Method for preparing piribedil in high-purity high-yield manner

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

[0001] The invention relates to a preparation method of a medicine for treating Parkinson's disease, in particular to a novel synthesis method for preparing piribedil from piperonylcycline. Background technique

[0002] Piribedil (Piribedil), suitable for Parkinson's patients, is a dopaminergic agonist that can stimulate the post-synaptic D2 receptors in the brain's nigrostriatum and the D2 and D3 receptors, providing potent dopamine effects.

[0003] The chemical name of piribedil is 2-[4-(1,3-benzodioxol-5-ylmethyl)-piperazin-1-yl]pyrimidine, and its structural formula is as follows.

[0004]

[0005] (I)

[0006] At present, the synthetic method of the piribedil reported in the literature mainly contains the following kinds:

[0007] Chinese patent application CN1884280A discloses a preparation method of piribedil (Piribedil), which uses piperonal as a starting material, carries out ammoniation reduction reaction with piperazine, and then docks w...

Examples

preparation example Construction

[0066] 4) Preparation of formula (I) piribedil

[0067] Dissolve 1-(3,4-methylenedioxybenzyl)piperazine of formula (V) in an appropriate solvent, add 2-chloropyrimidine, react at a suitable temperature under alkaline conditions, and the reaction is complete Afterwards, through appropriate aftertreatment, obtain product piribedil formula (I).

[0068]

[0069] The suitable solvent is at least any one of water, methanol, ethanol, isopropanol, acetonitrile, methylene chloride or chloroform, but is not limited thereto. In preferred embodiments of the present invention, it is preferred that the reaction be carried out in ethanol or carried out in methanol; the suitable temperature is -20°C to 100°C, and the preferred reaction temperature is 60°C to 80°C; the alkali in the alkaline condition is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, At least any one of triethylamine or ammonia, but not limited thereto, preferably potassium car...

Embodiment 1

[0071] Example 1 Preparation of 3,4-methylenedioxybenzyl chloride

[0072] Add 1.0kg (8.19mol) of piperonine, 3L of concentrated hydrochloric acid, 0.05kg of tetrabutylammonium bromide, 0.83kg (9.22mol) of paraformaldehyde into a 10L flask, stir at a low temperature of 0°C to 5°C for half an hour, then continue to heat up React at 15°C to 20°C for 2 hours. Add dichloromethane to extract 3kg*3 (extraction 3 times), wash the organic layer with water, add anhydrous sodium sulfate to dry for 6 hours, and concentrate to dryness to obtain a colorless and transparent oily product. The crude product is obtained by vacuum distillation to obtain 3, 4-Methylenedioxybenzyl chloride, 1.02kg (5.98mol), yield 74%.

Embodiment 2

[0073] Example 2 Preparation of 3,4-methylenedioxybenzyl chloride

[0074] Add 1kg (8.19mol) of piperonine, 3L of concentrated hydrochloric acid, 0.05kg of PEG-200, 0.73kg (8.1mol) of paraformaldehyde into a 10L flask, stir at a low temperature of -10°C to 0°C for half an hour, then continue to heat up to 20°C to React at 30°C for 2 hours. Add dichloromethane to extract 3kg*3, wash the organic layer with water, add anhydrous sodium sulfate to dry for 6 hours, and then concentrate to dryness to obtain a colorless and transparent oily product. After rectification, 3,4-methylenedioxybenzyl chloride is obtained. 1.08kg (6.33mol), yield 78%.

technical field

[0001] The invention relates to a preparation method of a medicine for treating Parkinson's disease, in particular to a novel synthesis method for preparing piribedil from piperonylcycline. Background technique

[0002] Piribedil (Piribedil), suitable for Parkinson's patients, is a dopaminergic agonist that can stimulate the post-synaptic D2 receptors in the brain's nigrostriatum and the D2 and D3 receptors, providing potent dopamine effects.

[0003] The chemical name of piribedil is 2-[4-(1,3-benzodioxol-5-ylmethyl)-piperazin-1-yl]pyrimidine, and its structural formula is as follows.

[0004]

[0005] (I)

[0006] At present, the synthetic method of the piribedil reported in the literature mainly contains the following kinds:

[0007] Chinese patent application CN1884280A discloses a preparation method of piribedil (Piribedil), which uses piperonal as a starting material, carries out ammoniation reduction reaction with piperazine, and then docks w...

Examples

preparation example Construction

[0066] 4) Preparation of formula (I) piribedil

[0067] Dissolve 1-(3,4-methylenedioxybenzyl)piperazine of formula (V) in an appropriate solvent, add 2-chloropyrimidine, react at a suitable temperature under alkaline conditions, and the reaction is complete Afterwards, through appropriate aftertreatment, obtain product piribedil formula (I).

[0068]

[0069] The suitable solvent is at least any one of water, methanol, ethanol, isopropanol, acetonitrile, methylene chloride or chloroform, but is not limited thereto. In preferred embodiments of the present invention, it is preferred that the reaction be carried out in ethanol or carried out in methanol; the suitable temperature is -20°C to 100°C, and the preferred reaction temperature is 60°C to 80°C; the alkali in the alkaline condition is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, At least any one of triethylamine or ammonia, but not limited thereto, preferably potassium car...

Embodiment 1

[0071] Example 1 Preparation of 3,4-methylenedioxybenzyl chloride

[0072] Add 1.0kg (8.19mol) of piperonine, 3L of concentrated hydrochloric acid, 0.05kg of tetrabutylammonium bromide, 0.83kg (9.22mol) of paraformaldehyde into a 10L flask, stir at a low temperature of 0°C to 5°C for half an hour, then continue to heat up React at 15°C to 20°C for 2 hours. Add dichloromethane to extract 3kg*3 (extraction 3 times), wash the organic layer with water, add anhydrous sodium sulfate to dry for 6 hours, and concentrate to dryness to obtain a colorless and transparent oily product. The crude product is obtained by vacuum distillation to obtain 3, 4-Methylenedioxybenzyl chloride, 1.02kg (5.98mol), yield 74%.

Embodiment 2

[0073] Example 2 Preparation of 3,4-methylenedioxybenzyl chloride

[0074] Add 1kg (8.19mol) of piperonine, 3L of concentrated hydrochloric acid, 0.05kg of PEG-200, 0.73kg (8.1mol) of paraformaldehyde into a 10L flask, stir at a low temperature of -10°C to 0°C for half an hour, then continue to heat up to 20°C to React at 30°C for 2 hours. Add dichloromethane to extract 3kg*3, wash the organic layer with water, add anhydrous sodium sulfate to dry for 6 hours, and then concentrate to dryness to obtain a colorless and transparent oily product. After rectification, 3,4-methylenedioxybenzyl chloride is obtained. 1.08kg (6.33mol), yield 78%.

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