CN103373991A - Method for preparing piribedil in high-purity high-yield manner - Google Patents
Method for preparing piribedil in high-purity high-yield manner Download PDFInfo
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Abstract
The invention discloses a new method for preparing piribedil in a high-purity high-yield manner. The method is characterized by comprising the following steps of: utilizing piperidine as a raw material, and preparing the piribedil through four-step reaction, namely a blanc chloromethylation, an N-single protection piperazine ammoniation, deprotection and 2-cloro pyridine condensation. Compared with the traditional method, the method provided by the invention has the advantages that the N-single protection piperazine replaces piperazine, the piperazine dosage is reduced, a side reaction is alleviated, the impurities of a reaction process are reduced, the operation is simple, the condition is mild and is easy to control, the aftertreatment is convenient, according to the method, the environmental protection is realized, the total recovery is high, and the method is novel and used for industrially compounding piribedil.
Description
Technical field
The present invention relates to a kind of preparation method who treats the Parkinson medicine, relate to particularly a kind of brand-new synthetic method for preparing Piribedil (Piribedil) take piperonyl cyclonene as raw material.
Background technology
Piribedil (Piribedil) is applicable to patient Parkinson, is a kind of Dopaminergic Agents, can stimulate the postsynaptic D2 acceptor of brain nigrostriatum and midbrain cortex, and the D2 of midbrain marginal convolution path and D3 acceptor provide effective Dopamine HCL effect.
Piribedil, chemical name are 2-[4-(1,3-benzo dioxole-5-ylmethyl)-piperazine-1-yl] pyrimidine, its structural formula is as follows.
(I)
At present, the synthetic method of the Piribedil of bibliographical information mainly contains following several:
Chinese patent application CN1884280A discloses the preparation method of a kind of Piribedil (Piribedil), and the method is carried out the ammonification reduction reaction take piperonylaldehyde as starting raw material with piperazine, again with the 2-chloropyrimide to being bonded into Piribedil.Raw material of the present invention is easy to get, cost is lower, simple to operate, yield is higher, suitability for industrialized production stable and controllable for quality and suitable, but needs to carry out hydro-reduction under the pressure condition of 20-60bar, the reaction pressure conditional request is higher.
(the J.Am.Chem.Soc.131 (5) such as M.H Hamid, 1766-1774,2009) and Haniti, (the Tetrahedron letts.48 (47) such as M., 8263-8265,2007) following another kind of synthetic route is disclosed, adopt the Ru catalyzer synthetic, because of the needs noble metal catalyst, expensive.
(Tetrahedron Letts.47 (15), 2549-2552,2006) such as Matthew A J Duncton disclose the third following synthetic route, because of needs to the piperonylaldehyde reduction amination, yield is lower.
Poland Patent PL167397 and Zdzislaw Chilmonczyk(Arch.Pharm. (weinheim), 326 (4), 241-242,1993) etc. the 4th kind of following synthetic route disclosed, this synthetic route yield is lower.
US Patent No. 3299067 discloses the 5th kind of synthetic route, and the method synthetic route is also lower, and by three-step reaction, product yield only has 32%.
Therefore still need a kind of brand-new method for preparing Piribedil, can prepare with high yield highly purified Piribedil, possess again simple to operately, mild condition is easily controlled, convenient post-treatment, the characteristics such as environmental friendliness.
Summary of the invention
The purpose of this invention is to provide a kind of brand-new method for preparing Piribedil, solve the deficiency that prior art exists, and possess above-mentioned beneficial effect.
For realizing above purpose of the present invention, the present invention adopts following technical scheme:
The method of a kind of high purity, high yield preparation formula (I) Piribedil; it is characterized in that take piperonyl cyclonene as raw material, through the blanc chloromethylation, through the single protection of N-piperazine condensation; take off the Boc protection, 2-chloropyrimide condensation four-step reaction prepares the product Piribedil.
(I)
In a specific embodiment, said method comprising the steps of:
(1) formula III 3, the preparation of 4-methylene-dioxy benzyl chloride:
Raw material formula II compound piperonyl cyclonene is dissolved in hydrochloric acid, adds polyoxymethylene and phase-transfer catalyst, under suitable temperature, react, through the Blanc chloromethylation, after reacting completely, through suitable aftertreatment, obtain product formula III 3,4-methylene-dioxy benzyl chloride;
(2) formula (IV) 1-(3,4-methylenedioxy benzyl)-preparation of 4-R-piperazine:
With formula III 3,4-methylene-dioxy benzyl chloride is dissolved in the suitable solvent, the aqueous solution that adds the single protection of N-piperazine, at alkaline condition, under suitable temperature, react, after reacting completely, through suitable aftertreatment, obtain product formula (IV) 1-(3, the 4-methylenedioxy benzyl)-the 4-R-piperazine;
(3) formula V 1-(3, the 4-methylenedioxy benzyl) preparation of piperazine:
With formula (IV) 1-(3,4-methylenedioxy benzyl)-the 4-R-piperazine is raw material, is dissolved in the suitable solvent, reacts under suitable condition, deprotection prepares formula (V) 1-(3, the 4-methylenedioxy benzyl) and piperazine;
(4) preparation of formula (I) Piribedil:
With formula (V) 1-(3,4-methylenedioxy benzyl) piperazine dissolved is in suitable solvent, and adding 2-chloropyrimide under alkaline condition, reacts under suitable temperature, after reacting completely, through suitable aftertreatment, obtains product Piribedil formula (I).
Wherein, the Wei trioxane of polyoxymethylene described in the described step (1) or Paraformaldehyde 96; Described formula (II) piperonyl cyclonene: the consumption mol ratio of polyoxymethylene is 1:1 ~ 1:3; Described phase-transfer catalyst be selected from benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, PEG200, tween 80 or the 18 crown ether six at least any one; Described phase-transfer catalyst quality consumption is 0.5% ~ 5% of described formula (II) piperonyl cyclonene; The suitable temperature of described reaction is-20 ℃ ~ 70 ℃.
Preferably, polyoxymethylene is trioxane described in the described step (1); Described formula (II) piperonyl cyclonene: the consumption mol ratio of polyoxymethylene is 1:1 ~ 1:1.5; Described phase-transfer catalyst is selected from Tetrabutyl amonium bromide; Described phase-transfer catalyst quality consumption is 0.5% ~ 1% of described formula (II) piperonyl cyclonene; The suitable temperature of described reaction is-10 ℃ ~ 20 ℃.
Wherein, suitable solvent described in the described step (2) be selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one; The alkali of described alkaline condition be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine or the ammoniacal liquor at least any one; Described suitable temperature is-20 ℃ ~ 100 ℃; Described formula III compound 3,4-methylene-dioxy benzyl chloride: the consumption mol ratio of the single protection of alkali: N-piperazine is 1:1 ~ 3:0.5 ~ 3.
Preferably, suitable solvent is selected from methyl alcohol or ethanol described in the described step (2); The alkali of described alkaline condition is selected from sodium hydroxide or potassium hydroxide; Described suitable temperature is 60 ℃-80 ℃; Described formula III compound 3,4-methylene-dioxy benzyl chloride: the consumption mol ratio of the single protection of alkali: N-piperazine is 1:3:1.1; The R blocking group of the single protection of described N-piperazine is the BOC blocking group.
Wherein, suitable solvent described in the described step (3) be selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one; Described suitable condition is to select different deprotection methods according to different blocking groups; Described R blocking group is the N blocking group, is selected from CbzCl, BOC acid anhydrides or the ethanoyl any one.
Preferably, described suitable solvent is selected from methyl alcohol or ethanol; Described suitable condition is the following acidic conditions of zero degrees celsius, and described acid is hydrochloric acid or trifluoroacetic acid; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl)-the 4-Boc-piperazine: the hydrochloric acid mol ratio is 1:2.
Wherein, suitable solvent described in the described step (4) be in water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one; The alkali of described alkaline condition be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine or the ammoniacal liquor at least any one; Described suitable temperature is-20 ℃ ~ 100 ℃; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl) piperazine: alkali: the consumption mol ratio of 2-chloropyrimide is 1:1 ~ 3:1 ~ 5.
Preferably, suitable solvent is methyl alcohol or ethanol described in the described step (4); The alkali of described alkaline condition is selected from yellow soda ash or salt of wormwood; Described suitable temperature is 60 ℃ ~ 80 ℃; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl) piperazine: alkali: the consumption mol ratio of 2-chloropyrimide is 1:2:1.1.
Prepare the method for Piribedil according to high purity of the present invention, high yield, utilize piperonyl cyclonene to be raw material, through the Blanc chloromethylation, the ammonification of the single protection of N-piperazine, deprotection, and 2-chloropyrimide condensation four steps preparation Piribedil.This technological line is only by some simple intermediate reactions, realize that with four-step reaction total recovery reaches the yield about 60%, obtain logical formula I 2-[4-(1,3-benzo dioxole-5-ylmethyl) piperazine-1-yl] pyrimidine, it is Piribedil, three step of the technological line total recovery of the US Patent No. of comparing 3299067 is 32%, and the present invention is succinct, efficient more economically.
The method for preparing Piribedil according to high purity of the present invention, high yield, compare with traditional method and to have the following advantages: be simple to operate, product purity is high, side reaction is few, mild condition is easily controlled, convenient post-treatment, environmental friendliness, total recovery is higher, is the method for the synthetic Piribedil of a kind of brand-new industrialization.
Description of drawings
Fig. 1 is Piribedil preparation method's of the present invention synthetic route synoptic diagram.
Fig. 2 is the Piribedil HPLC collection of illustrative plates that the present invention prepares.
Fig. 3 is the Piribedil 1HNMR collection of illustrative plates that the present invention prepares.
Embodiment
Below in conjunction with embodiment more specifically the present invention is done further expansion explanation, but it is to be noted, Piribedil preparation method of the present invention is not limited to this specific reagent and selects or processing parameter the scope that these embodiment do not limit the present invention in any way.Obviously be understandable that for those skilled in the art, even the following description content is not done any adjustment or correction, also can be directly applied in these unspecified other similar chemical reagent or processing condition.
As shown in Figure 1; high purity, high yield prepare the method for Piribedil; take piperonyl cyclonene as raw material; through the blanc chloromethylation; through the single protection of N-piperazine condensation; take off the Boc protection; 2-chloropyrimide condensation four-step reaction prepares formula (I) product Piribedil; and through high performance liquid chromatography and NMR (Nuclear Magnetic Resonance) spectrum characterization test; as shown in Figures 2 and 3; show that technological line of the present invention is reliable, can prepare efficiently Piribedil, and the purity 99.90% of HPLC detection display Piribedil.
In concrete embodiment, may further comprise the steps:
1) formula III 3, the preparation of 4-methylene-dioxy benzyl chloride
Formula II starting compound piperonyl cyclonene is dissolved in hydrochloric acid, add polyoxymethylene and phase-transfer catalyst, under suitable temperature, react, preferably-20 ℃ ~ 70 ℃ temperature of reaction, through the Blanc chloromethylation, after reacting completely, through suitable aftertreatment, obtain product formula III 3,4-methylene-dioxy benzyl chloride.
This reaction can be carried out under any suitable temperature, is not limited to react under-20 ℃ ~ 70 ℃ the temperature, and preferable reaction temperature is-10 ℃ to 20 ℃; Polyoxymethylene can be trioxane partner Paraformaldehyde 96, and preferred polyoxymethylene is trioxane; Phase-transfer catalyst is preferably Tetrabutyl amonium bromide; The consumption of catalyzer phase-transfer catalyst is preferably 0.5% ~ 1% of formula II compound piperonyl cyclonene quality.In a preferred embodiment of the invention, preferred described (II) compound piperonyl cyclonene: the polyoxymethylene mol ratio is 1:1.5.Wherein, concentration and the consumption of hydrochloric acid are not particularly limited, and the preferred higher hydrochloric acid of purity is avoided bringing pollution to product, the consumption of hydrochloric acid for example can for reaction vessel mention 20%, 30%, 40%, 50%, 60%, 70% or 80%, but be not limited to this.
In addition, well-known to those skilled in the artly be, during organic synthesis or medicine are synthetic, suitable aftertreatment normally separates reaction product or required target intermediate product, the process of purifying, include but not limited at least wherein a certain treatment step such as extraction, filtration, distillation, rectifying, drying, certainly also comprise the supplementary meanss such as washing that some are necessary, and other means such as adjusting pH value that may need.This is not core key point of the present invention, and it also is those skilled in the art in the situation of the reactant of each step reaction of knowing reaction course and intermediate product, readily appreciates that and selects which kind of post processing mode; For example aftertreatment must separate the intermediate product of reaction, purify, so that as the reactant of next step reaction; When reaction system is sour environment, if next step reaction requires alkaline environment, then correspondingly want the pH value of conditioned reaction product system; Simultaneously, also with the step of washing, with other impurity that minimizing intermediate product or product are carried secretly, these aftertreatment means all are that those skilled in the art institute is apparent to the processes such as filtering separation.
In the present invention and embodiment, " conventional aftertreatment " expression: if necessary, add entry, regulate as required the pH value and depend on the formation of product to 1-13(), mixture is with ethyl acetate, chloroform or dichloromethane extraction, separation of phases, organic phase is with anhydrous sodium sulphate or anhydrous magnesium sulfate drying, underpressure distillation, product is purified by silica gel chromatography and/or recrystallization, and the Rf value obtains at silica gel.
2) formula (IV) 1-(3,4-methylenedioxy benzyl)-preparation of 4-Boc-piperazine
With formula III 3; 4-methylene-dioxy benzyl chloride is dissolved in the suitable solvent; the aqueous solution that adds the single protection of N-piperazine; at alkaline condition; under suitable temperature, react, after reacting completely, through suitable aftertreatment; obtain product formula (IV) 1-(3, the 4-methylenedioxy benzyl)-the 4-R-piperazine.
This reaction can be carried out under suitable temperature, and preferable reaction temperature is-20 ℃ ~ 100 ℃, more preferably 60 ℃-80 ℃ of temperature of reaction.Wherein, described suitable solvent be selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one, but be not limited to this; Be preferably methyl alcohol or ethanol.The alkali of described alkaline condition be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine or the ammoniacal liquor at least any one, but be not limited to this; Be preferably sodium hydroxide or potassium hydroxide; Described R blocking group is the N blocking group, is selected from CbzCl, BOC acid anhydrides or the ethanoyl any one, is preferably the BOC blocking group; Described formula III compound 3,4-methylene-dioxy benzyl chloride: the consumption mol ratio of the single protection of alkali: N-piperazine is 1:1 ~ 3:0.5 ~ 3, is preferably 1:3:1.1.
3) formula (V) 1-(3, the 4-methylenedioxy benzyl) preparation of piperazine
With formula (IV) 1-(3,4-methylenedioxy benzyl)-the 4-R-piperazine is raw material, is dissolved in the suitable solvent, reacts under suitable condition, deprotection prepares formula (V) 1-(3, the 4-methylenedioxy benzyl) and piperazine.
Described suitable solvent be selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one, be preferably alcohol or ethanol, but be not limited to this; Described suitable condition is to select different deprotection methods according to different blocking groups, and when for example the R blocking group was the BOC acid anhydrides, described suitable condition was the following acidic conditions of zero degrees celsius, and described acid is preferably hydrochloric acid; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl)-the 4-Boc-piperazine: the hydrochloric acid mol ratio is 1:2.
4) preparation of formula (I) Piribedil
With formula (V) 1-(3,4-methylenedioxy benzyl) piperazine dissolved is in suitable solvent, and adding 2-chloropyrimide under alkaline condition, reacts under suitable temperature, after reacting completely, through suitable aftertreatment, obtains product Piribedil formula (I).
Described suitable solvent be in water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one, but be not limited to this, in a preferred embodiment of the invention, preferred this reaction is carried out in ethanol or methyl alcohol; Described suitable temperature is-20 ℃ ~ 100 ℃, and preferable reaction temperature is 60 ℃ ~ 80 ℃; The alkali of described alkaline condition be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine or the ammoniacal liquor at least any one, but be not limited to this, be preferably salt of wormwood or yellow soda ash; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl) piperazine: alkali: the consumption mol ratio of 2-chloropyrimide is 1:1 ~ 3:1 ~ 5, is preferably 1:2:1.1.
The below will come more detailed description the present invention by specific embodiment, but only be for a better understanding of the present invention, its to protection scope of the present invention without any restriction.
Embodiment 13, the preparation of 4-methylene-dioxy benzyl chloride
In the 10L flask, add 1.0kg (8.19mol) piperonyl cyclonene, the 3L concentrated hydrochloric acid, the 0.05kg Tetrabutyl amonium bromide, 0.83kg (9.22mol) Paraformaldehyde 96 after 0 ℃ to 5 ℃ of low temperature stirs half an hour, continues to be warming up to 15 ℃ to 20 ℃ reactions 2 hours.Add dichloromethane extraction 3kg*3(extraction 3 times), the organic layer washing added anhydrous sodium sulfate drying after 6 hours, be concentrated into driedly, obtain water white oily matter, thick product obtains 3 through rectification under vacuum, 4-methylene-dioxy benzyl chloride, 1.02kg (5.98mol), yield 74%.
Embodiment 23, the preparation of 4-methylene-dioxy benzyl chloride
In the 10L flask, add 1kg (8.19mol) piperonyl cyclonene, the 3L concentrated hydrochloric acid, 0.05kgPEG-200,0.73kg (8.1mol) Paraformaldehyde 96, low temperature-10 ℃ continue to be warming up to 20 ℃ to 30 ℃ reactions 2 hours after stirring half an hour to 0 ℃.Add dichloromethane extraction 3kg*3, the organic layer washing added anhydrous sodium sulfate drying after 6 hours, was concentrated into driedly, obtained obtaining 3,4-methylene-dioxy benzyl chloride after the water white oily matter rectifying, 1.08kg (6.33mol), yield 78%.
Embodiment 33, the preparation of 4-methylene-dioxy benzyl chloride
In the 10L flask, add 1kg (8.19mol) piperonyl cyclonene, 4L hydrochloric acid, the 0.05kg Tetrabutyl amonium bromide, 1.09kg (12.1mol) Paraformaldehyde 96, low temperature-10 ℃ continue to be warming up to 20 ℃ to 30 ℃ reactions 2 hours after stirring half an hour to 0 ℃.Add dichloromethane extraction 3kg*3, the organic layer washing added anhydrous sodium sulfate drying after 6 hours, was concentrated into driedly, obtained obtaining 3,4-methylene-dioxy benzyl chloride after the water white oily matter rectifying, 1.05kg (6.16mol), yield 76.7%.
Embodiment 4 1-(3,4-methylenedioxy benzyl)-preparation of 4-Boc-piperazine
The 10L flask adds 3,4-methylene-dioxy benzyl chloride, 1.08kg (6.33mol), with the dilution of 5kg dissolve with ethanol, be added dropwise to 1.3kg (5.38mol), in the aqueous solution of Boc-piperazine and 0.76kg sodium hydroxide configuration 10%, drip and finish, be warming up to backflow, about 78 ℃ of reflux temperatures reacted 5 to 6 hours.
Reaction solution distillation ethanol, about salt acid for adjusting pH value=2, add chloroform 2kg*3 extraction, organic layer with the saturated common salt water washing is once washed once, added anhydrous magnesium sulfate drying 6 hours, concentrated solvent obtains light yellow oil 2.0kg to doing, and is product 1-(3, the 4-methylenedioxy benzyl)-and the 4-Boc-piperazine, quantitative yield.
Embodiment 5 1-(3,4-methylenedioxy benzyl)-preparation of 4-Boc-piperazine
The 10L flask adds 3,4-methylene-dioxy benzyl chloride, 1.02kg (5.98mol), dilute with the 4.5kg dissolve with methanol, be added dropwise in the aqueous solution of 1.22kg (6.54mol) Boc-piperazine and 0.76kg sodium hydroxide configuration 10%, drip and finish, be warming up to backflow, 65 ℃ of reflux temperatures reacted 3 hours.
The reaction solution distillating carbinol, hydrochloric acid is regulated about pH=2, add chloroform 2kg*3 extraction, organic layer with the saturated common salt water washing is once washed once, added anhydrous magnesium sulfate drying 6 hours, concentrated solvent obtains light yellow oil 1.9kg to doing, and obtains product 1-(3, the 4-methylenedioxy benzyl)-and the 4-Boc-piperazine, quantitative yield.
Embodiment 6 1-(3,4-methylenedioxy benzyl)-preparation of 4-Boc-piperazine
The 10L flask adds 3,4-methylene-dioxy benzyl chloride, 1.05kg (6.16mol), with the dilution of 4.5kg dissolve with methanol, be added dropwise to 1.26kg (6.77mol), in the aqueous solution of Boc-piperazine and 1.06kg potassium hydroxide configuration 10%, drip and finish, be warming up to backflow, 65 ℃ of reflux temperatures reacted 4 hours.
The reaction solution distillating carbinol, hydrochloric acid is regulated about pH=2, add chloroform 2kg*3 extraction, organic layer with the saturated common salt water washing is once washed once, added anhydrous magnesium sulfate drying 6 hours, concentrated solvent obtains light yellow oil 1.96kg to doing, and obtains product 1-(3, the 4-methylenedioxy benzyl)-and the 4-Boc-piperazine, quantitative yield.
Embodiment 7 1-(3,4-methylenedioxy benzyl) preparation of piperazine
20L glass reaction still adds 2kg (6.24mol), 1-(3,4-methylenedioxy benzyl)-the 4-Boc-piperazine, add 10kg methyl alcohol, stirring and dissolving is cooled to below the zero degrees celsius, drips hydrochloric acid 0.7kg, slowly is warming up to about 25 ℃, stirs 1 hour.
After reaction finishes, 10% sodium hydroxide is regulated about pH=10, add chloroform 3kg*3 extraction, organic layer with the saturated common salt water washing is once washed once, added anhydrous magnesium sulfate drying 6 hours, concentrated solvent obtains light yellow oil 1.29 (5.86mol) kg to doing, and obtains product 1-(3, the 4-methylenedioxy benzyl) piperazine, yield 94%.
Embodiment 8 1-(3,4-methylenedioxy benzyl) preparation of piperazine
20L glass reaction still adds 1.9kg (5.93mol), 1-(3,4-methylenedioxy benzyl)-the 4-Boc-piperazine, add 10kg methyl alcohol, stirring and dissolving is cooled to below the zero degrees celsius, drip hydrochloric acid 0.68kg, slowly be warming up to about 25 ℃, stirred 1 hour.
After reaction finishes, 10% sodium hydroxide is regulated about pH=10, add methylene dichloride 3kg*3 extraction, organic layer with the saturated common salt water washing is once washed once, added anhydrous magnesium sulfate drying 6 hours, concentrated solvent obtains light yellow oil 1.23kg (5.69mol) to doing, and obtains product 1-(3, the 4-methylenedioxy benzyl) piperazine, yield 96%.
Embodiment 9 1-(3,4-methylenedioxy benzyl) preparation of piperazine
20L glass reaction still adds 1.96kg (6.1mol), 1-(3,4-methylenedioxy benzyl)-the 4-Boc-piperazine, add the 10kg ethyl acetate, stirring and dissolving is cooled to below the zero degrees celsius, drip trifluoroacetic acid 1.4kg, slowly be warming up to about 25 ℃, stirred 30 minutes.
After reaction finishes, 10% sodium hydroxide is regulated about pH=10, add methylene dichloride 3kg*3 extraction, organic layer with the saturated common salt water washing is once washed once, added anhydrous magnesium sulfate drying 6 hours, concentrated solvent obtains light yellow oil 1.21kg (5.5mol) to doing, and obtains product 1-(3, the 4-methylenedioxy benzyl) piperazine, yield 90%.
The preparation of embodiment 10 Piribedils
The 10L flask adds 1-(3,4-methylenedioxy benzyl) piperazine, 1.29kg (5.86mol), with the clarification of 6kg dissolve with methanol, disposable adding 0.73kg (6.4mol) 2-chloropyrimide adds 2.18kg salt of wormwood, slow temperature rising reflux, 65 ℃ of temperature were reacted 24 hours.
The cooling suction filtration, after the filter cake methanol wash, filtrate concentrates out 2/3rds methyl alcohol, and mother liquor is cooled to zero degree after taking out, and leaves standstill crystallization 12 hours.Separate out to get the crystal suction filtration, a small amount of methyl alcohol drip washing once, 50 ℃ of drying under reduced pressure obtain white crystal and are the Piribedil product, 1.48kg (4.97mol), yield 85%, HPLC purity 〉=99%, 98 ~ 100 ℃ of fusing points.
The preparation of embodiment 11 Piribedils
The 10L flask adds 1-(3,4-methylenedioxy benzyl) piperazine, 1.23kg (5.59mol), with 6kg acetonitrile dissolving clarification, disposable adding 0.7kg (6.14mol) 2-chloropyrimide adds 2.18kg salt of wormwood, slow temperature rising reflux, 78 ℃ of temperature were reacted 22 hours.
The cooling suction filtration, after the washing of filter cake acetonitrile, filtrate concentrates out 2/3rds acetonitrile, and mother liquor is cooled to zero degree after taking out, and leaves standstill crystallization 12 hours.Separate out to get the crystal suction filtration, a small amount of acetonitrile drip washing once, 50 ℃ of drying under reduced pressure obtain white crystal and are the product Piribedil, 1.48kg (4.97mol), yield 89%, HPLC purity 〉=99%, 98 ~ 100 ℃ of fusing points.
The preparation of embodiment 12 Piribedils
The 10L flask adds 1-(3,4-methylenedioxy benzyl) piperazine, 1.21kg (5.5mol), with the clarification of 6kg dissolve with ethanol, disposable adding 0.689kg (6.04mol) 2-chloropyrimide adds 1.67kg yellow soda ash, slow temperature rising reflux, 78 ℃ of temperature were reacted 28 hours.
The cooling suction filtration, after the filter cake washing with alcohol, filtrate concentrates out 2/3rds ethanol, and mother liquor is cooled to zero degree after taking out, and leaves standstill crystallization 12 hours.Separate out to get the crystal suction filtration, a small amount of ethanol drip washing once, 50 ℃ of drying under reduced pressure obtain white crystal and are the product Piribedil, 1.31kg (4.4mol), yield 80%, HPLC purity 〉=99%, 98 ~ 100 ℃ of fusing points.
Although above the specific embodiment of the present invention has been given to describe in detail and explanation; but what should indicate is; we can carry out various equivalences to above-mentioned embodiment according to conception of the present invention and change and modification; when its function that produces does not exceed spiritual that specification sheets and accompanying drawing contain yet, all should be within protection scope of the present invention.
Claims (10)
1. the method for a high purity, high yield preparation formula (I) Piribedil; it is characterized in that take piperonyl cyclonene as raw material, through the blanc chloromethylation, through the single protection of N-piperazine condensation; take off the Boc protection, 2-chloropyrimide condensation four-step reaction prepares the product Piribedil.
2. method according to claim 1 is characterized in that said method comprising the steps of:
(1) formula III 3, the preparation of 4-methylene-dioxy benzyl chloride
Raw material formula II compound piperonyl cyclonene is dissolved in hydrochloric acid, adds polyoxymethylene and phase-transfer catalyst, under suitable temperature, react, through the Blanc chloromethylation, after reacting completely, through suitable aftertreatment, obtain product formula III 3,4-methylene-dioxy benzyl chloride;
(2) formula (IV) 1-(3,4-methylenedioxy benzyl)-preparation of 4-R-piperazine
With formula III 3,4-methylene-dioxy benzyl chloride is dissolved in the suitable solvent, the aqueous solution that adds the single protection of N-piperazine, at alkaline condition, under suitable temperature, react, after reacting completely, through suitable aftertreatment, obtain product formula (IV) 1-(3, the 4-methylenedioxy benzyl)-the 4-R-piperazine;
(3) formula V 1-(3, the 4-methylenedioxy benzyl) preparation of piperazine
With formula (IV) 1-(3,4-methylenedioxy benzyl)-the 4-R-piperazine is raw material, is dissolved in the suitable solvent, reacts under suitable condition, deprotection prepares formula (V) 1-(3, the 4-methylenedioxy benzyl) and piperazine;
(4) preparation of formula (I) Piribedil
With formula (V) 1-(3,4-methylenedioxy benzyl) piperazine dissolved is in suitable solvent, and adding 2-chloropyrimide under alkaline condition, reacts under suitable temperature, after reacting completely, through suitable aftertreatment, obtains formula (I) product Piribedil.
3. method according to claim 2 is characterized in that the Wei trioxane of polyoxymethylene described in the described step (1) or Paraformaldehyde 96; Described formula (II) piperonyl cyclonene: the consumption mol ratio of polyoxymethylene is 1:1 ~ 1:3; Described phase-transfer catalyst be selected from benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, PEG200, tween 80 or the 18 crown ether six at least any one; The quality consumption of described phase-transfer catalyst is 0.5% ~ 5% of described formula (II) piperonyl cyclonene; The suitable temperature of described reaction is-20 ℃ ~ 70 ℃.
4. method according to claim 3 is characterized in that polyoxymethylene is trioxane described in the described step (1); Described formula (II) piperonyl cyclonene: the consumption mol ratio of polyoxymethylene is 1:1 ~ 1:1.5; Described phase-transfer catalyst is selected from Tetrabutyl amonium bromide; Described phase-transfer catalyst quality consumption is 0.5% ~ 1% of described formula (II) piperonyl cyclonene; The suitable temperature of described reaction is-10 ℃ ~ 20 ℃.
5. method according to claim 2, it is characterized in that suitable solvent described in the described step (2) be selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one; The alkali of described alkaline condition be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine or the ammoniacal liquor at least any one; Described suitable temperature is-20 ℃ ~ 100 ℃; Described formula III compound 3,4-methylene-dioxy benzyl chloride: the consumption mol ratio of the single protection of alkali: N-piperazine is 1:1 ~ 3:0.5 ~ 3.
6. method according to claim 5 is characterized in that suitable solvent is selected from methyl alcohol or ethanol described in the described step (2); The alkali of described alkaline condition is selected from sodium hydroxide or potassium hydroxide; Described suitable temperature is 60 ℃-80 ℃; Described formula III compound 3,4-methylene-dioxy benzyl chloride: the consumption mol ratio of the single protection of alkali: N-piperazine is 1:3:1.1; The R blocking group of the single protection of described N-piperazine is the BOC blocking group.
7. method according to claim 2, it is characterized in that suitable solvent described in the described step (3) be selected from water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one; Described suitable condition is to select different deprotection methods according to different blocking groups; Described R blocking group is the N blocking group, is selected from CbzCl, BOC acid anhydrides or the ethanoyl any one.
8. method according to claim 7 is characterized in that described suitable solvent is selected from methyl alcohol or ethanol; Described suitable condition is the following acidic conditions of zero degrees celsius, and described acid is hydrochloric acid or trifluoroacetic acid; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl)-the 4-Boc-piperazine: the hydrochloric acid mol ratio is 1:2.
9. method according to claim 2, it is characterized in that solvent suitable described in the described step (4) be in water, methyl alcohol, ethanol, Virahol, acetonitrile, methylene dichloride or the chloroform at least any one; The alkali of described alkaline condition be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine or the ammoniacal liquor at least any one; Described suitable temperature is-20 ℃ ~ 100 ℃; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl) piperazine: alkali: the consumption mol ratio of 2-chloropyrimide is 1:1 ~ 3:1 ~ 5.
10. method according to claim 9 is characterized in that solvent suitable described in the described step (4) is methyl alcohol or ethanol; The alkali of described alkaline condition is selected from yellow soda ash or salt of wormwood; Described suitable temperature is 60 ℃ ~ 80 ℃; Described formula (IV) compound 1-(3, the 4-methylenedioxy benzyl) piperazine: alkali: the consumption mol ratio of 2-chloropyrimide is 1:2:1.1.
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Cited By (6)
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| 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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| CN106432212A (en) * | 2016-09-21 | 2017-02-22 | 苏州弘森药业股份有限公司 | Synthetic method of piribedil |
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| 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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