characterized in that comprising the steps:
(1) with 4-methylbenzylamine for starting raw material, obtain 2 through acylation reaction;
(2) carry out nucleophilic reaction 2 with morpholine, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out into hydrochloride 4 and be obtained by reacting target product 5,
2. preparation method according to claim 1, is characterized in that, the reagent that described acylation reaction prepares compound 2 used is selected from chloroacetyl chloride; Described nucleophilic reaction is prepared compound 3 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus, sodium methylate, sodium ethylate; Described reduction substitution reaction is prepared compound 4 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; The reagent that described salt-forming reaction prepares compound 5 used is selected from hydrogenchloride.
3. preparation method according to claim 2, it is characterized in that, described acylation reaction is prepared compound 2 solvent used and is selected from tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described nucleophilic reaction is prepared compound 3 solvent used and is selected from methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), toluene, tetrahydrofuran (THF), toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described reduction reaction prepares compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Compound 5 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described salt-forming reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
4. preparation method according to claim 3, is characterized in that, described acylation reaction prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described nucleophilic reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; It is 0 DEG C ~ room temperature that described reduction reaction prepares compound 4 temperature used; Described one-tenth hydrochloride reaction prepare compound 5 used be 0 DEG C ~ room temperature.
5. according to the preparation method in claim 1-4 described in any one, it is characterized in that, it is 0 DEG C that described acylation reaction prepares compound 2 temperature of reaction used; Described nucleophilic reaction prepares the reflux temperature that compound 3 temperature used is solvent; It is room temperature that described reduction reaction prepares compound 4 temperature used; Described one-tenth hydrochloride reaction prepare compound 5 used be 0 DEG C.
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| 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 |
| CN107778268A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of nitrogenous oxygen organic compound |
| CN107778267A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of synthetic method of morpholine derivative |
| CN107778269A (en) * | 2016-08-30 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of morpholine kind compound |
| CN107162986A (en) * | 2017-05-31 | 2017-09-15 | 湖南华腾制药有限公司 | A kind of preparation method of the pyrimidine derivatives containing morpholinyl |
| CN107033105A (en) * | 2017-06-01 | 2017-08-11 | 湖南华腾制药有限公司 | A kind of preparation method of morpholino ethylamine hydrochloride |
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| WO2000068202A1 (en) * | 1999-05-06 | 2000-11-16 | Neurogen Corporation | Substituted 4-oxo-quinoline-3-carboxamides: gaba brain receptor ligands |
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Denomination of invention: Preparation method of (p-methylphenyl) methylamine-N-morpholinoethyl hydrochloride Effective date of registration: 20200318 Granted publication date: 20160413 Pledgee: Bank of Changsha Limited by Share Ltd science and Technology Branch Pledgor: HUNAN HUATENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2020980000827 |
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