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Synthetic method of telaprevir intermediate

A synthetic method and technology of telaprevir are applied in the field of drug synthesis, and can solve problems such as unfavorable large-scale industrial production, potential safety hazards, long reaction steps, etc., to avoid chiral racemization phenomenon, suitable for large-scale industrial production, Simple to use effects

Inactive Publication Date: 2015-01-21
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although this synthesis method avoids the use of reagents such as cyclopropyl isonitrile, the reaction steps are long, requiring ten steps of reaction to obtain the final product, and the production cycle is long, resulting in high production costs, and the highly toxic cyanide is used in the synthesis method , there are potential safety hazards, which is not conducive to large-scale industrial production

Method used

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  • Synthetic method of telaprevir intermediate
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  • Synthetic method of telaprevir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0039]Add 100mL of formic acid to the three-necked reaction flask, add 10.5g of sodium percarbonate, 20g of ethyl butyryl acetate, and 1.3g of iodobenzene in sequence at 15-20°C. After the addition, continue to keep the internal temperature at 15-20°C for 2 hours. The complete conversion of the raw material was monitored by gas chromatography, the solvent formic acid was removed by concentration, and the residue was distilled under reduced pressure to obtain 19 g of intermediate B with a yield of 86.3%.

[0040] Make 13.75g of ammonium formate and 19g of intermediate B into a 100mL solution, adjust the pH of the solution to 8 with ammonia water, then add 0.3g of nicotinamide adenine dinucleotide (NAD) and 0.07g of dithiothreitol to obtain a mixed solution , adding the mixed solution into a 100mL solution containing 0.5g Pichia pastoris extract to form a reaction solution, the cell extract contains phenylalanine dehydrogenase and formate dehydrogenase by measuring; the reaction ...

Embodiment 2

[0043] Add 200mL of formic acid to the three-necked reaction flask, add 10.3g of sodium perborate, 39g of ethyl butyroacetate, and 2.2g of iodobenzene at 15-20°C. The complete conversion of raw materials was monitored by chromatography, the solvent formic acid was removed by concentration, and the residue was distilled under reduced pressure to obtain 27.3 g of intermediate B with a yield of 63.5%.

[0044] Make 19.8g of ammonium formate and 27.3g of intermediate B into a 150mL solution, adjust the pH of the solution to 8 with ammonia water, then add 0.44g of nicotinamide adenine dinucleotide (NAD) and 0.1g of dithiothreitol to obtain a mixture solution, the mixed solution was added into a 150mL solution containing 1.0g Pichia pastoris extract to form a reaction solution, and the cell extract contained phenylalanine dehydrogenase and formate dehydrogenase by measuring; Keep the temperature of the reaction solution at 35-40°C, stir at a speed of 80rpm, maintain the pH of the re...

Embodiment 3

[0047] Add 15mL of acetonitrile, 15mL of hydrogen peroxide, and 7g of sodium carbonate to the three-necked reaction flask in sequence. After stirring for 0.5 hours, continue to add 100mL of formic acid, 20g of ethyl butyryl acetate, and 1.3g of iodobenzene. After 2.5 hours, the complete conversion of the raw material was monitored by gas chromatography, the solvent formic acid was removed by concentration, and the residue was distilled under reduced pressure to obtain 8.5 g of intermediate B with a yield of 38.6%.

[0048] Prepare 6.15g of ammonium formate and 8.5g of intermediate B into a 50mL solution, adjust the pH of the solution to 8 with ammonia water, then add 0.13g of nicotinamide adenine dinucleotide (NAD) and 0.04g of dithiothreitol to obtain a mixture solution, the mixed solution was added into a 50mL solution containing 0.25g Pichia pastoris extract to form a reaction solution, and the cell extract contained phenylalanine dehydrogenase and formate dehydrogenase by m...

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Abstract

The invention relates to a synthetic method of a telaprevir intermediate (S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride, which belongs to the technical field of medicine synthesis. The synthetic method comprises the following steps: adding an oxidizing agent, a raw material ethyl butyrylacetate and a catalyst in formic acid in order, reacting at 15-20 DEG C to obtain an intermediate B; preparing ammonium formate and the intermediate B to obtain a solution, then adding the solution in nicotinamide adenine dinucleotide and dithiothreitol to obtain a mixed liquor, adding the mixed liquor in a solution of a pachia pastoris extract product, reacting under 35-40 DEG C and pH value of 8, adding di-tert-butyl dicarbonate ester, reacting at 0-5 DEG C to obtain an intermediate C; heating cyclopropylamine and the intermediate C to 65-75 DEG C and fully reacting, and processing to obtain the final products. A structural formula of the intermediate B and the intermediate C is shown as follows. The synthetic method has the advantages of low cost, environmental protection, simple operation, high product purity and high yield, and is suitable for large scale industrial production.

Description

technical field [0001] The invention relates to a synthesis method of a telaprevir intermediate, belonging to the technical field of drug synthesis. Background technique [0002] Telaprevir (telaprevir) is developed and marketed by Vertex Pharmaceutical Company. It is a new antiviral drug specific for hepatitis C. It is a reversible, selective, covalent, tight and slow binding of HCV NS3-4A protease Inhibitor, this protease is critical in viral replication. Telaprevir is approved for use in combination with pegylated interferon alfa and ribavirin for the treatment of patients who have not been treated with interferon-based anti-infective drugs, or who have not responded well to such treatments. The chemical name of telaprevir is (1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrainylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-(( cyclopropylamino)oxoacetyl)butyl)octahydrocyclopenta[c]pyrrole-1-carboxamide, CAS accession number: 402957-28-2, its chemical structural formula is: [0003] ...

Claims

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Application Information

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IPC IPC(8): C12P13/02
Inventor 李志强王伸勇王晓俊胡长春
Owner SUZHOU UUGENE BIOPHARMA
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