Preparation method of chiral aminochloroquinoline

A technology of aminochloroquinoline and dichloroquinoline, applied in the field of medicine, can solve problems such as few chloroquine synthesis methods, and achieve the effect of high yield

Pending Publication Date: 2020-11-10
珠海润都制药股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The chemical synthesis method research of chloroquine is earlier, and route is mature, but only be limited to the synthetic method of racemate, and the synthetic method about (R) or (S)-chloroquine is less

Method used

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  • Preparation method of chiral aminochloroquinoline
  • Preparation method of chiral aminochloroquinoline
  • Preparation method of chiral aminochloroquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The reaction formula is as follows:

[0033] 1. Resolution of 2-amino-5-diethylaminopentane:

[0034]

[0035] 2. Enantiomer synthesis:

[0036]

[0037] 1. Resolution of 2-amino-5-diethylaminopentane:

[0038] a. 80g of 2-amino-5-diethylaminopentane, 0.51mol, add 40ml of isopropanol, heat to dissolve, add 41g of D-mandelic acid, 0.27mol, stir for 6 hours, filter with suction, keep the filtrate for use, and collect off-white solid . Vacuum drying at 60-65°C yielded 67g of L-mandelic acid salt;

[0039] b. Add 41 g of L-mandelic acid (0.27 mol) to the filtrate of the previous step, stir at room temperature for 10 hours, filter, and collect an off-white solid. Vacuum drying at 60-65°C yielded 62 g of D-mandelic acid salt.

[0040] 2. Preparation of enantiomeric salts:

[0041] a. 67g of the L-mandelate prepared in the above 1(a), add 150g of purified water, add 20% sodium hydroxide to neutralize to PH = 11, add 500g of dichloromethane, stir for 30min, separate...

Embodiment 2

[0045] 1. Resolution of 2-amino-5-diethylaminopentane:

[0046]a. 80g of 2-amino-5-diethylaminopentane, 0.51mol, add 45ml of isopropanol, heat to dissolve, add 43g of D-mandelic acid, 0.28mol, stir for 7 hours, filter with suction, keep the filtrate for use, and collect off-white solid . Vacuum drying at 60-65°C yielded 68.3 g of L-mandelic acid salt;

[0047] b. Add 43g of L-mandelic acid (0.28mol) to the filtrate of the previous step, stir at room temperature for 10 hours, filter, and collect an off-white solid. Vacuum drying at 60-65°C yielded 63.4 g of D-mandelic acid salt;

[0048] 2. Preparation of enantiomeric salts:

[0049] a. Add 68.3g of L-mandelate prepared in the above 1(a), add 155g of purified water, add 25% sodium hydroxide to neutralize to PH=11, add 550g of dichloromethane, stir for 30min, separate layers, concentrate under reduced pressure for two Chloromethane, to get the side chain left-handed free base.

[0050] b. Add 43.6 g (0.22 mol) of 4,7-dichlo...

Embodiment 3

[0053] 1. Resolution of 2-amino-5-diethylaminopentane:

[0054] a. 80g 2-amino-5-diethylaminopentane 0.51mol), add 40ml isopropanol, heat to dissolve, add 60g D-camphorsulfonic acid, 0.27mol, stir for 6 hours, filter with suction, keep the filtrate for use, collect off-white solid. Vacuum drying at 60-65°C to obtain 85g of levocamphorsulfonate;

[0055] b. Add 60 g of L-camphorsulfonic acid (0.26 mol) to the filtrate of the previous step, stir at room temperature for 10 hours, filter, and collect an off-white solid. Vacuum drying at 60-65°C to obtain 80g of D-camphorsulfonate;

[0056] 2. Preparation of enantiomeric salts:

[0057] a. Add 85 g of the levocamphorsulfonate prepared in the above 1 (a), add 180 g of purified water, add 20% sodium hydroxide to neutralize to PH=11, add 500 g of dichloromethane, stir for 30 min, separate layers, and concentrate under reduced pressure. Chloromethane, to get the side chain left-handed free base.

[0058] b. Add 42 g (0.21 mol) of ...

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Abstract

The invention discloses a preparation method of chiral aminochloroquinoline, which comprises the following steps: splitting a chiral side chain, preparing enantiomer salt, splitting the side chain andchiral acid crystals to obtain chiral acid salt, neutralizing the chiral acid salt to obtain free basic groups, and reacting the free basic groups with 4, 7-dichloroquinoline to obtain chiral aminochloroquinoline. The yield of the chiral aminochloroquinoline obtained by the method is high, and the purity reaches 99.7%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of chiral aminochloroquinoline. Background technique [0002] Aminochloroquine structural formula is as follows: [0003] any of the. [0004] Chloroquine is an antimalarial drug that has been on the market for many years. In 1820, two French pharmacologists extracted the earliest antimalarial drug in history—quinine through cinchona bark. In 1934, German scientists modified the structure of quinine. Synthesized a quinine substitute—chloroquine with simplified structure and significant single-drug effect. [0005] The emergence of chloroquine has replaced quinine as a routine drug for preventing malaria and anti-rheumatic diseases. Chloroquine was originally used for malaria. In continuous research and development, it has benefits in skin diseases, immunology, rheumatism and severe infectious diseases. . Later, scholars discovered that if a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46
CPCC07D215/46C07B2200/07
Inventor 董雪林邹永莫泽艺张骞中刘杰蒋毅覃志俊胡双龙蔡强兰柳琴
Owner 珠海润都制药股份有限公司
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