CN101830891A - Synthesizing method of piribedil - Google Patents
Synthesizing method of piribedil Download PDFInfo
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- CN101830891A CN101830891A CN201010174466A CN201010174466A CN101830891A CN 101830891 A CN101830891 A CN 101830891A CN 201010174466 A CN201010174466 A CN 201010174466A CN 201010174466 A CN201010174466 A CN 201010174466A CN 101830891 A CN101830891 A CN 101830891A
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Abstract
The invention relates to a synthesizing method of piribedil, belonging to the technical field of medicine. The synthesizing method of the piribedil comprises the following steps of: preparing piperonyl chlorine through Blanc reaction by using piperonyl cyclonene as a starting raw material; then carrying out selective monofunctional alkylation on piperazine to obtain piperonyl piperazine; and finally carrying out alkylation reaction on the piperonyl piperazine to obtain the piribedil by using 2-cloro pyridine. The invention has the advantages of easy raw material obtaining, moderate reaction condition, easy operation, higher yield and lower cost and is suitable for industrialized production.
Description
Technical field
The invention belongs to medical technical field, relate to the synthetic method of a kind of Piribedil (piribedil).
Background technology
Piribedil is a kind of dopaminergic agonist, can stimulate the postsynaptic D of brain nigrostriatum
2Acceptor and midbrain cortex, the D of midbrain marginal convolution path
2And D
3Acceptor produces effective Dopamine HCL effect, is widely used in Parkinsonian treatment.Structure is as follows:
At present, the preparation about Piribedil of reported literature mainly contains following several method:
Aforesaid method can be with reference to following document: J.Am.Chem.Soc.131 (5) route 1: 1), 1766-1774,2009; 2) Tetrahetron letts.48 (47), 8263-8265,2007; Route 2:US3299067 (1967). route 3: method 1,1) PL167397 (1995); 2) Arch.Pharm. (weinheim) 326 (4), 241-242,1993; Method 2, Tetrahedron Letts.47 (15), 2549-2552,2006; Route 4:CN1884280 (2006).
Route 1-3 all prepares Piribedil by important intermediate 1-(2-pyrimidyl) piperazine; Route 4 is a raw material with the piperonylaldehyde, and through reduction amination, the synthetic Piribedil of hydrocarbonylation two-step reaction, all there is different defectives in four kinds of methods, and are as follows respectively:
Route 1 is a raw material with 1-(2-pyrimidyl) piperazine directly, at [Ru (p-cymene) Cl
2]
2Catalysis under, with piperitol it is carried out the N-alkylation reaction, obtain Piribedil, this method yield 87%, weak point is: ruthenium reagent and piperitol price are higher.
Route 2, with the 2-chloropyrimide is starting raw material, piperazine is carried out the single hydrocarbonylation of selectivity, get 1-(2-pyrimidyl) piperazine (yield 60%), with piperonyl chlorine it is carried out alkylation reaction again, condition is Anhydrous potassium carbonate catalysis, refluxes yield 54% (in 1-(2-pyrimidyl) piperazine) in dimethylbenzene.This method yield not high (total recovery 32.4%), and the solvent xylene boiling point is higher, toxicity is bigger, is not easy to suitability for industrialized production.
Route 3 comprises two kinds of synthetic methods: method 1, and adopt the method for route 2 to synthesize 1-(2-pyrimidyl) piperazine, in formic acid, carry out reductive amination process with piperonylaldehyde then, obtain Piribedil, the single step yield has only 53%; Method 2 is a raw material with the 2-chloropyrimide, and the 1-tert-butoxycarbonyl-piperazine is carried out the N-hydrocarbonylation, behind the mode deprotection of spent ion exchange resin with " adsorbing-dissociate ", obtains 1-(2-pyrimidyl) piperazine; Be reductive agent with the cyano group hydroborate again, carry out reductive amination process, obtain Piribedil with piperonylaldehyde.This method operation is loaded down with trivial details, and intermediate and finished product all use the ion exchange chromatography purifying, are not suitable for suitability for industrialized production.
Route 4 is a starting raw material with the piperonylaldehyde, under the hydrogen-pressure of 2～60bar, carries out reduction amination with Piperazine anhydrous, obtains piperonyl piperazine (yield 78%), with the 2-chloropyrimide it is carried out the N-hydrocarbonylation again, obtains Piribedil.Wherein N-alkylation reaction Anhydrous potassium carbonate catalysis, reaction solvent are DMF or tetrahydrofuran (THF), the reaction yield in two kinds of solvents respectively 40% and 44%, and other has document (GB1101425 (1968)) report is solvent with dimethylbenzene, yield 53%.This method reduction amination needs pressurization, reaction conditions is had relatively high expectations, and the alkylation reaction yield is lower.
Route 1-4 reported method, raw materials used piperonylaldehyde, piperitol or piperonyl chlorine price are all higher, do not have cost advantage.And design a kind of simple to operately, and yield is higher, and lower-cost novel method also is that those skilled in the art are making great efforts to explore.
Summary of the invention
The objective of the invention is to overcome the defective of above prior art, is starting raw material with the piperonyl cyclonene, and a kind of simple method for preparing Piribedil is provided, and to simplify preparation condition, improves yield, reduces cost.
The present invention is with reference to the synthetic method of route 4, designed a new synthetic method: with piperonyl cyclonene cheap and easy to get is starting raw material, through Blanc reaction, the single hydrocarbonylation of selectivity, the synthetic Piribedil of hydrocarbonylation three-step reaction, simple to operate, yield is higher, and cost greatly reduces.
The present invention adopts following technical scheme to prepare Piribedil:
This technical scheme comprises the steps:
(1) with the piperonyl cyclonene be starting raw material, through the piperonyl chlorine shown in the Blanc prepared in reaction formula I:
Piperonyl cyclonene and Paraformaldehyde 96 are dropped in the reactor, drip concentrated hydrochloric acid, make piperonyl chlorine.Wherein, the mol ratio of three kinds of raw materials is piperonyl cyclonene: Paraformaldehyde 96: concentrated hydrochloric acid=1: 1.4～1.8: 2.5～5, preferred 1: 1.59: 3.88; Temperature of reaction is 15～30 ℃; Reaction times is 4～8 hours, preferred 5 hours.
(2) piperonyl chlorine carries out the single hydrocarbonylation of selectivity to piperazine, the piperonyl piperazine shown in the preparation formula II:
Piperazine anhydrous is made piperazine or piperazine mono-hydrochloric salts solution, and the piperonyl chlorine of using step (1) to make then carries out the single hydrocarbonylation of selectivity, synthetic piperonyl piperazine to it.
Use the dissolution with solvents Piperazine anhydrous, drip concentrated hydrochloric acid and make piperazine mono-hydrochloric salts solution, drip piperonyl chlorine or its solution, stirring reaction, suction filtration, filtration cakes torrefaction reclaims piperazine hydrochloride; Filtrate decompression is concentrated into dried, adds water, and 10%NaOH transfers pH to 10, chloroform extraction, and anhydrous sodium sulfate drying filters, and is evaporated to driedly, obtains the piperonyl piperazine;
Or make piperazine solution with the dissolution with solvents Piperazine anhydrous, and dripping piperonyl chlorine or its solution, stirring reaction is evaporated to driedly, adds water, chloroform extraction, anhydrous sodium sulfate drying filters, and is evaporated to driedly, obtains the piperonyl piperazine.
Wherein the mol ratio of piperonyl chlorine and piperazine is 1: 2.5～7, preferred 1: 5; Reaction solvent is an acetone, chloroform, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol etc., preferred dehydrated alcohol; Temperature of reaction is 0～80 ℃, preferred room temperature reaction; 1～8 hour reaction times, preferred 4 hours.
(3) the 2-chloropyrimide carries out alkylation reaction to the piperonyl piperazine, the Piribedil shown in the preparation formula III:
With the 2-chloropyrimide piperonyl piperazine that step (2) makes is carried out alkylation reaction, synthetic Piribedil.
With the 2-chloropyrimide, the piperonyl piperazine, catalyzer and solvent drop into stirring reaction in the reactor, synthetic Piribedil, the thick product of gained by washing and starching with 75% ethanol, is used the dehydrated alcohol recrystallization purifying again.
Wherein, the mol ratio of piperonyl piperazine and 2-chloropyrimide is 1: 0.9～1.5, preferred 1: 1.2; Mineral alkali or organic basess such as triethylamine, pyridine such as catalyzer available hydrogen sodium oxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, preferred triethylamine; Reaction solvent can be acetone, methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), N, dinethylformamide, methyl alcohol, ethanol, Virahol etc., preferred Virahol; Temperature of reaction is 20～80 ℃, preferred 40～60 ℃; 1～8 hour reaction times, preferred 4 hours.
The invention has the advantages that: the raw material piperonyl cyclonene, cheap and easy to get; The reaction conditions gentleness need not high temperature, high pressure or special catalyst; Simple to operate, yield is higher, and steady quality is fit to suitability for industrialized production.
Embodiment
The present invention will be helped to understand by following example, but content of the present invention can not be limited to.
Embodiment 1
1. the preparation of piperonyl chlorine
In reaction flask, add piperonyl cyclonene (170.0g, 1.39mol) and Paraformaldehyde 96 (66.7g, 2.22mol), 25 ℃ of following vigorous stirring drip concentrated hydrochloric acid (452ml), and about 1h finishes, and continue to stir 4h, tell organic layer, get the slightly muddy oily matter 215.0g of grey, yield: 90.5%.
2. the preparation of piperonyl piperazine
In reaction flask, add Piperazine anhydrous (100.9g, 1.17mol) and dehydrated alcohol (320ml), stir in the ice-water bath, drip concentrated hydrochloric acid (101ml), about 20min finishes, rise to room temperature, and slow dropping piperonyl chlorine under stirring (40.0g, 0.23mol), 55min finishes, and holding temperature continues to stir 2h, temperature rising reflux 1h, cooling, a small amount of absolute ethanol washing of suction filtration, filter cake, drying reclaims piperazine hydrochloride 63.1g; Filtrate decompression is concentrated into dried, add water (120ml), transfer pH to 10 with 10%NaOH (130ml), chloroform (120ml * 3) extraction merges organic layer, saturated aqueous common salt (180ml) washing, anhydrous sodium sulfate drying spends the night, and filters, and filtrate decompression is concentrated into dried, get weak yellow liquid 45.2g, yield 87.6%.
3. the preparation of Piribedil
In reaction flask, add the above-mentioned piperonyl piperazine that makes (45.2g, 0.21mol), and the 2-chloropyrimide (28.2g, 0.25mol), triethylamine (43.6g, 0.43mol) and Virahol (158ml), 50 ℃ of reaction 4h, cooling, suction filtration, filter cake with a small amount of absolute ethanol washing after, add water (136ml) and stir 20min, suction filtration, use 75% ethanol (90ml) to wash and starch 1.5h again, suction filtration, dehydrated alcohol (110ml) recrystallization, get white crystalline powder 41.5g, yield: 67.8%.mp：96.8-98.0.℃。MS?m/z：299.0[M+H]
+。
1H?NMR(600MHz，CDCl
3)：δ8.29(d，2H，J＝4.7Hz)，6.89(s，1H)，6.76(d，1H，J＝8.2Hz)，6.75(d，1H，J＝7.9Hz)，6.45(t，1H，J＝4.7Hz)，5.94(s，2H)，3.81(t，4H，J＝4.9Hz)，3.45(s，2H)，2.48(t，4H，J＝4.9Hz)。
Embodiment 2
1. the preparation of piperonyl chlorine
With embodiment 1.
2. the preparation of piperonyl piperazine
In reaction flask, add Piperazine anhydrous (100.9g 1.17mol) and Virahol (160ml), stirs in the ice-water bath, dropping concentrated hydrochloric acid (101ml), about 20min finishes, and rises to room temperature; (40.0g 0.23mol), slowly drops to above-mentioned reaction flask, and about 1h finishes, and continues to stir 5h, a small amount of absolute ethanol washing of suction filtration, filter cake, drying, recovery piperazine hydrochloride 71.1g with methylene dichloride (160ml) dissolving piperonyl chlorine for other; Filtrate decompression is concentrated into dried, add water (120ml), transfer pH to 10 with the 10%NaOH aqueous solution (130ml), chloroform (120ml * 3) extraction merges organic layer, saturated aqueous common salt (180ml) washing, anhydrous sodium sulfate drying spends the night, and filters, and filtrate decompression is concentrated into dried, get weak yellow liquid 41.2g, yield 79.8%.
3. the preparation of Piribedil
In reaction flask, add the above-mentioned piperonyl piperazine that makes (41.2g, 0.19mol), and the 2-chloropyrimide (25.7g, 0.22mol), Anhydrous potassium carbonate (54.3g, 0.39mol) and dehydrated alcohol (206ml), back flow reaction 4h, cooling is evaporated to dried, add water (165ml), stir suction filtration, filter cake with the less water washing, uses 75% ethanol (82ml) to wash and starch 1.5h, suction filtration earlier then, dehydrated alcohol (100ml) recrystallization gets white crystalline powder 32.2g, yield: 57.7%.mp：96.9-98.3℃。MS?m/z：299.0[M+H]
+。
1H?NMR(600MHz，CDCl
3)：δ8.29(d，2H，J＝4.7Hz)，6.89(s，1H)，6.76(d，1H，J＝8.2Hz)，6.75(d，1H，J＝7.9Hz)，6.45(t，1H，J＝4.7Hz)，5.94(s，2H)，3.81(t，4H，J＝4.9Hz)，3.45(s，2H)，2.48(t，4H，J＝4.9Hz)。
Embodiment 3
1. the preparation of piperonyl chlorine
With embodiment 1.
2. the preparation of piperonyl piperazine
In reaction flask, (50.4g 0.59mol) and acetone (80ml), stirs under the room temperature to add Piperazine anhydrous; (20.0g 0.12mol), drops in the above-mentioned reaction flask with acetone (80ml) dissolving piperonyl chlorine in addition, about 40min finishes, after keeping temperature of reaction and stirring 2h, and temperature rising reflux 3h, cooling is evaporated to driedly, adds water (80ml), chloroform (60ml * 3) extraction merges organic layer, saturated aqueous common salt (90ml) washing, anhydrous sodium sulfate drying spends the night, and filters, and filtrate decompression is concentrated into dried, get pale brown look liquid 16.4g, yield 63.5%.
3. the preparation of Piribedil
In reaction flask, add the above-mentioned piperonyl piperazine that makes (16.4g, 0.075mol), and the 2-chloropyrimide (10.2g, 0.089mol), Anhydrous potassium carbonate (21.6g, 0.16mol) and acetone (82ml), back flow reaction 6h, cooling is evaporated to dried, add water (66ml), stir suction filtration, with the less water washing, 1.5h, suction filtration are washed and starched with 75% ethanol (33ml) in the back to filter cake earlier, dehydrated alcohol (40ml) recrystallization gets off-white color crystalline powder 13.3g, yield: 59.9%.mp：96.8-98.0℃。MS?m/z：299.0[M+H]
+。
1H?NMR(600MHz，CDCl
3)：δ8.29(d，2H，J＝4.7Hz)，6.89(s，1H)，6.76(d，1H，J＝8.2Hz)，6.75(d，1H，J＝7.9Hz)，6.45(t，1H，J＝4.7Hz)，5.94(s，2H)，3.81(t，4H，J＝4.9Hz)，3.45(s，2H)，2.48(t，4H，J＝4.9Hz)。
Claims (15)
1. the preparation method of a Piribedil is characterized in that, this method comprises the steps:
1) with the piperonyl cyclonene is starting raw material, through the synthetic piperonyl chlorine of Blanc reaction;
2) piperonyl chlorine carries out the single hydrocarbonylation of selectivity to piperazine, obtains the piperonyl piperazine;
3) the 2-chloropyrimide carries out alkylation reaction to the piperonyl piperazine, obtains Piribedil.
2. the preparation method of Piribedil according to claim 1 is characterized in that: step 2) in the piperonyl piperazine prepare by the following method:
Use the dissolution with solvents Piperazine anhydrous, drip concentrated hydrochloric acid and make piperazine mono-hydrochloric salts solution, drip piperonyl chlorine or its solution, stirring reaction, suction filtration, filtration cakes torrefaction reclaims piperazine hydrochloride; Filtrate decompression is concentrated into dried, adds water, and 10%NaOH transfers pH to 10, chloroform extraction, and anhydrous sodium sulfate drying filters, and is evaporated to driedly, obtains the piperonyl piperazine;
Or make piperazine solution with the dissolution with solvents Piperazine anhydrous, and dripping piperonyl chlorine or its solution, stirring reaction is evaporated to driedly, adds water, chloroform extraction, anhydrous sodium sulfate drying filters, and is evaporated to driedly, obtains the piperonyl piperazine.
3. according to the preparation method of the described Piribedil of claim 2, it is characterized in that described solvent is acetone, methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), methyl alcohol, ethanol or Virahol.
4. according to the preparation method of the described Piribedil of claim 2, it is characterized in that described temperature of reaction is 0～80 ℃; The described reaction times is 1～8 hour.
5. according to the preparation method of the described Piribedil of claim 2, it is characterized in that the mol ratio of described raw material piperonyl chlorine and Piperazine anhydrous is 1: 2.5～7.
6. according to the preparation method of the described Piribedil of claim 2, it is characterized in that preferred 1: 5 of the mol ratio of described raw material piperonyl chlorine and Piperazine anhydrous.
7. according to the preparation method of the described Piribedil of claim 3, it is characterized in that the preferred dehydrated alcohol of described solvent.
8. the preparation method of Piribedil according to claim 1, it is characterized in that: in the step 3), with the 2-chloropyrimide, the piperonyl piperazine, catalyzer and solvent drop into stirring reaction in the reactor, synthetic Piribedil, the thick product of gained, by washing and starching, use the dehydrated alcohol recrystallization purifying again with 75% ethanol.
9. according to the preparation method of the described Piribedil of claim 8, it is characterized in that the mol ratio of described piperonyl piperazine and 2-chloropyrimide is 1: 0.9～1.5.
10. according to the preparation method of the described Piribedil of claim 8, it is characterized in that preferred 1: 1.2 of the mol ratio of described piperonyl piperazine and 2-chloropyrimide.
11. the preparation method according to the described Piribedil of claim 8 is characterized in that, described catalyzer is selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, pyridine; The add-on of catalyzer is in 1.5～3.0 times of amounts of piperonyl piperazine mole number.
12. the preparation method according to the described Piribedil of claim 8 is characterized in that, described reaction solvent is an acetone, methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), N, dinethylformamide, methyl alcohol, ethanol, Virahol.
13. the preparation method according to the described Piribedil of claim 8 is characterized in that, described temperature of reaction is 20～80 ℃; 1～8 hour described reaction times.
14. the preparation method according to the described Piribedil of claim 8 is characterized in that, preferred triethylamine of described catalyzer and Anhydrous potassium carbonate.
15. the preparation method according to the described Piribedil of claim 8 is characterized in that, preferred dehydrated alcohol of described solvent and Virahol.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102952121A (en) * | 2012-07-27 | 2013-03-06 | 北京海步国际医药科技发展有限公司 | Improved preparation method for piperazine derivant |
| 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 |
| CN106432212A (en) * | 2016-09-21 | 2017-02-22 | 苏州弘森药业股份有限公司 | Synthetic method of piribedil |
| CN107163032A (en) * | 2017-06-19 | 2017-09-15 | 太仓卡斯特姆新材料有限公司 | A kind of piribedil preparation method in high yield |
| CN107216318A (en) * | 2017-06-19 | 2017-09-29 | 太仓弘杉环保科技有限公司 | A kind of piribedil preparation method |
| CN107266429A (en) * | 2017-06-19 | 2017-10-20 | 太仓大唐化纤厂 | A kind of piribedil preparation method of high-quality |
| RU2737721C2 (en) * | 2017-12-15 | 2020-12-02 | Алексей Георгиевич Александров | Method for preparing pharmaceutical substance based on piribedil |
| CN112724120A (en) * | 2020-12-29 | 2021-04-30 | 爱斯特（成都）生物制药股份有限公司 | Method for synthesizing piperonyl chloride through continuous flow reaction |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102952121A (en) * | 2012-07-27 | 2013-03-06 | 北京海步国际医药科技发展有限公司 | Improved preparation method for piperazine derivant |
| 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 |
| CN106432212A (en) * | 2016-09-21 | 2017-02-22 | 苏州弘森药业股份有限公司 | Synthetic method of piribedil |
| CN106432212B (en) * | 2016-09-21 | 2019-01-11 | 苏州弘森药业股份有限公司 | A method of synthesis piribedil |
| CN107163032A (en) * | 2017-06-19 | 2017-09-15 | 太仓卡斯特姆新材料有限公司 | A kind of piribedil preparation method in high yield |
| CN107216318A (en) * | 2017-06-19 | 2017-09-29 | 太仓弘杉环保科技有限公司 | A kind of piribedil preparation method |
| CN107266429A (en) * | 2017-06-19 | 2017-10-20 | 太仓大唐化纤厂 | A kind of piribedil preparation method of high-quality |
| RU2737721C2 (en) * | 2017-12-15 | 2020-12-02 | Алексей Георгиевич Александров | Method for preparing pharmaceutical substance based on piribedil |
| CN112724120A (en) * | 2020-12-29 | 2021-04-30 | 爱斯特（成都）生物制药股份有限公司 | Method for synthesizing piperonyl chloride through continuous flow reaction |
| CN112724120B (en) * | 2020-12-29 | 2022-05-17 | 爱斯特（成都）生物制药股份有限公司 | Method for synthesizing piperonyl chloride through continuous flow reaction |
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Application publication date: 20100915 |