CN102675247A - Preparing method of buflomedil hydrochloride - Google Patents
Preparing method of buflomedil hydrochloride Download PDFInfo
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- CN102675247A CN102675247A CN201210168833XA CN201210168833A CN102675247A CN 102675247 A CN102675247 A CN 102675247A CN 201210168833X A CN201210168833X A CN 201210168833XA CN 201210168833 A CN201210168833 A CN 201210168833A CN 102675247 A CN102675247 A CN 102675247A
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- butanone
- trimethoxyphenyl
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Abstract
The invention relates to a preparing method of buflomedil hydrochloride. The preparing method includes 1, 3, 5-trimethoxy-benzaldehyde is subjected to Friedel-Crafts acylation reaction with 4-neoprene acyl chloride to produce 4-chloro-1-(2',4',6'-trimethoxyphenyl)-1-butanone; the 4-chloro-1-(2',4',6'-trimethoxyphenyl)-1-butanone is subjected to amination reaction with pyrrolidine to produce 4-(1-pyrrolidinyl)-1-(2',4',6'-trimethoxyphenyl)-1-butanone; and the 4-(1-pyrrolidinyl)-1-(2',4',6'-trimethoxyphenyl)-1-butanone is subjected to salt forming reaction to produce buflomedil hydrochloride. The preparing method of buflomedil hydrochloride has the advantages that the process route is simple, the cost is low, the yield coefficient is high, and the preparing method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of LL-1656.
Background technology
LL-1656 is a kind of vasoactive agent with multiple pharmacotoxicological effect, chemistry 4-(1-pyrrolidyl) by name-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone hydrochloride, and molecular formula is C
17H
25NO
4HCl, structural formula is following:
The pharmacological action of LL-1656 is for suppressing the utilization of alpha adrenergic receptor, anticoagulant, enhancing ED, non-specific calcium antagonism and enhancing oxygen; Thereby improve ischemic tissue's nutritional blood flow, can be used for treating the symptom that peripheral vascular disease and chronic cerebral blood vessel blood supply insufficiency cause.Also do not see at present Chinese patent report about the preparation method of LL-1656.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiency of prior art, provides that a kind of operational path is simple, cost is low, yield is high, is suitable for the preparation method of the LL-1656 of suitability for industrialized production.
For solving above technical problem, the following technical scheme that the present invention takes:
A kind of preparation method of LL-1656, it comprises the steps:
(1), makes 1; 3,5-trimethoxy-benzene and 4-chlorobutanoylchloride generation friedel-crafts acylation generate 4-chloro-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-the 1-butanone; Wherein, friedel-crafts acylation carries out in 35 ℃ ~ 45 ℃ of temperature and organic solvent under the katalysis of aluminum trichloride (anhydrous);
(2), make step (1) gained 4-chloro-1-(2 '; 4 '; 6 '-trimethoxyphenyl)-1-butanone and tetramethyleneimine generation amination reaction generation 4-(1-pyrrolidyl)-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone; Wherein, amination reaction carries out in the presence of Tetrabutyl amonium bromide and potassiumiodide and in the organic solvent;
(3), make step (2) gained 4-(1-pyrrolidyl)-1-(2 '; 4 ', 6 '-trimethoxyphenyl)-1-butanone generation salt-forming reaction generation 4-(1-pyrrolidyl)-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-and 1-butanone hydrochloride, be LL-1656.
According to a concrete aspect of the present invention, in the step (1), said organic solvent is a trichloromethane.The implementation process of step (1) is following: suction trichloromethane in the Friedel-Crafts reaction still, stir adding 1,3 down, the 5-trimethoxy-benzene; It is fully dissolved, and refrigated cooling adds aluminum trichloride (anhydrous) down, in 0～5 ℃ of mixed solution that splashes into 4-chlorobutanoylchloride and trichloromethane, stirs; Be warmed up to 35 ℃ ~ 45 ℃, insulation reaction 4 ~ 6 hours after reaction finishes, is added with the reaction solution adding in the 1wt% ~ 5wt% aqueous hydrochloric acid below 10 ℃ in advance; Static layering is used aqueous hydrochloric acid and the washing of saturated saleratus solution of 1wt% ~ 5wt% more successively, reclaims trichloromethane to the greatest extent, gets brown oily liquids; Be 4-chloro-1-(2,4, the 6-trimethoxy) butanone.Preferably, in the step (1), 1,3, the molar ratio of 5-trimethoxy-benzene and 4-chlorobutanoylchloride is 1: 1.02 ~ 1.1.
According to another concrete aspect of the present invention, in the step (2), the temperature of amination reaction is 70 ℃ ~ 80 ℃, and solvent is a toluene.The implementation process of step (2) is following: suction toluene, tetramethyleneimine in the amination reaction still, and potassiumiodide and four butyl bromation amine stir and are warming up to 70 ℃ ~ 80 ℃, slowly add 4-chloro-1-(2 '; 4 ', 6 '-trimethoxyphenyl)-and the mixed solution of 1-butanone and toluene carries out amination reaction, and insulation reaction 4 ~ 6 hours is after reaction finishes; Reclaim toluene and tetramethyleneimine to the greatest extent, add entry, after the gained ethyl acetate layer washs with saturated brine with ETHYLE ACETATE extracts; Add 5wt% ~ 15wt% hydrochloric acid and transfer pH to 1 ~ 2, tell the sour water layer, regulate pH to 10 ~ 11 with liquid caustic soda; Use ethyl acetate extraction again, after the gained ethyl acetate layer washed with saturated brine, reclaim under reduced pressure ETHYLE ACETATE was to most; Get brown viscous liquid and be 4-(1-pyrrolidyl)-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone.Preferably; In the step (2), 4-chloro-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-molar ratio of 1-butanone and tetramethyleneimine is 1: 1.5 ~ 2.5; The weight that feeds intake of Tetrabutyl amonium bromide and potassiumiodide is respectively 0.8% ~ 1.5% of 4-chloro-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone weight.More preferably, in the step (2), the molar ratio of 4-chloro-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone and tetramethyleneimine is 1: 2 ~ 2.2.
Preferably, the implementation process of step (3) is following: suction Virahol in the salt-forming reaction still adds 4-(1-pyrrolidyl)-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-and the 1-butanone, stir and be warming up to 40 ℃ ~ 50 ℃, begin to feed hydrogen chloride gas to pH 2～3; Be warming up to 60～65 ℃, be incubated 30 ~ 60 minutes, slowly be cooled to below 15 ℃; Get rid of material, use isopropyl alcohol, get the bullion of LL-1656.
Further, said method comprises that also the damp bullion to LL-1656 carries out the purified step, and this purified implementation process is following: suction ethanol in the solubilizing reaction still adds the bullion and the gac of LL-1656; Stirring is warming up to 75 ℃ ~ 85 ℃ backflow 0.5h ~ 1.5 hour, and press filtration while hot is cooled to below 50 ℃ to another crystallization kettle; Logical again hydrogen chloride gas is to pH 2～3, and crystallization is separated out in cooling; Get rid of material below 15 ℃,, promptly get the purified LL-1656 with ethanol rinsing crystallization.
Owing to take above technical scheme, the present invention compared with prior art has following advantage:
The preparation method of LL-1656 provided by the invention, operational path is simple, cost is low, yield is high, is suitable for the suitability for industrialized production LL-1656.
Embodiment
Below in conjunction with concrete embodiment the present invention is done further detailed explanation, but the invention is not restricted to following examples.
Embodiment 1 friedel-crafts acylation prepares 4-chloro-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone
(1) feeding intake of friedel-crafts acylation referring to table 1:
Table 1
| The supplementary material title | Charging capacity (Kg) | The supplementary material title | Charging capacity (Kg) |
| Trichloromethane | 400 | 31wt% hydrochloric acid | 40+19 |
| 1,3, the 5-trimethoxy-benzene | 50 | Water | 300+200 |
| Aluminum trichloride (anhydrous) | 41.2 | Ice | 100 |
| The 4-chlorobutanoylchloride | 45.5 | Saturated sodium bicarbonate | 100 |
| Trichloromethane | 100 |
(2) practical implementation process is following:
Suction trichloromethane 400Kg in 500L Friedel-Crafts reaction still stirs adding 1,3 down, and 5-trimethoxy-benzene 50Kg fully dissolves it, and refrigated cooling adds aluminum trichloride (anhydrous) 41.2Kg down; In 0～5 ℃ of mixed solution that splashes into 4-chlorobutanoylchloride 45.5Kg and trichloromethane 100Kg, added in 2～2.5 hours, stirring at room 1h is warmed up to 40 ± 2 ℃; Insulation reaction 5 hours, another 1000L of suction extracts in the still, adds 31% hydrochloric acid 40Kg in advance, water 300Kg; Ice 100Kg, restir 1h, the static organic layer of telling is used 31% hydrochloric acid 19Kg again; Water 200Kg washs 1 time again, and saturated saleratus solution 100Kg washing 1 time is reclaimed trichloromethane to most; Get brown oily liquids 80～85Kg, be 4-chloro-1-(2,4, the 6-trimethoxy) butanone (call fourth in the following text and cough up the ketone group thing).
Embodiment 2 amination reaction system 4-(1-pyrrolidyl)-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone
(1) feeding intake of amination reaction referring to table 2:
Table 2
| The supplementary material title | Charging capacity (Kg) | The supplementary material title | Charging capacity (Kg) |
| Toluene | 230+80 | ETHYLE ACETATE | 200+150 |
| Tetramethyleneimine | 55.3 | Saturated brine | 150×4 |
| Potassiumiodide | 0.9 | 10wt% hydrochloric acid | In right amount |
| TBAB | 1 | The 30wt% liquid caustic soda | In right amount |
| Embodiment 1 gained fourth is coughed up the ketone group thing | 80～85 | ETHYLE ACETATE | 200+150 |
| Water | 200 |
(2) practical implementation process is following:
Suction toluene 230Kg, tetramethyleneimine 55.3Kg in 500L amination reaction still, potassiumiodide 0.9Kg, and TBAB1Kg stir and are warming up to 75 ± 1 ℃, slowly add the mixed solution that fourth is coughed up ketone group thing 80～85Kg and toluene 80Kg, add in about 3 hours, are incubated 4 hours.Reclaim toluene and tetramethyleneimine to most (next batch is applied mechanically), add entry 200Kg, ETHYLE ACETATE 200Kg+150Kg second extraction, the combined ethyl acetate layer is with saturated brine washing 2 times, 150Kg/ time.Ethyl acetate layer adds 10% hydrochloric acid and transfers pH to 1～2, tells the sour water layer, with 30wt% liquid adjusting PH with base to 10～11; Extract secondary with ETHYLE ACETATE 200Kg+150Kg, the combined ethyl acetate layer is with saturated brine washing 2 times; 150Kg/ time, reclaim under reduced pressure ETHYLE ACETATE gets brown viscous liquid 70～75Kg to the greatest extent; Be buflomedil, content >=96.0%.
Embodiment 3 salt-forming reactions prepare LL-1656
(1) preparation of LL-1656 bullion:
Suction Virahol 308Kg adds buflomedil 70～75Kg in 500L salt-forming reaction still, stirs and is warming up to 45 ± 1 ℃, begins to feed hydrogen chloride gas to pH2～3; Be warming up to 60～65 ℃, be incubated 30 minutes, slowly be cooled to 15 ℃; Get rid of material, use the 10Kg isopropyl alcohol, get bullion 68～73Kg.The bullion proterties is following: the off-white color crystalline powder; Odorless, flavor are slightly bitter; 190 ℃～198 ℃ of fusing points; Weight loss on drying≤6.5%; Content>=98.0%.
(2) the LL-1656 bullion is refining
Suction ethanol 198Kg in 500L solubilizing reaction still adds LL-1656 bullion 68～73Kg and gac 3.5Kg, stirs and is warming up to 78 ± 1 ℃ of backflow 1h, and press filtration while hot is to another crystallization kettle; Be cooled to 50 ℃, logical again hydrogen chloride gas is to pH 2～3, and crystallization is separated out in cooling; Get rid of material below 15 ℃, with 10Kg ethanol rinsing crystallization, drying; Get white or off-white color crystalline powder 50～56Kg, be LL-1656, content 98.5%; Fusing point: 194～198 ℃, fusion is decomposed simultaneously.
More than the present invention has been done detailed description; Its purpose is to let the personage that is familiar with this art can understand content of the present invention and implements; Can not limit protection scope of the present invention with this; All equivalences of doing according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (10)
1. the preparation method of a LL-1656, it is characterized in that: said preparation method comprises the steps:
(1), makes 1; 3,5-trimethoxy-benzene and 4-chlorobutanoylchloride generation friedel-crafts acylation generate 4-chloro-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-the 1-butanone; Wherein, friedel-crafts acylation carries out in 35 ℃ ~ 45 ℃ of temperature and organic solvent under the katalysis of aluminum trichloride (anhydrous);
(2), make step (1) gained 4-chloro-1-(2 '; 4 '; 6 '-trimethoxyphenyl)-1-butanone and tetramethyleneimine generation amination reaction generation 4-(1-pyrrolidyl)-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone; Wherein, amination reaction carries out in the presence of Tetrabutyl amonium bromide and potassiumiodide and in the organic solvent;
(3), make step (2) gained 4-(1-pyrrolidyl)-1-(2 '; 4 ', 6 '-trimethoxyphenyl)-1-butanone generation salt-forming reaction generation 4-(1-pyrrolidyl)-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-and 1-butanone hydrochloride, be LL-1656.
2. the preparation method of LL-1656 according to claim 1, it is characterized in that: in the step (1), said organic solvent is a trichloromethane.
3. the preparation method of LL-1656 according to claim 2, it is characterized in that: the implementation process of step (1) is following: suction trichloromethane in the Friedel-Crafts reaction still, stir down and add 1,3; The 5-trimethoxy-benzene fully dissolves it, and refrigated cooling adds aluminum trichloride (anhydrous) down, in 0～5 ℃ of mixed solution that splashes into 4-chlorobutanoylchloride and trichloromethane; Stir, be warmed up to 35 ℃ ~ 45 ℃, insulation reaction 4 ~ 6 hours; After reaction finishes, the reaction solution adding is added with in the 1wt% ~ 5wt% aqueous hydrochloric acid below 10 ℃ static layering in advance; Use aqueous hydrochloric acid and the washing of saturated saleratus solution of 1wt% ~ 5wt% more successively, reclaim trichloromethane, get brown oily liquids to the greatest extent; Be 4-chloro-1-(2,4, the 6-trimethoxy) butanone.
4. according to the preparation method of claim 1 or 3 described LL-1656s, it is characterized in that: in the step (1), 1,3, the molar ratio of 5-trimethoxy-benzene and 4-chlorobutanoylchloride is 1: 1.02 ~ 1.1.
5. the preparation method of LL-1656 according to claim 4, it is characterized in that: in the step (2), the temperature of amination reaction is 70 ℃ ~ 80 ℃, and solvent is a toluene.
6. the preparation method of LL-1656 according to claim 5, it is characterized in that: the implementation process of step (2) is following: suction toluene, tetramethyleneimine in the amination reaction still, potassiumiodide and four butyl bromation amine; Stirring is warming up to 70 ℃ ~ 80 ℃, slowly adds 4-chloro-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-and the mixed solution of 1-butanone and toluene carries out amination reaction, and insulation reaction 4 ~ 6 hours is after reaction finishes; Reclaim toluene and tetramethyleneimine to the greatest extent, add entry, after the gained ethyl acetate layer washs with saturated brine with ETHYLE ACETATE extracts; Add 5wt% ~ 15wt% hydrochloric acid and transfer pH to 1 ~ 2, tell the sour water layer, regulate pH to 10 ~ 11 with liquid caustic soda; Use ethyl acetate extraction again, after the gained ethyl acetate layer washed with saturated brine, reclaim under reduced pressure ETHYLE ACETATE was to most; Get brown viscous liquid and be 4-(1-pyrrolidyl)-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone.
7. according to the preparation method of claim 1 or 6 described LL-1656s; It is characterized in that: in the step (2), 4-chloro-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-molar ratio of 1-butanone and tetramethyleneimine is 1: 1.5 ~ 2.5; The weight that feeds intake of said Tetrabutyl amonium bromide and potassiumiodide is respectively 0.8% ~ 1.5% of said 4-chloro-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone weight.
8. the preparation method of LL-1656 according to claim 7, it is characterized in that: in the step (2), the molar ratio of 4-chloro-1-(2 ', 4 ', 6 '-trimethoxyphenyl)-1-butanone and tetramethyleneimine is 1: 2 ~ 2.2.
9. the preparation method of LL-1656 according to claim 1, it is characterized in that: the implementation process of step (3) is following: suction Virahol in the salt-forming reaction still adds 4-(1-pyrrolidyl)-1-(2 ', 4 '; 6 '-trimethoxyphenyl)-and the 1-butanone, stir and be warming up to 40 ℃ ~ 50 ℃, begin to feed hydrogen chloride gas to pH 2～3; Be warming up to 60～65 ℃, be incubated 30 ~ 60 minutes, slowly be cooled to below 15 ℃; Get rid of material, use isopropyl alcohol, get the bullion of LL-1656.
10. the preparation method of LL-1656 according to claim 9, it is characterized in that: said method comprises that also the damp bullion to said LL-1656 carries out the purified step, and said purified implementation process is following: suction ethanol in the solubilizing reaction still; The bullion and the gac that add LL-1656 stir and to be warming up to 75 ℃ ~ 85 ℃ backflow 0.5h ~ 1.5 hour, and press filtration while hot is to another crystallization kettle; Be cooled to below 50 ℃, logical again hydrogen chloride gas cools off to pH 2～3; Separate out crystallization; Get rid of material below 15 ℃,, promptly get the purified LL-1656 with ethanol rinsing crystallization.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924411A (en) * | 2016-05-10 | 2016-09-07 | 王珍 | Bullomedil hydrochloride compound and pharmaceutical composition thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220006A (en) * | 2007-12-19 | 2008-07-16 | 齐鲁天和惠世制药有限公司 | Buflomedil production method |
| CN101665488A (en) * | 2009-10-10 | 2010-03-10 | 北京紫萌同达科技有限公司 | New production technique of hydrobromic acid darifenacin |
-
2012
- 2012-05-29 CN CN201210168833XA patent/CN102675247A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220006A (en) * | 2007-12-19 | 2008-07-16 | 齐鲁天和惠世制药有限公司 | Buflomedil production method |
| CN101665488A (en) * | 2009-10-10 | 2010-03-10 | 北京紫萌同达科技有限公司 | New production technique of hydrobromic acid darifenacin |
Non-Patent Citations (2)
| Title |
|---|
| 刘增勋: "《相转移催化剂在有机化学和农药合成中的应用》", 31 December 1987, 科学出版社 * |
| 杨庆华: "盐酸丁咯地尔的合成工艺研究", 《中国优秀博硕士学位论文全文数据库（硕士）工程科技I辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924411A (en) * | 2016-05-10 | 2016-09-07 | 王珍 | Bullomedil hydrochloride compound and pharmaceutical composition thereof |
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Application publication date: 20120919 |