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Intermediate for preparing bedaquiline and its preparation method and application

A bedaquiline and intermediate technology, which is applied in the field of preparation of intermediates for the treatment of multidrug-resistant tuberculosis drug bedaquiline, can solve the problems of low yield, incomplete conversion of raw materials, and poor purity of bedaquiline racemates. Advanced problems, to achieve the effect of high purity, great positive progress effect and practical application value, stable and controllable quality

Active Publication Date: 2017-08-08
CHINA NAT MEDICINES GUORUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are two reasons for the low yield. One is that the α-position hydrogen of the carbonyl in compound 6 is removed under the reaction conditions, and the generated carbanion attacks the carbonyl, and various side reactions between molecules occur, resulting in very complicated reaction products; The second is due to the enolization of compound 6 (shown below), resulting in incomplete conversion of the starting material
In addition, the purity of the resulting bedaquiline racemate is not high, which seriously affects the efficiency of its resolution

Method used

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  • Intermediate for preparing bedaquiline and its preparation method and application
  • Intermediate for preparing bedaquiline and its preparation method and application
  • Intermediate for preparing bedaquiline and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)

[0037] 1-Naphthyl ethyl ketone (170.0g, 1.0mol) was added to DMF-DMA (178.0g, 1.5mol) at room temperature, heated to 120°C, after 24h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, dilute the residue with 200ml of toluene, and evaporate to dryness under reduced pressure at 55°C to obtain 230.1g of a yellow oil, with a crude yield of 102% and a purity of 98.5% by HPLC, which can be directly used in the next reaction .

[0038] 1 H-NMR (CDCl 3 )δ: 2.93-3.14 (m, 6H); 5.73 (d, 1H, J = 12.4Hz); 7.38-7.49 (m, 2H); 7.82 (d, 1H, J = 12.4Hz); 7.78 (m, 1H ),8.14-3.18(m,2H),8.29(d,2H,J=8.4Hz),9.45(d,2H,J=8.8Hz).ESI-MS(m / z)=226.2[M+H] +

Embodiment 2

[0040] Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)

[0041] 1-Naphthylethanone (150.0g, 0.88mol) was added to DMF-DMA (57.5g, 1.5mol) at room temperature, heated to 90°C, after 24h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, add 200ml of toluene to the residue to dilute, and evaporate to dryness under reduced pressure at 55°C to obtain 202.5g of yellow oil, crude yield 102%, HPLC purity 98.8%. ESI-MS(m / z)=226.2[M+H] +

Embodiment 3

[0043]Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)

[0044] 1-Naphthyl ethyl ketone (250.0g, 1.47mol) was added to DMF-DMA (262.5g, 2.20mol) at room temperature, heated to 90°C, after 48h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, add 200ml of toluene to the residue to dilute, and evaporate to dryness under reduced pressure at 55°C to obtain 334.2g of yellow oil with a crude yield of 101% and an HPLC purity of 98.2%. ESI-MS(m / z)=226.2[M+H] +

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Abstract

The invention discloses an intermediate for preparing bedaquiline and a preparation method therefor. The intermediate disclosed by the invention has the advantages that the intermediate avoids hydrogenation and enolization of an alpha-site in the intermediate, reduces occurrence of side reactions, and increases the conversion rate of raw materials and the total yield of reaction, and is suitable for large-scale industrial production. The intermediate for preparing bedaquiline is characterized by being a compound with a structural formula (9) or an optical isomer thereof: FORMULA is shown in the description.

Description

technical field [0001] The invention relates to an intermediate used for preparing bedaquiline, a drug for treating multidrug-resistant tuberculosis, and a preparation method and application thereof. Background technique [0002] Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis, which can affect multiple organ systems throughout the body. According to the statistics of the World Health Organization, about 1 / 3 of the world's population is infected with Mycobacterium tuberculosis every year and about 3,800 people die of tuberculosis every day [Curr Opin Immunol, 2011,23(4):464-472.]. Tuberculosis has become one of the major diseases that seriously threaten human health in the 21st century. [0003] The main reason for the worldwide spread of tuberculosis is the strong viability of Mycobacterium tuberculosis. In fact, Mycobacterium tuberculosis, as one of the most threatening pathogens, has evolved a series of mechanisms to counteract the host...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 李建其刘育邴绍昌周爱南吴夏冰黄雷金仁力王健蒋敏王磊
Owner CHINA NAT MEDICINES GUORUI PHARMA
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