Synthetic method of anti-tuberculosis candidate drug PA-824

A technology of PA-824 and synthesis method, which is applied in the direction of organic chemistry, can solve the problems of high price, achieve the effect of easy to obtain raw materials, avoid low temperature reaction, and simple operation

Inactive Publication Date: 2014-12-03
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

PA-824 was synthesized by Pathogenesis Company, and its synthesis route used silicon protect...

Method used

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  • Synthetic method of anti-tuberculosis candidate drug PA-824
  • Synthetic method of anti-tuberculosis candidate drug PA-824
  • Synthetic method of anti-tuberculosis candidate drug PA-824

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preparation example Construction

[0026] The synthetic method of nitroimidazole pyran class anti-tuberculosis drug candidate PA-824 comprises the following steps:

[0027]

[0028] (1) In concentrated H 2 SO 4 In, compound 1 was mixed with 4 times concentrated HNO 3 The reaction is nitroated to obtain compound 2;

[0029] (2) In acetic acid and acetic anhydride, compound 2 was reacted with fuming nitric acid for re-nitration to obtain compound 3;

[0030] (3) Compound 3 undergoes thermal rearrangement in chlorobenzene to obtain compound 4;

[0031] (4) Compound 4 and ( S )-(+)-glycidyl butyrate undergoes a nucleophilic ring-opening reaction to obtain compound 5;

[0032] (5) in CH 2 Cl 2 Among them, compound 5 and 3,4-dihydropyran protect the hydroxyl group under the action of catalyst PPTS to obtain compound 6;

[0033] (6) in CH 3 In OH, compound 6 is in an equimolar amount of K 2 CO 3 Under the action of ester hydrolysis and intramolecular nucleophilic ring closure reaction, compound 7 was obt...

Embodiment 1

[0045] compound 2 preparation of

[0046] Add 320 ml of concentrated H to a 2000 ml three-neck flask 2 SO 4 , slowly add 100 g of imidazole with stirring in an ice bath, continue to stir after the addition, and after the solution becomes clear, slowly add 240 ml of concentrated HNO 3 . After dripping, raise the temperature to 125 °C for reflux reaction for 10 h, stop the reaction, cool to room temperature, pour into about 10 times of crushed ice, a large amount of white solid precipitates, filter with suction, wash with cold water, and dry the filter cake to obtain the product 4 -Nitroimidazole 155g, the filtrate was adjusted to pH 3-4 with concentrated ammonia water, and the solid was precipitated, suction filtered, washed with cold water, and the filter cake was dried to obtain 13 g of the product 4-nitroimidazole, and a total of 178 g of the product was obtained. 85.04%. 1 H-NMR (400M, d6-DMSO): δ 7.85 (s, 1H), 8.32 (s, 1H).

[0047] compound 3 preparation of

[004...

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Abstract

The invention relates to a synthetic method of an anti-tuberculosis candidate drug PA-824. The method involves an eight-step reaction and comprises the following steps: firstly obtaining a key intermediate compound 8 and then reacting with 4-trifluoromethoxy benzyl bromide to obtain the final product PA-824. The entire reaction has the advantages of easily available raw materials, simplicity in operation, convenience in purification and easiness in scale production. The compound 8 is as shown in the specification.

Description

technical field [0001] The invention relates to a synthesis method of an anti-tuberculosis candidate drug PA-824, belonging to the field of medicinal chemistry. Background technique [0002] PA-824 is a nitroimidazole pyran compound, which is effective against sensitive and drug-resistant Mycobacterium tuberculosis, can kill Mycobacterium tuberculosis in the incubation period, and has no cross-resistance with first-line anti-tuberculosis drugs. In 2002, the Global Alliance Against Tuberculosis (TB Alliance) and the National Institute of Allergy and Infectious Diseases of the United States reached an agreement to use PA-824 as a new type of anti-tuberculosis drug research, and it has now entered phase II clinical trials. Star and pyrazinamide form a new compound preparation—PaMZ, which is currently in Phase II clinical trials. [0003] PA-824, light yellow crystalline powder, molecular formula: C 13 h 12 N 3 o 5 f 3 , Molecular weight: 359. PA-824 is synthesized by Pat...

Claims

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Application Information

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IPC IPC(8): C07D498/04
CPCC07D498/04
Inventor 刘雪英王力彬弥乐陈卫平
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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