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Preparation methods for chiral impurities of vincamine

A technique for vincamine and chiral isomers, which is applied in the field of preparation of chiral impurities in vincamine, can solve the problems such as no seven preparation methods of chiral impurities reported in the literature, and achieves simple preparation steps and post-processing, and mild reaction conditions. , the effect of simple operation

Active Publication Date: 2019-02-26
北京康派森医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The seven chiral isomer impurities of vincamine have been clearly reported in the existing literature, but there is no specific preparation method for the seven chiral impurities reported in the prior art

Method used

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  • Preparation methods for chiral impurities of vincamine
  • Preparation methods for chiral impurities of vincamine
  • Preparation methods for chiral impurities of vincamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080]

[0081] 1.1, (4aR,15bR)-4a-ethyl-4a,5,6,7,10,15-hexahydro-2H,9H-indolo[2,3-a]pyrano[3,2- i] quinozine-3,3(4H)-dicarboxylate and (4aS,15bS)-4a-ethyl-4a,5,6,7,10,15-hexahydro-2H,9H-indolo Preparation of [2,3-a]pyrano[3,2-i]quinazine-3,3(4H)-dicarboxylate (CCT064-A-106(1)&CCT064-A-107)

[0082] Add CCT064-A-105 (216g, 0.476mol, 1.0eq), ethanol (2.16L), dichloromethane (DCM) (110mL) into a 3L three-necked flask, heat the oil bath to 30°C and add L-dibenzoyl Tartaric acid hydrate (178.8g, 0.473mol, 1.0eq) was added and stirred for about 1h. The reaction solution was filtered, the filter cake was rinsed with ethanol (300 mL), and dried at 40° C. to obtain CCT064-A-106 (236 g, 61%) as a yellow solid.

[0083] The collected filtrate was concentrated to dryness at 40°C under reduced pressure to obtain a yellow foamy solid (250g), which was added with dichloromethane (500mL), and 10% potassium carbonate aqueous solution (500mL) was stirred and separated, and the aqueous pha...

Embodiment 2

[0120]

[0121] 2.1, 2-(((1R,12bR)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinazine-1- Base) the preparation of methyl) diethyl malonate (CCT064-F-101)

[0122] Add CCT064-A-106(1) (55.2g, 0.12mol, 1.0eq), N,N dimethylformamide (DMF) (220mL, 4vol) into a 500mL three-necked flask, stir magnetically at room temperature, and wait until the reaction solution dissolves After clearing, add palladium carbon (5.5g, 0.1w / w) and replace with hydrogen three times. After about 4 hours of reaction, TLC (DCM / MeOH=20 / 1) shows that the raw material has reacted by 1 / 2. Filter the reaction solution and replace the palladium carbon , continue to react for about 5h, TLC raw material reaction is complete. The reaction solution was filtered to remove palladium carbon, and the filtrate was added with concentrated ammonia water (55 mL) and stirred for 1 h. Then add water (600mL) to the reaction solution, stir ethyl acetate (200mL) thoroughly, separate the liquids, extract the aqueous pha...

Embodiment 3

[0153]

[0154] 3.1, 2-(((1S,12bR)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinazine-1- Base) the preparation of methyl) diethyl malonate (CCT064-G-101)

[0155] Add CCT064-A-107 (20g, 0.044mol, 1.0eq), ethanol (300mL, 15vol) into a 1L three-neck flask, stir magnetically at room temperature, then add glacial acetic acid (10.8mL, 0.3vol) and stir for 10min, then add in batches Sodium borohydride (3.35g, 0.088mol, 2.0eq), stirred for 10min after addition, added concentrated ammonia water (8mL, 0.4vol), moved to an oil bath and heated to 50°C, reacted for about 1h, TLC (DCM / MeOH=20 / 1) shows that the raw material has reacted completely. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent to obtain 28.8 g of a yellow solid, which was added with dichloromethane (300 mL), and water (200 mL) was stirred and separated, and the aqueous phase was extracted three times with dichloromethane (200 mL×3), and combined ...

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Abstract

The invention relates to preparation methods for chiral impurities of vincamine. Through oriented synthesis method and the later column chromatography separation, high purity product of seven chiral impurities can be obtained, and the preparation methods can be used for the qualitative and quantitative analysis of impurities in the production of vincamine, so that the separation and confirmation of the seven chiral impurities in vincamine drugs can be realized, and the drug standard of the vincamine can be enhanced, and therefore, the vincamine with high purity can be obtained. Compared with existing preparation methods for the vincamine, the preparation methods relate to the preparation of seven chiral isomers, and are more complete and simpler in operation.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of vincamine chiral impurities. Background technique [0002] The chemical structural formula of vincamine is: [0003] [0004] Vincamine is a drug used for sequelae of stroke, ischemic hypertensive encephalopathy, cerebral arteriosclerosis, cerebral ischemia, and cerebral embolism; it is suitable for the elimination of symptoms of premature aging brain degeneration, such as dizziness, headache, and memory loss , inattention, aphasia, Meniere's syndrome, etc.; it can also be used for retinal hemorrhage, nervous tachycardia and other autonomic dysfunction. [0005] The quality control of drugs is mainly to control the content of active ingredients and related substances, especially the content of related substances needs to meet the requirements for medicinal use. Related substances can also be called impurities, which mainly come...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D461/00
CPCC07D461/00
Inventor 梁飞郑祖爽赵国伟张子娇张媛媛
Owner 北京康派森医药科技有限公司
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