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Polymorphic substances of E-type lumefantrine and preparation methods thereof

A technology of polymorphs and crystal forms, which is applied in the preparation of organic compounds, the preparation of aminohydroxyl compounds, chemical instruments and methods, etc., can solve the problems of long melting range, decreased yield of E formula, low melting point of products, etc.

Inactive Publication Date: 2013-09-18
SHANGHAI DESANO PHARMA INVESTMENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] According to the existing preparation method, benzfluorenol is produced in batches, and the product obtained has a low melting point, a long melting range, and low product purity.
Above-mentioned method also has many defectives, as reaction time is long, or reaction temperature raises and causes E formula productive rate to decline
At present, there is no literature report on any preparation of high-purity E-isomer

Method used

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  • Polymorphic substances of E-type lumefantrine and preparation methods thereof
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  • Polymorphic substances of E-type lumefantrine and preparation methods thereof

Examples

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preparation example Construction

[0079] 1. Crystal of (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]-9H-fluorene-4-methanol The preparation method of the polymorph of type I, comprises the steps:

[0080] (1) Provide (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]-9H dissolved in an inert solvent - a solution of fluorene-4-methanol, the (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]- The chemical purity of 9H-fluorene-4-methanol is ≥95%;

[0081] The solution is prepared by dissolving benzfluorenol containing E-type benzfluorenol in an inert solvent; preferably, the weight-volume ratio of benzfluorenol to the inert solvent is 1g:3~300ml; preferably 1g:3 ~30ml.

[0082] Wherein, the inert solvent is selected from the group consisting of ketone solvents, ester solvents, aromatic hydrocarbon solvents, ether solvents, or mixtures thereof;

[0083] The ketone solvent is selected from the group consisting of acetone, butanone,...

Embodiment 1

[0127] Example 1 Preparation of (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]-9H-fluorene-4-methanol (E isomer)

[0128] Under the protection of nitrogen, add NaOH (7.0g, 0.18mol), 200ml of absolute ethanol, and 40ml of toluene into the reaction flask, stir and dissolve at 25°C, add α-(di-n-butylaminomethyl)-2,7- Dichloro-4-fluorenylmethanol (20.0 g, 0.049 mol) was added to p-chlorobenzaldehyde (8.0 g, 0.057 mol) g, and the reaction was kept under nitrogen atmosphere and stirred at 25°C for 3 hours. After the reaction was complete as detected by TLC, 1N hydrochloric acid ethanol solution was added to adjust the pH of the reaction solution to 7. The reaction mixture was concentrated to dryness under reduced pressure. The concentrate was heated to 65° C. with 200 ml of toluene and stirred to dissolve, the organic phase was washed with water until the pH value of the aqueous phase was 6.5, the organic phase was separated, and concentrated to drynes...

Embodiment 2

[0134] Example 2 Preparation of (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]-9H-fluorene-4-methanol Form I

[0135] 5.0g (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]-9H-fluorene-4-methanol, 20ml of ethyl acetate was added into the reaction flask, stirred and dissolved at room temperature under nitrogen atmosphere. Cool down to 0°C for crystallization. After filtering, the filter cake was dried to dryness under reduced pressure at 50° C. to obtain 3.2 g of needle crystals.

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Abstract

The invention relates to polymorphic substances of E-type lumefantrine and preparation methods thereof. Specifically, the invention discloses two polymorphic substances of (9E)-2,7-dichloro-9-[(4-chlorophenyl) methylene)-alpha-[(di-n-butylamino) methyl]-9H-fluorene-4- methanol, namely, a polymorphic substance with a crystal form I and a polymorphic substance with a crystal form II. Furthermore, the invention also discloses preparation methods of the two polymorphic substances and usage of the polymorphic substances in preparation of antimalarial medicaments.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to (9E)-2,7-dichloro-9-[(4-chlorophenyl)methylene]-α-[(di-n-butylamino)methyl]-9H - Polymorphs of fluorene-4-methanol and processes for their preparation. Background technique [0002] Benefantrine (also known as lumefantrine) was developed by the Institute of Microbiology and Epidemiology of the Academy of Military Medical Sciences in the 1970s for the treatment of falciparum malaria. The compound preparation made of it and artemether is effective in treating severe malaria, concurrent malaria and falciparum malaria, including cerebral malaria. [0003] The chemical name of benzfluorenol is α-(di-n-butylaminomethyl)-2,7-dichloro-9H-9-(p-chlorophenylmethylene)-4-fluorenylmethanol, and its structural formula is as formula (I) Shown: [0004] [0005] Benfluorenol has two isomers of E formula and Z formula, and the chemical name of the Z formula isomer is (9Z)-2,7-di...

Claims

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Application Information

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IPC IPC(8): C07C215/38C07C213/10A61K31/137A61P33/06
CPCY02A50/30
Inventor 李金亮赵楠王锰
Owner SHANGHAI DESANO PHARMA INVESTMENT
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