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Chiral inducer for synthesizing (1R,2S)-Bedaquiline

A technology of chiral induction and bedaquiline, applied in organic chemistry, organic chemical methods, etc., can solve the problem of low yield of bedaquiline and achieve the effect of increasing yield

Inactive Publication Date: 2017-06-20
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above various synthetic methods have their own shortcomings. In the original research patent, the total yield of the mixture of 4 optical isomers is also close to 40%, but after resolution (1 R ,2 S )-bedaquiline yields are still low

Method used

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  • Chiral inducer for synthesizing (1R,2S)-Bedaquiline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Under nitrogen protection, add THF 45ml and N-benzyl-L-prolinol 15.4g (80.5mmol, 1.10eq) into a dry 500mL four-necked glass reaction flask, and place the reaction flask in a cold trap (- 72~ -78℃), then add 2.5M n-butyllithium n-hexane solution 32ml (80.5mmol), then add 2.0M LDA (mixed solvent of heptane-ethylbenzene-tetrahydrofuran) 44.0ml (88.0mmol), THF 21 ml. Dissolve 24.0 g (73.2 mmol, 1.0 eq) of 6-bromo-3-benzyl-2-methoxyquinoline in THF 30 ml, slowly drop it into the above-mentioned four-necked bottle, and complete the dropwise addition within 70 min , keep the internal temperature at -72~-78°C during the feeding process, and continue stirring for 3 h after the addition. In the following 160 min, slowly add dropwise a solution of 17.4 g (76.9 mmol) of 3-N,N-dimethylamino-1-naphthyl-1-propanone and 50 ml of THF, and keep the internal temperature during the dropwise addition -72~-78°C, after adding, continue to react for 3h. The HPLC test results of the reaction...

Embodiment 2

[0037] Under nitrogen protection, add THF 67ml and N-benzyl-L-prolinol 22.4g (117mmol, 1.50eq) into a dry 500mL four-necked glass reaction flask, and place the reaction flask in a cold trap (-72 ~ -78°C), then add 46.5ml (117mmol) of 2.5M n-butyllithium n-hexane solution, other steps and material consumption are the same as in Example 1, the obtained reaction material HPLC detection result: enantiomer A / A' =81:19; diastereomer (A+A') / (B+B') = 5:1.

Embodiment 3

[0039] Under nitrogen protection, add THF 90ml and N-benzyl-L-prolinol 30.8g (161mmol, 2.0eq) into a dry 500mL four-necked glass reaction flask, and place the reaction flask in a cold trap (-72 ~ -78°C), and then add 64ml (161mmol) of 2.5M n-butyllithium n-hexane solution, other steps and material consumption are the same as in Example 1, and the obtained reaction material HPLC detection result: enantiomer A / A'=82 :18; diastereomer (A+A') / (B+B') = 5.1:1.

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Abstract

The invention relates to a chiral inducer for synthesizing (1R,2S)-Bedaquiline. Di(isopropyl)lithium ammonium takes off benzyl-bit protons from 6-bromo-3-benzyl-2-methoxy quinoline at a low temperature in the presence of the chiral inducer, i.e., lithium N-benzyl-L-prolinol and then is subjected to addition with 3-dimethylamino-1-naphthyl-1-acetone. Chiral o-amino lithium alkoxide remarkably increases the proportion of a target enantiomer, i.e., (1R,2S)-Bedaquiline and can be used for further preparing a drug, i.e., (1R,2S)-Bedaquiline fumarate.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to synthesis (1 R ,2 S )-chiral inducer of bedaquiline. [0002] technical background [0003] Multi-drug-resistant tuberculosis (MDR-TB) is a bacterial disease that is resistant to isoniazid and rifampicin, as well as any fluoroquinolones and any second-line injectable anti-TB drugs (A mikacin, kanamycin, or capreomycin) have drug-resistant TB. To treat these forms of TB, standard 6-month first-line anti-TB drugs do not work and may require up to two years or more of treatment, which are less effective and more toxic than a course of standard TB drugs. The cost is around $20, while MDR-TB drugs can cost as much as $5,000 or more. Globally, 50% of patients treated are cured. The survey found that 100% of patients who failed MDR-TB therapy died within 3 years, and there is an urgent need for drugs with better efficacy. [0004] In December 2012, the U.S. FDA...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/227
CPCC07B2200/09C07D215/227
Inventor 赵学清黄杨威郑治尧林燕琴陈忠
Owner FUJIAN INST OF MICROBIOLOGY
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