Preparation method of naphthoquine phosphate

A technology of naphthoquine phosphate and phosphoric acid, which is applied in the field of medicine, can solve the problems of low reaction conversion rate, unfavorable production, large alloy consumption, etc., and achieves the effects of easy availability of raw materials, solving process safety problems, and less environmental pollution

Pending Publication Date: 2021-02-26
CHONGQING KANGLE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route uses aluminum-nickel alloy as the reducing agent, the amount of alloy is large, the reaction conversion rate is low, and the diazotization reaction is easy to cause safety accidents, which is not conducive to production

Method used

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  • Preparation method of naphthoquine phosphate
  • Preparation method of naphthoquine phosphate
  • Preparation method of naphthoquine phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Preparation of 4-amino-5,6,7,8-tetrahydro-1-naphthol formula IV

[0023] Add 54.6g of p-aminophenol to a 1L reaction flask, add 327.6g of dichloromethane and stir, cool to 0°C~5°C, add 20g of anhydrous aluminum chloride in batches, and slowly add 63.5g of 1,4-dichlorobutane dropwise After the dropwise addition, the temperature was raised to 25°C to 35°C to react, TLC followed the reaction progress, the reaction was complete, the reaction solution was poured into ice water, 50% sodium hydroxide aqueous solution was added, the pH was adjusted to 8-9, the layers were separated, and the organic layer was After washing with water for several times, the solvent was removed under reduced pressure to obtain 75.6 g of the product with a content of 89.5% and a yield of 82.9%.

Embodiment 2

[0024] Example 2 Preparation of 4-amino-5,6,7,8-tetrahydro-1-naphthol formula IV

[0025] Add 54.6g of p-aminophenol to a 1L reaction flask, add 327.6g of dichloromethane and stir, cool with ice water to 0°C-5°C, add 30g of anhydrous aluminum trichloride in batches, slowly add 108.0g of 1,4-dibromo After the addition of butane, the temperature was raised to 25°C to 35°C to react, TLC followed the reaction, and the reaction was complete. Pour the reaction solution into ice water, add 50% sodium hydroxide aqueous solution, adjust the pH to 8-9, and separate layers. The organic layer was washed several times with water, and the solvent was removed under reduced pressure to obtain 79.2 g of the product with a content of 87.5% and a yield of 84.9%.

Embodiment 3

[0026] Example 3 Preparation of 4-amino-5,6,7,8-tetrahydro-1-naphthol formula IV

[0027] Add 54.6g of p-aminophenol into a 1L reaction flask, add 382.2g of dichloromethane and stir, cool with ice water to 0°C-5°C, add 97.3g of anhydrous ferric chloride in batches, slowly add 63.5g of 1,4-dichloromethane Chlorobutane, after the dropwise addition, heat up to 25°C to 35°C to react, TLC to track the reaction progress, the reaction is complete, pour the reaction solution into ice water, add 50% sodium hydroxide aqueous solution, adjust the pH to 8-9, and separate layers , the organic layer was washed several times with water, and the solvent was removed under reduced pressure to obtain 65.9 g of the product with a content of 77.8% and a yield of 62.8%.

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Abstract

The invention discloses a preparation method of naphthoquine phosphate formula I. The preparation method is characterized by comprising the following steps: reacting p-aminophenol formula VI with 1, 4-disubstituted butane formula V to obtain 4-amino-5, 6, 7, 8-tetrahydro-1-naphthol formula IV, and reacting the formula IV with 4, 7-dichloroquinoline formula VII to obtain 4-(7-chloro-4-quinoline amino)-5, 6, 7, 8-tetrahydro-1-naphthol formula III, reacting the formula III with formaldehyde and tert-butylamine to obtain naphthoquine basic formula II, and salifying the naphthoquine basic formula II with phosphoric acid to obtain naphthoquine phosphate formula I; the process route has the advantages of simple and accessible raw materials, high yield and low pollution and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of naphthoquine phosphate. Background technique [0002] Naphthoquine Phosphate Formula I is a new class I antimalarial drug developed by the Chinese Academy of Military Medical Sciences. It belongs to the 4-aminoquinoline antimalarial drugs like chloroquine and amodiaquine. Naphthoquine Phosphate has high antimalarial activity. The effect is long-lasting, and the elimination half-life is as long as 255h or more. Naphthoquine phosphate has a short clinical course of treatment and good compliance. The compound drug "Compound Naphthoquine Phosphate Tablets" composed of it and artemisinin is currently the only compound antimalarial drug on the market in the world that can achieve the purpose of curing with a single dose. medicine. [0003] [0004] The preparation methods disclosed by CN1093356 and CN105085505 use 1-naphthol as a starting mater...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 魏常喜张莉杨忠鑫蔡中文张勇
Owner CHONGQING KANGLE PHARMA
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