Patent Watch

July 22, 2013

This improved hepatitis drug synthesis proceeds through some new intermediates. Inventor J. Dener describes a process for preparing compounds such as 11 that are intermediates in the synthesis of potential drugs for treating hepatitis C and related disorders. An alternative process for the preparation of these compounds uses cyclopropyl isonitrile, which is unstable on prolonged storage, has a highly unpleasant odor, and is therefore unsuitable for large-scale production. The process disclosed in this patent avoids this reagent. The preparation of 11 is outlined in Figure 1.

The first step is protection of the amine group in L-norvaline (1) with a benzyl group. The carboxylic acid group is esterified in the same reaction. Product 2 is isolated as a brown oil that is used without purification in the next step. Hydrolysis of benzyl ester 2 with NaOH gives acid 3, isolated as a white solid. The purity and yield are not reported.

Process for making key intermediate 11

Carboxylic acid 3 is treated with N-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3′-diaminopropyl)carbodiimide (EDCI), then HCl salt 4 and N-methylmorpholine (NMM). Product 5 is isolated as a syrupy oil; no yield or purity data are provided. Aldehyde 6 is prepared by treating 5 with LiAlH4. The reaction is monitored by TLC, and the product is recovered as a light yellow oil in 94% yield. It is used without purification in the next step.

Aldehyde 6 is converted to hydroxy nitrile 7 by treating it with NaHSO3, then NaCN. The reaction is monitored by TLC, and the crude product is isolated in 68.6% yield as a solid that consists of >99% of a single diastereomer. Acid hydrolysis of the hydroxy nitrile produces hydroxy acid 8, recovered as a solid in 96% yield. The reaction of 8 with cyclopropylamine (9) in the presence of HOBT and EDCI gives cyclopropylamide 10, isolated in pure form in 60% yield. The benzyl protecting groups in 10 are removed by hydrogenation over Pd(OH)2/C. Final product 11 is obtained in 92.2% isolated yield.

The inventor determined the absolute configuration of 11 by treating it with triphosgene to produce the corresponding oxazolidinone. He compared the 1H NMR data of the oxazolidinone with those of a similar compound reported in the literature.

Several of the steps of the synthesis are carried out on a kilogram scale. Analogues of 11 in which the n-propyl group is replaced by ethyl can be prepared by the same route, but experimental details are not provided.

The inventor discusses the utility of compound 11 for preparing hepatitis C inhibitor 17. Figure 2 outlines this synthesis, starting with the reaction of 11 with pyrrolidinecarboxylic acid 12 to form tert-butoxycarbonyl (Boc)–protected 13. The reaction is carried out by adding 2-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to a solution of 12 and i-Pr2NEt in DMF, then adding the HCl salt of 11. Product 13 is recovered in 67.6% yield with HPLC purity of 98.6 area%.

Process for making hepatitis C drug 17

The BOC protection in 13 is removed by treatment with HCl in MeOH to give HCl salt 14. This is recovered in 98% yield and 97.4 area% purity. The product is used without further purification in the next step, in which it is treated with urea derivative 15 in the presence of i-Pr2NEt in DMF. Product 16 is isolated in 71.6% yield and 99.2 area% purity.

In the final step, 16 is treated with the Dess–Martin periodinane (DMP) reagent to convert the hydroxyl group to carbonyl. Target compound 17 is isolated in 87.8% yield with 97.3 area% purity. The inventor gives 1H NMR data for many of the reported reaction products.

Even though the title of the patent is “Process for the preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivatives”, its only claim covers intermediates N-methoxyamide 5, nitrile 7, and acid 8: all newly reported compounds. The value of the reported process is that it may be suitable for large-scale production of a hepatitis C drug. (Virobay [Menlo Park, CA]. US Patent 8,431,733, April 30, 2013; Keith Turner)

View patent information from CAplus(SM) database.

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