CN104292143A - 2-(4-bromine benzyl) pyrrolidine preparation method - Google Patents
2-(4-bromine benzyl) pyrrolidine preparation method Download PDFInfo
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- CN104292143A CN104292143A CN201410403135.2A CN201410403135A CN104292143A CN 104292143 A CN104292143 A CN 104292143A CN 201410403135 A CN201410403135 A CN 201410403135A CN 104292143 A CN104292143 A CN 104292143A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract
The present invention discloses a 2-(4-bromine benzyl) pyrrolidine preparation method, a target product is prepared from by bromophenyl acetic acid as a starting material by esterification, coupling, ring opening, ring closing and reduction, and the compound is an important pharmaceutical 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 2-(4-bromobenzyl) tetramethyleneimine.
Technical background
Compound 2-(4-bromobenzyl) tetramethyleneimine, English 2-(4-bromobenzyl) pyrrolidine by name, structural formula is:
This compound 2-(4-bromobenzyl) tetramethyleneimine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 2-(4-bromobenzyl) tetramethyleneimine is comparatively difficult.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 2-(4-bromobenzyl) tetramethyleneimine, with to bromo-acid for starting raw material, obtain target product 6 through over-churning, coupling, open loop, closed loop, reduction.Synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with to bromo-acid for starting raw material, obtain 2 through esterification;
(2) carry out ring closure reaction 2 with 2-ethyl fourth amidine, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out ring closure reaction 4 and obtain 5,
(5) carry out reduction reaction 5 and obtain target compound 6,
One preferred embodiment in, the catalyzer that described esterification prepares compound 2 used is selected from p-methyl benzenesulfonic acid; The alkali that described ring closure reaction prepares compound 3 used is selected from salt of wormwood; The reductive agent used that described reduction reaction prepares compound 4 used is selected from borine; The alkali that described ring closure reaction prepares compound 5 used is selected from sodium hydroxide; The reductive agent that described reduction reaction prepares compound 6 used is selected from sodium borohydride.
One preferred embodiment in, described esterification prepares compound 2 solvent selected from methanol used; The solvent that described ring closure reaction prepares compound 3 used is selected from o-Xylol; Described reduction reaction prepares compound 4 solvent selected from ethanol used; The solvent that described ring closure reaction prepares compound 5 used is selected from toluene; Described reduction reaction prepares compound 6 solvent selected from methanol used.
One preferred embodiment in, it is room temperature that described esterification prepares compound 2 temperature of reaction used; Described ring closure 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 ring closure reaction prepares the reflux temperature that compound 5 temperature used is solvent; It is room temperature that described reduction reaction prepares compound 6 temperature used.
The present invention relates to the preparation method of a kind of 2-(4-bromobenzyl) tetramethyleneimine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 2-(4-bromobenzyl) tetramethyleneimine.
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 2-(4-bromophenyl) methyl acetate
20g is joined in 400ml methyl alcohol bromo-acid, adds 2g toluene sulfonic acide, stirring at room temperature 24 hours, concentrated, add water and extraction into ethyl acetate, separatory, drying, concentrated, residuum upper prop is separated and obtains 22g 2-(4-bromophenyl) methyl acetate.
(2) synthesis of 3-(2-(4-bromophenyl) ethanoyl) pyrrolidin-2-one
20g 2-(4-bromophenyl) methyl acetate is joined in 320ml o-Xylol; add 14g 2-ethyl fourth amidine again; add 9g salt of wormwood, heated overnight at reflux, be cooled to room temperature; concentrated; add water and methylene dichloride again, extraction separatory, collects organic phase; separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 15g 3-(2-(4-bromophenyl) ethanoyl) pyrrolidin-2-one.
(3) synthesis of 5-amino-1-(4-bromophenyl) penta-2-ketone
14g 3-(2-(4-bromophenyl) ethanoyl) pyrrolidin-2-one is entered in 120ml ethanol; slowly add 30ml borine-tetrahydrofuran solution; stir 4 hours, concentrated, obtain the crude product of 11g 5-amino-1-(4-bromophenyl) penta-2-ketone.
(4) synthesis of 5-(4-bromobenzyl)-3,4-dihydro-2 h-pyrroles
The crude product of 10g 5-amino-1-(4-bromophenyl) penta-2-ketone is joined in 100ml toluene, add 3g sodium hydroxide, reflux 24 hours, be down to room temperature, filter, filtrate concentrates, and on residuum, silicagel column is separated and obtains 5.1g 5-(4-bromobenzyl)-3,4-dihydro-2 h-pyrroles.
(5) synthesis of 2-(4-bromobenzyl) tetramethyleneimine
5g 5-(4-bromobenzyl)-3,4-dihydro-2 h-pyrrole joins in 100ml methyl alcohol, slowly add 2.3g sodium borohydride, stirring at room temperature 6 hours, adds saturated ammonium chloride, then adds ethyl acetate and extract, separatory, drying, concentrated, on residuum, silicagel column is separated and obtains 4.1g 2-(4-bromobenzyl) tetramethyleneimine.
Claims (6)
1. prepare a method for 2-(4-bromobenzyl) tetramethyleneimine, with to bromo-acid for starting raw material, obtain target product 6 through over-churning, coupling, open loop, closed loop, reduction, synthetic route is as follows.
2. method according to claim 1, it is characterized by 5 described step reactions is,
(1) with to bromo-acid for starting raw material, obtain 2 through esterification;
(2) carry out ring closure reaction 2 with 2-ethyl fourth amidine, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out ring closure reaction 4 and obtain 5,
(5) carry out reduction reaction 5 and obtain target compound 6,
3. according to the method for claim 1-2, it is characterized in that, described esterification is prepared compound 2 catalyzer used and is selected from the mixture of one or more in DMAP, p-methyl benzenesulfonic acid, sulfuric acid, sulfur oxychloride; Described ring closure 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 reaction is prepared compound 4 reductive agent used used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; Described ring closure reaction is prepared compound 5 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 reaction is prepared compound 6 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.
4. according to the method for claim 1-2, it is characterized in that, described esterification prepares compound 2 solvent selected from methanol used, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described ring closure 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, methyl alcohol, ethanol, Virahol; 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; Described ring closure reaction prepares 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, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described reduction reaction prepares compound 6 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, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
5. according to the method for claim 1-2, it is characterized in that, described esterification prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described ring closure 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 ring closure reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent; It is 0 DEG C ~ room temperature that described reduction reaction prepares compound 6 temperature used.
6. according to the method for claim 1-2, it is characterized in that, it is room temperature that described esterification prepares compound 2 temperature of reaction used; Described ring closure 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 ring closure reaction prepares the reflux temperature that compound 5 temperature used is solvent; It is room temperature that described reduction reaction prepares compound 6 temperature used.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107033057A (en) * | 2017-06-01 | 2017-08-11 | 湖南华腾制药有限公司 | A kind of preparation method of 2 (2,6 difluorobenzyl) pyrrolidines |
| CN107286069A (en) * | 2016-04-05 | 2017-10-24 | 湖南华腾制药有限公司 | A kind of preparation method of 2- (4- luorobenzyls) pyrrolidines |
| CN107513029A (en) * | 2016-06-18 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of 2 (3 cyanobenzyls) pyrrolidines |
| CN108218753A (en) * | 2016-12-13 | 2018-06-29 | 湖南华腾制药有限公司 | A kind of preparation method of 2- (4- trifluoromethyl benzyls) pyrrolidines |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4279918A (en) * | 1976-07-28 | 1981-07-21 | Byk Gulden Lomberg Chemische Fabrik G.M.B.H. | 2-(Nuclearly-substituted)benzylpyrrolidines |
| CN102066354A (en) * | 2008-06-20 | 2011-05-18 | 先正达参股股份有限公司 | Novel microbiocides |
| CN102686563A (en) * | 2009-12-22 | 2012-09-19 | 霍夫曼-拉罗奇有限公司 | Substituted benzamide derivatives |
-
2014
- 2014-08-17 CN CN201410403135.2A patent/CN104292143A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4279918A (en) * | 1976-07-28 | 1981-07-21 | Byk Gulden Lomberg Chemische Fabrik G.M.B.H. | 2-(Nuclearly-substituted)benzylpyrrolidines |
| CN102066354A (en) * | 2008-06-20 | 2011-05-18 | 先正达参股股份有限公司 | Novel microbiocides |
| CN102686563A (en) * | 2009-12-22 | 2012-09-19 | 霍夫曼-拉罗奇有限公司 | Substituted benzamide derivatives |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286069A (en) * | 2016-04-05 | 2017-10-24 | 湖南华腾制药有限公司 | A kind of preparation method of 2- (4- luorobenzyls) pyrrolidines |
| CN107513029A (en) * | 2016-06-18 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of 2 (3 cyanobenzyls) pyrrolidines |
| CN108218753A (en) * | 2016-12-13 | 2018-06-29 | 湖南华腾制药有限公司 | A kind of preparation method of 2- (4- trifluoromethyl benzyls) pyrrolidines |
| CN107033057A (en) * | 2017-06-01 | 2017-08-11 | 湖南华腾制药有限公司 | A kind of preparation method of 2 (2,6 difluorobenzyl) pyrrolidines |
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