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Process for synthesizing paliperidone intermediate

A technology of paliperidone and its synthetic method, which is applied in the field of preparation of raw material pharmaceutical chemical products, can solve the problems of incomplete cyclization, difficult industrialization, poor dehalogenation selectivity, etc., and achieves convenient separation, high selectivity, and easy separation and purification Effect

Inactive Publication Date: 2009-05-27
SHANGHAI RECORD PHARM CO LTD
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Problems solved by technology

[0004] The main disadvantages of this method are: in the second step, the cyclization is incomplete, the yield is low, and it is difficult to industrialize after column purification; the selectivity to dehalogenation in the third step of pyridine ring hydrogenation is poor, and the product purification is difficult

Method used

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  • Process for synthesizing paliperidone intermediate
  • Process for synthesizing paliperidone intermediate

Examples

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Embodiment 1

[0027] In a 1L four-necked reaction flask equipped with a stirring device, a thermometer and a reflux water separation device, sequentially add 66g of compound 1, 650mL of xylene, 84.5g of compound 2 and 3.4g of methanesulfonic acid, heat to reflux for 8 hours, and stop After heating, the temperature of the system was reduced to 110-120°C, and filtered while it was still hot, and the filtrate was allowed to stand overnight at room temperature, and then filtered to obtain a solid, which was vacuum-dried (10mmHg) at 40°C for 10 hours to obtain 99g of compound 3. 1 H-NMR (500MHz, CDCl 3 ): δ 2.04(s, 3H), 2.42(t, 2H, J=6.1Hz), 3.13(t, 2H, J=6.1Hz), 5.61(t, 1H, J=7.2Hz), 5.68(d, 1H , J=7.3Hz), 6.78 (d, 1H, J=7.0Hz), yield 75%;

[0028] In a 1L four-necked reaction flask equipped with a stirring device, a thermometer, a gas conduit and a reflux device, 75g of compound 3 and 750mL of methanol were sequentially added, and 10g of 5% rhodium carbon was added under nitrogen replacement ...

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Abstract

The invention relates to a method for synthesizing an important intermediate of paliperidone. The method relates to the intermediate of 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydrochysene-9-oxhydryl-2-methyl-4H-pyridino-(1, 2-a)pyrimidine-4-kektone, and comprises: step one, in a solvent, catalytically cyclizing 2-amido-3-oxhydryl-pyridine and alpha-acetyl-gamma-butyrolactone by acid to obtain a compound 3; step two, in the solvent, catalytically hydrogenating a pyridine ring of the compound 3 by a transitional metal catalyst to obtain a compound 4; and step three, in the solvent, selectively chlorinating primary alcohol of the compound 4 by a chlorination reagent to obtain the intermediate of the paliperidone 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydrochysene-9-oxhydryl-2-methyl-4H-pyridino-(1, 2-a)pyrimidine-4-kektone. The method has the characteristics of high selectivity and easy operation; a product and the intermediate can be easily separated and purified; and a compound 1 and a compound 2 can be cyclized completely.

Description

technical field [0001] The invention belongs to the technical field of preparation of raw material drug chemical products, in particular to a method for synthesizing an important intermediate of paliperidone. Background technique [0002] Paliperidone is a new drug for the treatment of schizophrenia approved by the U.S. Food and Drug Administration (FDA) on December 20, 2006. Its chemical synthesis is formed by the docking of two important intermediates. One of them is: 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido(1,2-a)pyrimidine-4- ketone. [0003] The existing literature of this intermediate, such as US5158952, is divided into three steps: first, 2-amino-3-hydroxyl-pyridine is protected by 3-hydroxyl under the action of benzyl chloride, and then combined with α-acetyl-γ-butyrol The ester forms a pyridine ring under the action of POCl3, and the pyridine ring is hydrogenated to the target product while hydrogenation deprotection is carried out. [00...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 高红云李文翘张芳江
Owner SHANGHAI RECORD PHARM CO LTD
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