CN107163032A - A kind of piribedil preparation method in high yield - Google Patents
A kind of piribedil preparation method in high yield Download PDFInfo
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- CN107163032A CN107163032A CN201710464157.3A CN201710464157A CN107163032A CN 107163032 A CN107163032 A CN 107163032A CN 201710464157 A CN201710464157 A CN 201710464157A CN 107163032 A CN107163032 A CN 107163032A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides a kind of piribedil preparation method in high yield, including prepared by piperonyl chlorine, prepared by piperazine pyrimidine and prepared by piribedil, and its method is succinct, production cost is low, and overall high income is reacted, is easy to industrialized production, is had the great significance for popularization.
Description
Technical field
The invention belongs to organic compound synthesis technical field, in particular it relates to prepared by a kind of piribedil in high yield
Method.
Background technology
Entitled 2- [4- (3, the 4 methylene-dioxy benzyl)] piperazine -1- yl pyrimidines of piribedil chemistry, are a kind of spacetabs types
Dopamine agonist.Act on D2、D3Acceptor, acetylcholine and DOPA are recovered by improving the emerging property of dopamine receptor
Balance between amine system system, the clinically treatment for Parkinson's (PD).Piribedil joint levodopa application not only can be with
Improve morning PD patient motion functions well, and levodopa can be substantially reduced and control caused unusual fluctuation disease.Compared with levodopa,
There is motor complication using dopamine body activator is less.In addition, piribedil is alternative strong, Parkinson's can be used for
Each stage, its security is good, and dosage regimen is simple, is the drug of first choice of current treatment Parkinson's.
2011《Chinese Journal of Pharmaceuticals》The first phase volume 42 discloses a kind of synthetic method of piribedil（Wang Shaojie
Deng synthesis [J] Chinese Journal of Pharmaceuticals of piribedils, 2011,42 (1)：9-10.）.Pass through piperazine pyrimidine and piperonyl
Chlorine carries out alkylation reaction in triethylamine, isopropanol and prepares piribedil, and total recovery calculates 44 ~ 63.9% or so with 2- chlorine pyrimidine,
Purity 99.8%.However, the experiment of document second step yield repeats to be difficult to reach, and the step yield of document the 3rd is relatively low, and highest only has
68%。
The content of the invention
Goal of the invention：For the deficiencies in the prior art, the invention provides a kind of piribedil system in high yield
Preparation Method, production cost is low, and product yield is high, quality is good, the advantages of being easy to industrialized production.
Technical scheme：The invention provides a kind of piribedil preparation method in high yield, comprise the following steps：
（A）Prepared by piperonyl chlorine, comprise the following steps：
1）The sub- methoxybenzenes of 1,2- and paraformaldehyde are added to reaction unit, under room temperature, stirring condition, with 5-6ml/min
Speed hydrochloric acid 45-55min is added dropwise；
2）Continue to stir 1-3h under room temperature condition；
3）Add dichloromethane extraction；
4）Organic phase is filtered after drying；
5）Vacuum rotary steam removes dichloromethane under the conditions of 40 DEG C；
6）Vacuum distillation, obtains piperonyl chlorine；
（B）Prepared by piperazine pyrimidine, comprise the following steps：
1）Piperazine anhydrous, water and ammoniacal liquor are added under reaction unit, stirring condition and are heated to 95 DEG C -100 DEG C, with 0.5ml/
2- chlorine pyrimidine solution is added dropwise 3 hours in min speed；
2）0.5-1.5h is incubated under the conditions of 95 DEG C -100 DEG C；
3）Revolving is cooled to room temperature after evaporating the solvent except 1/3；
4）Add dichloromethane extraction；
5）Organic phase is filtered after drying；
6）Vacuum rotary steam removes dichloromethane under the conditions of 40 DEG C, obtains 2-（1- piperazinyls）Pyrimidine；
（C）Prepared by piribedil, comprise the following steps：
1）By step（B）Obtained 2-（1- piperazinyls）Pyrimidine, triethylamine and isopropanol are added to reaction unit, in room temperature, stir
Under the conditions of mixing, step is added dropwise（A）Obtained piperonyl chlorine；
2）50 DEG C are heated to, 3-6h is incubated；
3）It is cooled to after room temperature and filters under stirring condition；
4）Suction filtration after water mashing is added in filter cake；
5）Water washing filter cake obtains piribedil after 50 DEG C of drying.
Piribedil preparation method in high yield of the present invention, method is succinct, and production cost is low, and reacts overall
High income, has the great significance for popularization.Wherein, first step chloromethyl is reacted, and direct layering is substituted using dichloromethane extraction
Or EA extractions, effectively improve extraction yield.Chloromethyl crude product is purified with oil pump vacuum distillation simultaneously, and effectively control late phase reaction is miscellaneous
Matter content, improves later product quality and reaction yield.Second step prepares piperazine pyrimidine, and ethanol or aqueous second are substituted using aqueous phase
Alcohol, while adding ammoniacal liquor, effectively reduces piperazine consumption, is the 3/5 of document consumption, cost-effective, and yield more than 80%.Anti-
The excessive piperazine of some aqueous phase recovery is removed after should terminating to apply mechanically.Compared to document, be conducive to big production without concentration ethanol completely
Operation, while the crude product obtained by the step can put into next step reaction without fiat secundum artem, simplifies process.Three-step reaction, by text
The one pot reaction mode for offering introduction is changed to use isopropanol, triethylamine system, and piperonyl chlorine is added dropwise.Post processing changes text at present
The concentration isopropanol of introduction is offered, add water processing, and with 75% ethanol beating process, be adjusted to after the completion of reaction, directly cooling analysis
Crystalline substance filtering, solid wet product, which directly adds water, carries out mashing processing, obtains the high crude product of content.
It is used as a modification of the present invention, above-mentioned piribedil preparation method in high yield, the step（C）Also wrap afterwards
Piribedil subtractive process is included, the subtractive process comprises the following steps：
1）Piribedil, activated carbon and absolute ethyl alcohol are added in reaction unit, reflux temperature is heated to, 0.5-1h is incubated；
2）Heat filtering removes activated carbon, filtrate crystallisation by cooling under agitation；
3）Filtering, filter cake is dried after being rinsed with absolute ethyl alcohol, obtains refined piribedil.
Product purity after refined is high, and good product quality.Crude product is recrystallized using ethanol, activated carbon, obtains essence
Product, purity is high.Fine work yield is also significantly improved, and is significantly better than current document report, and indices meet national medicine
Allusion quotation requirement.
Further, above-mentioned piribedil preparation method in high yield, the hydrochloric acid is concentrated hydrochloric acid.Raw material sources are wide,
Application cost is low, and effect is good.
Further, above-mentioned piribedil preparation method in high yield, the drying means is dried for anhydrous calcium chloride.
Drying effect is good, and cost is low.In addition, recyclable moiety intermediate in calcium chloride, further improves yield.
Further, above-mentioned piribedil preparation method in high yield, the 2- chlorine pyrimidine solution is 10-12% 2-
The chlorine pyrimidine aqueous solution.Raw material is rationally, simple and easy to get.
Further, above-mentioned piribedil preparation method in high yield, the piperonyl chlorine in 30min in dripping off.Instead
Should be uniform.
Further, above-mentioned piribedil preparation method in high yield, the room temperature is 20-25 DEG C.
Further, above-mentioned piribedil preparation method in high yield, the reaction unit is three mouthfuls of reaction bulbs.From
Rationally, it is easy to use.
Further, above-mentioned piribedil preparation method in high yield, the reaction unit is single port bottle.From conjunction
Reason, it is easy to use.
Further, above-mentioned piribedil preparation method in high yield, the water is pure water.Raw material is easy to get, application
Cost is low.
Beneficial effect：Compared with prior art, the present invention has advantages below：Pyrrole shellfish in high yield of the present invention
That preparation method, method is succinct, and production cost is low, and reacts overall high income, and product quality is also stablized relatively, with very high
Promotional value.
Brief description of the drawings
Fig. 1 is the synthetic route chart of piribedil of the present invention.
Embodiment
Below will be by several specific embodiments, the present invention is furture elucidated, these embodiments simply to illustrate that problem,
It is not a kind of limitation.
Embodiment 1
The synthetic method of piribedil as shown in Figure 1, comprises the following steps：
1st, prepared by piperonyl chlorine
By 100g1,2- Asias methoxybenzene, 40g paraformaldehydes are put into tri- mouthfuls of reaction bulbs of 500ml, at room temperature（20-25℃）Stir
Mix, hydrochloric acid 266ml is added dropwise, be added dropwise about 50 minutes.Drip off and stir 2 hours at room temperature, add dichloromethane extraction 2 times, every time
100ml, combined dichloromethane adds 20g calcium chloride and is dried overnight, filter, vacuum rotary steam removes dichloromethane at 40 DEG C.Change oil
Pump high vacuum distillation, obtains product 73.7g, GC purity 92.6%, main peak rear impurity content 0.45%, yield 64.8%.Reclaim pepper
Ring 25.8g, purity 93.6% is available for applying mechanically.
2nd, prepared by piperazine pyrimidine
24g Piperazine anhydrous, 100ml water and 8ml ammoniacal liquor are put into tri- mouthfuls of reaction bulbs of 250ml, 95 DEG C DEG C, drop are heated under stirring
Plus 11g 2- chlorine pyrimidine and the mixed solution of 90ml water, dripped off at 3 hours or so, 1 hour is incubated at 95 DEG C DEG C.Rotated
Evaporate, remove about 120ml or so water, be cooled to room temperature, extracted 3 times with dichloromethane, each 30ml.Combined dichloromethane, plus
Enter 4g anhydrous calcium chlorides to dry 1 hour, filtering boils off except dichloromethane in 40 DEG C of backspins, obtains 14.4g products, liquid phase purity
89.74%, two substitution accessory substances（Two piperazinylpyrimidines）10%.GC analysis piperazines residual 0.19%, yield 80.7%.
3rd, prepared by piribedil crude product
Take in the content piperazine pyrimidines of 10g about 89.7%, 12g triethylamines, 34ml isopropanols input tri- mouthfuls of reaction bulbs of 100ml, room temperature is stirred
Lower dropwise addition piperonyl chlorine is mixed, was dripped off in 30 minutes.50 DEG C are heated to, 3 hours is incubated, room temperature is cooled under stirring, is filtered, is returned
Receive and the mashing of 20ml water, suction filtration are added in mother liquor, filter cake, then add 10ml water washing filter cakes.50 DEG C of drying, obtain piribedil crude product
14.3g, HPLC analyze content 99.1%.Yield 92%
4th, piribedil crude product refining
By 14g piribedil crude products（99.1%）, 0.2g activated carbons, 42ml absolute ethyl alcohols be added in 100ml single port bottles, heat
To reflux temperature, 45 minutes are incubated, heat filtering removes activated carbon, filtrate crystallisation by cooling under agitation obtains white crystalline solid.
Filtering, is rinsed with a small amount of absolute ethyl alcohol, drying, obtains 12.36g piribedil primary crystallization finished product, HPLC analysis contents
99.88%, refine yield 88.29%.
Embodiment 2
The synthetic method of piribedil as shown in Figure 1, comprises the following steps：
1st, prepared by piperonyl chlorine
By 100g1,2- Asias methoxybenzene, 40g paraformaldehydes are put into tri- mouthfuls of reaction bulbs of 500ml, at room temperature（20-25℃）Stir
Mix, hydrochloric acid 275ml is added dropwise, be added dropwise about 55 minutes.Drip off and stir 1 hour at room temperature, add dichloromethane extraction 2 times, every time
100ml, combined dichloromethane adds 20g calcium chloride and is dried overnight, filter, vacuum rotary steam removes dichloromethane at 40 DEG C.Change oil
Pump high vacuum distillation, obtains product 74.2g, GC purity 93.1%, main peak rear impurity content 0.44%, yield 70.3%.Reclaim pepper
Ring 26.2g, purity 94.1% is available for applying mechanically.
2nd, prepared by piperazine pyrimidine
24g Piperazine anhydrous, 100ml water and 8ml ammoniacal liquor are put into tri- mouthfuls of reaction bulbs of 250ml, 100 DEG C, drop are heated under stirring
Plus 12g 2- chlorine pyrimidine and the mixed solution of 90ml water, dripped off at 3 hours or so, 1.5 hours are incubated at 100 DEG C.Rotated
Evaporate, remove about 120ml or so water, be cooled to room temperature, extracted 3 times with dichloromethane, each 30ml.Combined dichloromethane, plus
Enter 4g anhydrous calcium chlorides to dry 1 hour, filtering boils off except dichloromethane in 40 DEG C of backspins, obtains 15.2g products, liquid phase purity
90.13%, two substitution accessory substances（Two piperazinylpyrimidines）9%.GC analysis piperazines residual 0.22%, yield 83.7%.
3rd, prepared by piribedil crude product
Take in the content piperazine pyrimidines of 10g about 89.7%, 12g triethylamines, 34ml isopropanols input tri- mouthfuls of reaction bulbs of 100ml, room temperature is stirred
Lower dropwise addition piperonyl chlorine is mixed, was dripped off in 30 minutes.50 DEG C are heated to, 6 hours is incubated, room temperature is cooled under stirring, is filtered, is returned
Receive and the mashing of 20ml water, suction filtration are added in mother liquor, filter cake, then add 10ml water washing filter cakes.50 DEG C of drying, obtain piribedil crude product
15.1g, HPLC analyze content 99.3%.Yield 93%
4th, piribedil crude product refining
By 15g piribedil crude products（99.3%）, 0.3g activated carbons, 45ml absolute ethyl alcohols be added in 100ml single port bottles, heat
To reflux temperature, 1 hour is incubated, heat filtering removes activated carbon, filtrate crystallisation by cooling under agitation obtains white crystalline solid.
Filtering, is rinsed with a small amount of absolute ethyl alcohol, drying, obtains 13.44g piribedil primary crystallization finished product, HPLC analysis contents
99.89%, refine yield 90.04%.
Embodiment 3
The synthetic method of piribedil as shown in Figure 1, comprises the following steps：
1st, prepared by piperonyl chlorine
By 100g1,2- Asias methoxybenzene, 40g paraformaldehydes are put into tri- mouthfuls of reaction bulbs of 500ml, at room temperature（20-25℃）Stir
Mix, hydrochloric acid 270ml is added dropwise, be added dropwise about 45 minutes.Drip off and stir 3 hours at room temperature, add dichloromethane extraction 2 times, every time
100ml, combined dichloromethane adds 20g calcium chloride and is dried overnight, filter, vacuum rotary steam removes dichloromethane at 40 DEG C.Change oil
Pump high vacuum distillation, obtains product 75.5g, GC purity 92.9%, main peak rear impurity content 0.39%.Yield 69.8%.Reclaim pepper
Ring 26.4g, purity 93.6% is available for applying mechanically.
2nd, prepared by piperazine pyrimidine
24g Piperazine anhydrous, 100ml water and 8ml ammoniacal liquor are put into tri- mouthfuls of reaction bulbs of 250ml, 98 DEG C, dropwise addition are heated under stirring
10g 2- chlorine pyrimidine and the mixed solution of 90ml water, were dripped off at 3 hours or so, and 0.5 hour is incubated at 98 DEG C.Revolving is carried out to evaporate,
About 120ml or so water is removed, room temperature is cooled to, is extracted 3 times with dichloromethane, each 30ml.Combined dichloromethane, adds 4g
Anhydrous calcium chloride is dried 1 hour, filtering, is boiled off in 40 DEG C of backspins except dichloromethane, is obtained 15.6g products, liquid phase purity 90.04%,
Two substitution accessory substances（Two piperazinylpyrimidines）11%.GC analysis piperazines residual 0.21%, yield 83.8%.
3rd, prepared by piribedil crude product
Take in the content piperazine pyrimidines of 10g about 89.7%, 12g triethylamines, 34ml isopropanols input tri- mouthfuls of reaction bulbs of 100ml, room temperature is stirred
Lower dropwise addition piperonyl chlorine is mixed, was dripped off in 30 minutes.50 DEG C are heated to, 5 hours is incubated, room temperature is cooled under stirring, is filtered, is returned
Receive and the mashing of 20ml water, suction filtration are added in mother liquor, filter cake, then add 10ml water washing filter cakes.50 DEG C of drying, obtain piribedil crude product
16.6g, HPLC analyze content 99.2%.Yield 92%
4th, piribedil crude product refining
By 16g piribedil crude products（99.2%）, 0.3g activated carbons, 42ml absolute ethyl alcohols be added in 100ml single port bottles, heat
To reflux temperature, 0.5 hour is incubated, heat filtering removes activated carbon, filtrate crystallisation by cooling under agitation obtains White crystal and consolidated
Body.Filtering, is rinsed with a small amount of absolute ethyl alcohol, drying, obtains 14.76g piribedil primary crystallization finished product, HPLC analysis contents
99.90%, refine yield 90.33%.
Described above is only several embodiments of invention, it is noted that for those skilled in the art
For, on the premise of inventive principle is not departed from, some improvement can also be made, these improvement also should be regarded as the protection of the present invention
Scope.
Claims (10)
1. a kind of piribedil preparation method in high yield, it is characterised in that：Comprise the following steps：
（A）Prepared by piperonyl chlorine, comprise the following steps：
1）The sub- methoxybenzenes of 1,2- and paraformaldehyde are added to reaction unit, under room temperature, stirring condition, with 5-6ml/min
Speed hydrochloric acid 45-55min is added dropwise；
2）Continue to stir 1-3h under room temperature condition；
3）Add dichloromethane extraction；
4）Organic phase is filtered after drying；
5）Vacuum rotary steam removes dichloromethane under the conditions of 40 DEG C；
6）Vacuum distillation, obtains piperonyl chlorine；
（B）Prepared by piperazine pyrimidine, comprise the following steps：
1）Piperazine anhydrous, water and ammoniacal liquor are added under reaction unit, stirring condition and are heated to 95 DEG C -100 DEG C, with 0.5ml/
2- chlorine pyrimidine solution is added dropwise 3 hours in min speed；
2）0.5-1.5h is incubated under the conditions of 95 DEG C -100 DEG C；
3）Revolving is cooled to room temperature after evaporating the solvent except 1/3；
4）Add dichloromethane extraction；
5）Organic phase is filtered after drying；
6）Vacuum rotary steam removes dichloromethane under the conditions of 40 DEG C, obtains 2-（1- piperazinyls）Pyrimidine；
（C）Prepared by piribedil, comprise the following steps：
1）By step（B）Obtained 2-（1- piperazinyls）Pyrimidine, triethylamine and isopropanol are added to reaction unit, in room temperature, stir
Under the conditions of mixing, step is added dropwise（A）Obtained piperonyl chlorine；
2）50 DEG C are heated to, 3-6h is incubated；
3）It is cooled to after room temperature and filters under stirring condition；
4）Suction filtration after water mashing is added in filter cake；
5）Water washing filter cake obtains piribedil after 50 DEG C of drying.
2. piribedil preparation method in high yield according to claim 1, it is characterised in that：The step（C）Afterwards also
Including piribedil subtractive process, the subtractive process comprises the following steps：
1）Piribedil, activated carbon and absolute ethyl alcohol are added in reaction unit, reflux temperature is heated to, 0.5-1h is incubated；
2）Heat filtering removes activated carbon, filtrate crystallisation by cooling under agitation；
3）Filtering, filter cake is dried after being rinsed with absolute ethyl alcohol, obtains refined piribedil.
3. piribedil preparation method in high yield according to claim 1, it is characterised in that：The hydrochloric acid is dense salt
Acid.
4. piribedil preparation method in high yield according to claim 1, it is characterised in that：The drying means is nothing
Water calcium chloride is dried.
5. piribedil preparation method in high yield according to claim 1, it is characterised in that：The 2- chlorine pyrimidine solution
For the 10-12% 2- chlorine pyrimidine aqueous solution.
6. piribedil preparation method in high yield according to claim 1, it is characterised in that：The piperonyl chlorine in
Dripped off in 30min.
7. piribedil preparation method in high yield according to claim 1, it is characterised in that：The room temperature is 20-25
℃。
8. piribedil preparation method in high yield according to claim 1, it is characterised in that：The reaction unit is three
Mouth reaction bulb.
9. piribedil preparation method in high yield according to claim 2, it is characterised in that：The reaction unit is single
Mouth bottle.
10. piribedil preparation method in high yield according to claim 1, it is characterised in that：The water is pure water.
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| CN201710464157.3A CN107163032A (en) | 2017-06-19 | 2017-06-19 | A kind of piribedil preparation method in high yield |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112062725A (en) * | 2019-06-11 | 2020-12-11 | 太仓市茜泾化工有限公司 | Preparation method of N- (2-pyrimidyl) piperazine |
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|---|---|---|---|---|
| US3299067A (en) * | 1963-11-19 | 1967-01-17 | Science Union & Cie | 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives |
| CN101735201A (en) * | 2009-12-17 | 2010-06-16 | 宁夏康亚药业有限公司 | Preparation method of piribedil |
| CN101830891A (en) * | 2010-05-18 | 2010-09-15 | 沈阳药科大学 | Synthesizing method of piribedil |
| CN103373991A (en) * | 2013-07-12 | 2013-10-30 | 安徽安腾药业有限责任公司 | Method for preparing piribedil in high-purity high-yield manner |
-
2017
- 2017-06-19 CN CN201710464157.3A patent/CN107163032A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3299067A (en) * | 1963-11-19 | 1967-01-17 | Science Union & Cie | 2-[1'-(benzyl and phenyl)-4'-piperazinyl]-pyrimidine derivatives |
| CN101735201A (en) * | 2009-12-17 | 2010-06-16 | 宁夏康亚药业有限公司 | Preparation method of piribedil |
| CN101830891A (en) * | 2010-05-18 | 2010-09-15 | 沈阳药科大学 | Synthesizing method of piribedil |
| CN103373991A (en) * | 2013-07-12 | 2013-10-30 | 安徽安腾药业有限责任公司 | Method for preparing piribedil in high-purity high-yield manner |
Non-Patent Citations (2)
| Title |
|---|
| 何湛 等: "吡贝地尔的合成工艺研究", 《中国药物化学杂志》 * |
| 王绍杰 等: "吡贝地尔的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112062725A (en) * | 2019-06-11 | 2020-12-11 | 太仓市茜泾化工有限公司 | Preparation method of N- (2-pyrimidyl) piperazine |
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