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Preparing method for medicament midbody for treating cystic fibrosis

An intermediate and nitration reaction technology, applied in the preparation of nitro compounds, organic chemistry, etc., can solve the problems of difficult removal, complex nitration reaction products, large solvent and silica gel consumption in column chromatography, etc.

Inactive Publication Date: 2013-04-17
CHINA PHARM UNIV +1
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (2) The nitration reaction product of V is complex, and only a mixture of VI-1 and VI-2 can be obtained after one column chromatography separation, which needs to be hydrolyzed to remove the methoxyacetyl group, and then another column chromatography can be obtained A single nitrated product VII-1 is then reduced to obtain intermediate VIII. Not only is the post-treatment cumbersome, but also the yield is low. Column chromatography consumes a large amount of solvent and silica gel, which is harmful to the environment.
[0013] (3) The condensing agent HBTU used in the preparation of II from intermediate VIII and 4-oxo-1,4-dihydroquinoline-3-carboxylic acid is expensive, difficult to remove after reaction, long reaction time, and cumbersome post-treatment , need to repeat the same procedure 5 times, the yield is only 52%

Method used

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  • Preparing method for medicament midbody for treating cystic fibrosis
  • Preparing method for medicament midbody for treating cystic fibrosis
  • Preparing method for medicament midbody for treating cystic fibrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 2,4-di-tert-butylphenyl ethyl carbonate (III, R=CH 2 CH 3 )Synthesis

[0040] Add compound IV (50g, 242.3mmol) and 600ml ethyl acetate into a 1L three-necked flask, stir and dissolve at room temperature, add triethylamine (55ml, 394.6mmol) after dissolution, cool to 0°C in an ice bath, and add dropwise Ethyl chloroformate (50ml, 525.2mmol), after adding, return to room temperature and react for 2~4h, filter with suction, wash the filtrate with water and saturated sodium chloride solution successively, separate the organic layer, anhydrous NaSO 4 After drying, filtering, and concentrating, 66.7 g of crude 2,4-di-tert-butylphenyl ethyl carbonate was obtained, with a yield of 98.9%, in the form of light yellow oil.

[0041] 1 H-NMR (300MHz, CDCL 3 ), δ(ppm): 7.38 (1H, d, J=2.3Hz, ArH), 7.24 (1H, dd, J 1 =8.5Hz,J 2 =2.4Hz, ArH), 7.0 (1H, d, J=8.4Hz, ArH), 4.32 (2H, q, J=7.1Hz, CH 2 ), 1.41 (9H, s, CH 3 ), 1.36 (3H, t, J=7.1Hz, CH 3 ), 1.29 (9H, s, CH 3 ).

[004...

Embodiment 2

[0046] 2,4-Di-tert-butyl-5-amino-phenylcarbonate ethyl ester (IX, R=CH 2 CH 3 )Synthesis

[0047]Put compound I (20g, 61.8mmol) into a 500ml single-necked bottle, add 250ml of anhydrous methanol, stir to dissolve, add 2g of 10% Pd / C, and react at room temperature for 2 to 4 hours in a hydrogen atmosphere, then remove palladium carbon by suction filtration, Concentrate the filtrate to remove methanol until solids appear in the bottle, stop the concentration, refrigerate overnight in the refrigerator, filter with suction, wash the filter cake with a small amount of methanol to obtain bright gray crystals, and repeat the above operation for the mother liquor to obtain 10.3 g of bright gray crystals, with a yield of 56.8%. m.p.142-144°C.

[0048] 1 H-NMR (300MHz, CDCL 3 ), δ(ppm): 7.20 (1H, s, ArH), 6.38 (1H, s, ArH), 4.32 (2H, q, J=7.1Hz, CH 2 ), 1.52 (3H, t, J=7.1Hz, CH 3 ), 1.42 (9H, s, CH 3 ), 1.35 (9H, s, CH 3 ). Carbonic acid 2,4-di-tert-butyl-5-(1,4-dihydro-4-oxoq...

Embodiment 3

[0055] Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ethyl ester (I, R=CH 2 CH 3 )Synthesis

[0056] Add compound III (20g, 71.8mmol) and 70ml of dichloromethane into a 250ml three-necked flask, cool in an ice bath to 0-5°C, add concentrated sulfuric acid (16ml) dropwise under stirring, dropwise for about 0.5 hours, then drop Add concentrated nitric acid (8ml), drop it, stir and react at 0-5°C for 0.5 hours, pour the reaction solution into 250ml of ice water, separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, and successively water, Wash with saturated NaCl solution, anhydrous NaSO 4 Dry and concentrate to obtain a yellow oil, add 5ml of petroleum ether, stir for 1 minute, refrigerate and crystallize overnight, a large number of light yellow crystals precipitate, filter with suction, wash the filter cake with petroleum ether until it is nearly white, after the mother liquor is concentrated, add 2.5ml of petroleum ether ...

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Abstract

The invention relates to the field of pharmaceutical synthesis, and in particular relates to a preparation method for a medicament Ivacaftor for treating cystic fibrosis. The method is characterized by comprising the following steps of: protecting phenolic hydroxyl by using alkoxycarbonyl by using 2,4-ditertiary butyl phenol as an initial raw material; nitrifying and reducing phenolic hydroxyl; condensing the phenolic hydroxyl with 4-oxo-1,4-dihydroquinolines-3-formyl chloride to obtain carbonic acid (2,4-ditertiary butyl-5-(1,4-dihydro-4-oxoquinoline-3-formamide) phenylester ethyl ester; and finally removing alkoxycarbonyl under an alkali condition to obtain the Ivacaftor. The method can be used for overcoming multiple defects of the existing synthetic method, is simple and easily available in raw materials, convenient to experimentally operate and postprocess, high in yiled, good in product quality and suitable for scale production.

Description

technical field [0001] The invention relates to the field of drug synthesis. In particular, it relates to a preparation method of an intermediate of Ivacaftor, a drug for treating cystic fibrosis. Background technique [0002] The chemical name of Ivacaftor is N-[2,4-di-tert-butyl-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, which was developed by Vertex Corporation of the United States. It was approved for marketing by the US Food and Drug Administration (FDA) on January 31, 2012. The drug is used to treat a rare form of cystic fibrosis (CF) caused by the G551D mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is suitable for patients aged 6 years and above. The structural formula of Ivacaftor is as follows: [0003] [0004] Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester ethyl ester (I) is an important intermediate for the synthesis of II, and its structural formula is as follows: [0005] [0006] wherein R ...

Claims

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Application Information

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IPC IPC(8): C07C205/43C07C201/08C07D215/56
Inventor 徐云根王均伟何广卫陆静
Owner CHINA PHARM UNIV
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