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Preparation method and application of antituberculous drug Pretomanid

An anti-tuberculosis and drug technology, applied in the field of drug synthesis, can solve the problems of low yield, difficult removal, increased trouble, etc., and achieve the effects of high chemical and optical purity, clear impurity spectrum, and easy availability of raw materials

Pending Publication Date: 2021-11-30
SHENYANG HONGQI PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the disadvantage of the two routes is that a large amount of silicon-based protective agent and tetrabutylammonium fluoride are used in the reaction. The two are more expensive and difficult to remove, which adds a lot of trouble to post-processing and is not conducive to large-scale production.
In 2016, Yao Ming and others used organic acids instead of silane protecting groups to protect hydroxyl groups, reducing raw material costs and simplifying post-processing schemes. However, the direct use of epoxy and imidazole will produce about 20% isomers, which is not conducive to product purification and impurity control.
In 2019, Zhai Xin et al introduced S-1-(tert-butyldimethylsilyloxy)-3-(2-bromo-4-nitro-1H-imidazol-1-yl)propan-2-ol Pretomanid is prepared as a key intermediate, but the key intermediate is selectively prepared with the same active dihydroxyl group, and the yield is low, and another part is further reacted and completely converted into impurities

Method used

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  • Preparation method and application of antituberculous drug Pretomanid
  • Preparation method and application of antituberculous drug Pretomanid
  • Preparation method and application of antituberculous drug Pretomanid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation method of anti-tuberculosis drug Pretomanid comprises the steps:

[0037] Step 1: Preparation of 2,5-dibromo-4-nitro-1-(vinylmethyl)imidazole (compound 3)

[0038] 2,5-dibromo-4-nitroimidazole (compound 1) (351 g, 1.3 mol), 3-bromopropene (compound 2) (238.4 g, 1.97 mol) and potassium carbonate solid (539 g, 3.9 mol) were added In N,N-dimethylformamide (2500mL), react at 50°C for 4h under the protection of nitrogen. After the reaction was completed, the temperature was lowered with an ice bath, and the reaction product was added into aqueous sodium bicarbonate solution (2000 mL), and extracted with ethyl acetate (4×2000 mL). The extract was washed with deionized water (2000 mL), concentrated under reduced pressure, and dried to obtain a pale yellow waxy solid 2,5-dibromo-4-nitro-1-(vinylmethyl)imidazole (compound 3), 370.8 g, yield 92%.

[0039] Step 2: Preparation of 2-bromo-4-nitro-1-(vinylmethyl)imidazole (compound 4)

[0040] Na 2 SO 3 (228g, 1...

Embodiment 2

[0052] The preparation method of anti-tuberculosis drug Pretomanid comprises the steps:

[0053] Step 1: Preparation of 2,5-dibromo-4-nitro-1-(vinylmethyl)imidazole (compound 3)

[0054] 2,5-dibromo-4-nitroimidazole (compound 1) (351g, 1.3mol), 3-bromopropene (compound 2) (238.4g, 1.97mol) and sodium hydroxide solid (152g, 3.9mol) Add it into dimethyl sulfoxide (2500 mL), and react at 40° C. for 4 h under the protection of nitrogen. After the reaction was completed, the temperature was lowered with an ice bath, and the reaction product was added into aqueous sodium bicarbonate solution (2000 mL), and extracted with ethyl acetate (4×2000 mL). The extract was washed with deionized water (2000mL), concentrated under reduced pressure, and dried to obtain 2,5-dibromo-4-nitro-1-(vinylmethyl)imidazole (compound 3), a light yellow waxy solid, 363g , yield 90.1%.

[0055] Step 2: Preparation of 2-bromo-4-nitro-1-(vinylmethyl)imidazole (compound 4)

[0056] Na 2 S 2 o 3 (284.6g, ...

Embodiment 3

[0066] The preparation method of anti-tuberculosis drug Pretomanid comprises the steps:

[0067] Step 1: Preparation of 2,5-dibromo-4-nitro-1-(vinylmethyl)imidazole (compound 3)

[0068] 2,5-dibromo-4-nitroimidazole (compound 1) (351g, 1.3mol), 3-bromopropene (compound 2) (238.4g, 1.97mol) and 4-dimethylaminopyridine (476.5g, 3.9mol) was added to isopropyl acetate (2500mL), and reacted at 70°C for 4h under nitrogen protection. After the reaction was completed, the temperature was lowered with an ice bath, and the reaction product was added into aqueous sodium bicarbonate solution (2000 mL), and extracted with ethyl acetate (4×2000 mL). The extract was washed with deionized water (2000 mL), concentrated under reduced pressure, and dried to obtain a pale yellow waxy solid 2,5-dibromo-4-nitro-1-(vinylmethyl)imidazole (compound 3), 366.7 g, yield 91%.

[0069] Step 2: Preparation of 2-bromo-4-nitro-1-(vinylmethyl)imidazole (compound 4)

[0070] Na 2 S 2 o 5 (342g, 1.8mol) s...

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Abstract

The invention relates to a preparation method of an antituberculous drug Pretomanid and an application of the antituberculous drug Pretomanid. According to the preparation method, 2, 5-dibromo-4-nitroimidazole is taken as an initial raw material, and a nucleophilic substitution reaction, a reduction elimination reaction, an oxidation cyclization reaction, an epoxy ring-opening reaction, a nucleophilic substitution reaction, a deprotection reaction and a cyclization reaction are sequentially carried out to prepare the target product, namely the antituberculous drug Pretomanid. The raw materials used in the whole process are cheap and easy to obtain, explosive dinitroimidazole is prevented from being used, generation of 4-nitro isomers is avoided, and the method is simple in process operation, easy to control and convenient to purify and can be used for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of an anti-tuberculosis drug Pretomanid, more specifically to a preparation method by introducing R-2-bromo-4-nitro-1-(epoxy-2-ylmethyl ) The preparation method of Pretomanid with imidazole as key intermediate. Background technique [0002] Pretomanid, the chemical name is S-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1, 3] Oxazine, light yellow crystalline powder, molecular formula: C 14 h 12 N 3 o 5 f 3 , Molecular weight: 359.26. Pretomanid is a nitroimidazole pyran compound. The drug mainly inhibits Mycobacterium tuberculosis through the dual mechanism of inhibiting bacterial protein synthesis and cell wall mycolic acid synthesis. It is effective against both sensitive and drug-resistant Mycobacterium tuberculosis. In 2002, the Global Tuberculosis Alliance (TB Alliance) took it as the latest anti-tuberculosis drug research,...

Claims

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Application Information

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IPC IPC(8): C07D498/04
CPCC07D498/04Y02P20/55
Inventor 卢鑫杨波蒙娅杨学娟徐琳琳王猛杨旺
Owner SHENYANG HONGQI PHARMA
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