A kind of preparation method of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochlorideTechnical 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.