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Etravirine preparing method and intermediate of etravirine

A technology for etravirine and compounds, applied in the field of drug synthesis, can solve the problems of inability to large-scale production, low yield of etravirine, many by-products of intermediates, etc., and achieves high yield, high reaction selectivity, Simple to use effects

Active Publication Date: 2012-09-19
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems of the existing etravirine, such as low yield, long steps, many intermediate by-products, and inability to produce on a large scale.

Method used

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  • Etravirine preparing method and intermediate of etravirine
  • Etravirine preparing method and intermediate of etravirine
  • Etravirine preparing method and intermediate of etravirine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Synthesis of Compound XIV

[0028]

[0029] Compound II (392g, 2.0mol, 1.0eq.), Compound XIII (452g, 4.0mmol, 2.0eq.) and potassium tert-butoxide (673g, 6.0mmol, 3.0eq.) were added to n-butanol (12L) and heated To reflux, reaction 8h. After complete reaction of the raw material, after cooling and concentration, add 1L of water, extract with EA (ethyl acetate) (1.5L×3), wash the organic phase with brine, dry over anhydrous sodium sulfate, and concentrate to obtain compound XIV as a white solid 393.1 g, yield: 86.5%. 1 HNMR (DMSO-d6, 400MHz): δ (ppm) 4.92 (s, 1H), 6.38 (brs, 2H), 7.67 (d, 2H, J = 8.8Hz), 7.92 (d, 2H, J = 8.8Hz) , 9.29 (b r, 1H), 10.22 (br, 1H); MS (m / z): 228.1.

[0030] Synthesis of Compound XV

[0031]

[0032] Compound XIV (50g, 220mmol) was added to POCl 3 (600mL), heated to 80°C for 12h. After the raw material has reacted, it is cooled and distilled under reduced pressure, and the residue is slowly poured into cold K in batches. 2 CO 3 I...

Embodiment 2

[0040] Synthesis of Compound XIV

[0041]

[0042]Compound II (39.2g, 0.2mol, 1.0eq.), Compound XIII (45.2g, 0.4mmol, 2.0eq.) and sodium ethoxide (54.4g, 0.8mmol, 4.0eq.) in ethanol (1 L) were heated to Reflux, reaction 8h. The raw materials were completely reacted, cooled, concentrated, added to 100mL of water, extracted with EA (ethyl acetate) (150mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 36.5g of compound XIV as a white solid , Yield: 80.5%. 1 HNMR (DMSO-d6, 400MHz): δ (ppm) 4.92 (s, 1H), 6.38 (brs, 2H), 7.67 (d, 2H, J = 8.8Hz), 7.92 (d, 2H, J = 8.8Hz) , 9.29 (br, 1H), 10.22 (br, 1H); MS (m / z): 228.1.

[0043] Synthesis of Compound XV

[0044]

[0045] Compound XIV (50g, 220mmol) was added to POCl 3 (600mL), heated to 120°C for 12h. After the raw material has reacted, it is cooled and distilled under reduced pressure, and the residue is slowly poured into cold K in batches. 2 CO 3 In the aqu...

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Abstract

The invention relates to the field of synthesis of medicines and intermediates, in particular to an etravirine (TMC125) preparing method and an intermediate of etravirine. The etravirine preparing method is characterized by comprising the following steps of: performing a cyclization reaction on a compound II and a compound III under the alkalic condition; performing a chlorination reaction and a bromination reaction to obtain an intermediate XVI; and performing a substitution reaction on the intermediate XVI and an intermediate VII to obtain the etravirine. The preparation method is high in reaction selectivity, easy to operate and high in yield, has the total yield which can reach 53.8 percent, and is suitable for large-scale preparation.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method of etravirine and an intermediate thereof. Background technique [0002] Etravirine, also known as TMC125, belongs to the type 1 human immunodeficiency virus (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI), which can directly bind to HIV-1 reverse transcriptase, by destroying the catalytic site of the enzyme And block the RNA-dependent and DNA-dependent DNA polymerase activity, thereby blocking the replication of HIV-1, and play the role of anti-HIV virus. NNRTI combination therapy has been used to treat HIV for more than 10 years, but its clinical application is limited by cross-resistance in this class of drugs, and resistance to one NNRTI usually means resistance to all NNRTIs. Etravirine has opened up a new world of NNRTI drug treatment and provided a new antiviral weapon for thousands of NNRTI-resistant HIV-infected patients. Etravirine can b...

Claims

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Application Information

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IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor 杨民民周西朋吴希罕
Owner PHARMABLOCK SCIENCES (NANJING) INC