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Synthetic method of antimalarial drug primaquine phosphate intermediate n-(4-bromopentyl)phthalimide

A technology of phthalimide and primaquine phosphate, which is applied in a new synthetic field, can solve the problems that recrystallization and purification cannot be used, and achieve high conversion rate, low cost and high content Effect

Active Publication Date: 2019-04-05
仪征市海帆化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it cannot be purified by distillation
On the other hand, the N-(4-bromopentyl)phthalimide produced by this synthetic route contains a lot of impurities, and its melting point is lower than minus 20°C, so it cannot be purified by recrystallization

Method used

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  • Synthetic method of antimalarial drug primaquine phosphate intermediate n-(4-bromopentyl)phthalimide
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  • Synthetic method of antimalarial drug primaquine phosphate intermediate n-(4-bromopentyl)phthalimide

Examples

Experimental program
Comparison scheme
Effect test

example 1-1

[0047] In a 1000ml four-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer, 50g (0.48mol) 5-chloro-1-pentene, 50g (0.27mol) phthalimide potassium salt, 2.5g triphenylmethylphosphine chloride, 0.5g cobalt acetate and 300g N,N-dimethylformamide. After the addition, the oil bath was heated to reflux at a temperature of 152° C. and kept for 8 hours.

[0048] After keeping warm, cool to room temperature. Filtration, the filter cake is the reaction by-product potassium chloride, polymerization inhibitor and catalyst. Rinse the filter cake with 100ml of fresh DMF, and combine the filtrate and washings. DMF and excess 5-chloro-1-pentene were evaporated under reduced pressure with a rotary evaporator. 54.5 g of light yellow viscous liquid was obtained, the content measured by liquid chromatography was 98.25%, and the yield was 93.79%.

example 1-2

[0050] In a 1000ml four-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer, 50g (0.48mol) 5-chloro-1-pentene, 50g (0.27mol) phthalimide potassium salt, 0.25g of triphenylmethylphosphine bromide, 2.5g of nickel sulfate and 500g of hexamethylphosphonic triamide. After the addition, the oil bath was heated to 200° C., and the reaction was kept for 3 hours.

[0051] After keeping warm, cool to room temperature. Filtration, the filter cake is the reaction by-product potassium chloride, polymerization inhibitor and catalyst. Rinse the filter cake with 100ml of fresh acetone, and combine the filtrate and washings. Acetone, hexamethylphosphonic triamide and excess 5-chloro-1-pentene were evaporated under reduced pressure with a rotary evaporator. 57g of red viscous liquid was obtained, the content measured by liquid chromatography was 94.81%, and the yield was 98.09%.

example 1-3

[0053] In a 2000ml four-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer, 200g (1.91mol) of 5-chloro-1-pentene, 200g (1.08mol) of phthalimide potassium salt, 5g of triphenylethylphosphine chloride, 4g of nickel sulfate, 4g of cobalt acetate and 800g of hexamethylphosphonic triamide. After the addition, the oil bath was heated to 100° C., and the reaction was kept for 8 hours.

[0054] After the heat preservation is finished, follow the post-treatment operation of Example 1-2 to obtain 224 g of light yellow viscous liquid, the content of which is 99.46% as measured by liquid chromatography, and the yield is 96.37%.

[0055] ②, the synthesis of N-(4-bromopentyl)phthalimide

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Abstract

The invention provides a synthesis method of an antimalarial drug primaquine phosphate intermediate N-(4-bromopentyl)phthalimide. N-(4-bromopentyl)phthalimide is an important intermediate of an antimalarial drug primaquine phosphate. The method comprises the following steps: carrying out a condensation reaction on 5-chloro-1-pentene and phthalimide potassium salt, and carrying out an addition reaction on a condensation product 5-(o-phthalimido)-1-pentene and hydrogen bromide to obtain the final product. The method has the advantages of low cost of raw materials, high conversion rate, high purity of the final product, mild conditions of every reaction, and simple and easily controlled reaction process.

Description

technical field [0001] The invention proposes a new synthesis method of the intermediate N-(4-bromopentyl)phthalimide of the antimalarial drug primaquine phosphate. Background technique [0002] Primaquine phosphate belongs to 8-aminoquinoline derivatives, and its antimalarial effect may be related to interference with DNA synthesis of Plasmodium. It can inhibit the oxidation of mitochondria and reduce the oxygen uptake of malaria parasites. The metabolite quinoline quinone derivatives of primaquine phosphate in the body has strong oxidative properties, which can convert reduced glutathione in red blood cells into oxidized glutathione, and interfere with pyridine nucleoside triphosphate in the infrared stage of Plasmodium The reduction process of acid affects the energy metabolism and respiration of Plasmodium and leads to death. It is mainly used to eradicate vivax malaria and control the spread of malaria, often in combination with chloroquine or pyrimethamine. The effi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 邹从伟
Owner 仪征市海帆化工有限公司
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