A kind of asymmetric synthetic method of optically pure (r)/(s)-chloroquine

A synthetic method and asymmetric technology, which is applied in the field of asymmetric synthesis of optically pure /-chloroquine, can solve the problems of low total yield and long synthetic route, and achieve the effects of short synthetic route, moderate solubility and moderate reducing ability

Active Publication Date: 2017-12-22
大连润生康泰医学检验实验室有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods all use chiral amino acids (or derivatives thereof) as raw materials, have long synthetic routes and low overall yields.

Method used

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  • A kind of asymmetric synthetic method of optically pure (r)/(s)-chloroquine
  • A kind of asymmetric synthetic method of optically pure (r)/(s)-chloroquine

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Add 200mL tetrahydrofuran (solvent), 2.64g (0.12mol) lithium borohydride (reducing agent) and 4.18g (0.012mol) (+)-binaphthol phosphate to a 500mL three-necked flask equipped with a constant pressure funnel and a reflux condenser Esters (chiral reagents), stirred at room temperature for 10 min to obtain a mixed solution, and added 17.8 g (0.1 mol) of 4-amino-7-chloroquinoline, 15.7 g (0.12 mol) of 5-diethylamino-2 - Pentanone and 100 mL of tetrahydrofuran, and slowly drop into the mixed solution from a constant pressure funnel (about 30 min), continue to react at room temperature for 1 h after the drop is completed, and then raise the temperature to 50 ° C and keep the temperature for the reaction. The reaction was detected by TLC. After the reaction was completed (this example required 16 h), it was naturally cooled to room temperature, and 400 mL of saturated saline was added to the reaction system, and then extracted with ethyl acetate, 150 mL each time, 3 times. The...

Embodiment 2

[0029] Reaction process and product treatment are similar to embodiment 1, difference is: solvent, reducing agent and chiral reagent are respectively: 250mL toluene (use 150mL in the three-necked flask, use 100mL in the constant pressure funnel), 11.83g (0.15mol) Potassium cyanoborohydride and 3.5 g (0.015 mol) of (D)-camphorsulfonic acid. 4-Amino-7-chloroquinoline and 5-diethylamino-2-pentanone were slowly dripped into the mixture of reducing agent and chiral reagent from the constant pressure funnel, and then continued to react at room temperature for 2 hours. The holding time is 24h.

[0030] The product is (+)-(S)-chloroquine 14.2g, and the yield is 44%; enantioselectivity is analyzed by chiral HPLC, ee%=81%, [α] 20.5 D =+83.6° (c=1.02, EtOH).

Embodiment 3

[0032] Reaction process and product treatment are similar to embodiment 1, and difference is: solvent, reducing agent and chiral reagent are respectively: 280mL dichloromethane (use 150mL in the three-necked flask, use 130mL in the constant pressure funnel), 42.4g (0.2 mol) sodium triacetoxyborohydride and 2.69 g (0.02 mol) (D)-malic acid. 4-Amino-7-chloroquinoline and 5-diethylamino-2-pentanone are slowly dropped into the mixture of reducing agent and chiral reagent from the constant pressure funnel, and then continue to react at room temperature for 1.5h, and the temperature of the heat preservation reaction is 60°C , holding time 18h.

[0033]The product is (+)-(S)-chloroquine 12.9g, yield rate is 40%; Enantioselectivity is analyzed by chiral HPLC, ee%=77%, [α] 20.5 D =+80.2° (c=1.01, EtOH).

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Abstract

The invention discloses an asymmetric synthesis method of optically pure (R) / (S)-chloroquine. 4-amino-7-chloroquinoline and 5-diethylin-2-pentanone are taken as starting raw materials and are subjected to an asymmetric reductive ammoniation reaction under the catalysis of chiral acid, optically pure chloroquine is obtained, and the spatial configuration of a product is controlled through spatial configuration of the chiral acid. The method adopts simple steps, the raw materials are easy to obtain, the yield is higher, the stereoselectivity is good, the chiral construction cost is relatively lower, the operation is simple, and the method is environment-friendly and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the fields of drug synthesis and organic synthesis, and relates to an asymmetric synthesis method of optically pure (R) / (S)-chloroquine. Background technique [0002] Chloroquine (Chloroquine) began to be used clinically in 1944. It was initially used to treat acute malaria or control malaria symptoms, and its use was gradually expanded later. In 1951, it was used to treat chloroquine rheumatoid arthritis, and it also had a certain effect; with the promotion of clinical application, it can also be used to treat hepatic amoebiasis, clonorchiasis, paragonimiasis, and connective tissue diseases. In addition, it can be used to treat photosensitivity diseases, such as sun erythema and so on. [0003] Recent studies have shown that chloroquine is effective in preventing cancer cell proliferation, slowing tumor growth, and normalizing cancer cell blood vessels, and is very promising to be developed into a new type of anticancer drug....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 陈福欣侯彬彬张少利侯春友龚频
Owner 大连润生康泰医学检验实验室有限公司
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