Process for the preparation of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid and alkyl esters and acid salts thereof
AssigneeViroBay, Inc.
InventorsBarry Hart, Jeff Dener, Michael Green, Michael Standen, Oldrich Kocian
Life of this patent
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Abstract
The present invention relates to a process for the preparation of alkyl esters of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid, which are intermediates useful in the synthesis of (S)—N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino)pentanamide and related compounds, which are compounds that are cysteine protease inhibitors.
Claims11
A process for the preparation of a (S)-alkyl 2-amino-5-cyclopropyl-4,4-difluoropentanoate hydrochloride of Formula 1:
- or salt thereof, where R1 is a primary or secondary alkyl having 1 to 5 carbon atoms, which process comprises:
- (a) selectively hydrolyzing a compound of Formula 2:
- where PG is an amino protecting group and R2 is alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, wherein any alkyl group comprising R2 is a primary or secondary alkyl having 1 to 5 carbon atoms, to give a mixture of protected (R)-2-amino-5-cyclopropyl-4,4-difluoropentanoate and protected (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid;
- (b) isolating the protected (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid;
- (c) deprotecting the protected (S)-2-(amino)-5-cyclopropyl-4,4-difluoropentanoic acid to give (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid;
- (d) treating the (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid with alcohol R1OH;
- (e) optionally converting the free base of the compound of Formula I to the acid addition salt.
A process for the preparation of a compound of Formula 2:
- where PG is an amino protecting group and R2 is alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, wherein any alkyl group comprising R2 is a primary or secondary alkyl having 1 to 5 carbon atoms, which process comprises:
- (a) condensing 3-cyclopropyl-2,2-difluoropropyl perfluoroalkane-1-sulfonate of Formula 4:
- where n is 0, 1, 2, 3 or 4, with a 2-(diphenylmethyleneamino)acetate anion of Formula 3:
- where R2 is alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, wherein any alkyl group comprising R2 is a primary or secondary at having 1 to 5 carbon atoms, to give the corresponding (R,S)-2-(diphenylmethyleneamino)-5-cyclopropyl-4,4-difluoropentanoate;
- (b) hydrolyzing the (R,S)-2-(diphenylmethyleneamino)-5-cyclopropyl-4,4-difluoropentanoate with acid to give the corresponding (R,S)-2-amino-5-cyclopropyl-4,4-difluoropentanoate;
- (c) optionally treating the (R,S)-2-amino-5-cyclopropyl-4,4-difluoropentanoate with acid to give the corresponding (R,S)-2-amino-5-cyclopropyl-4,4-difluoropentanoate acid addition salt;
- and
- (d) treating the (R,S)-2-amino-5-cyclopropyl-4,4-difluoropentanoate or salt thereof with an amino protecting agent.
A process for the preparation of the 3-cyclopropyl-2,2-difluoropropyl perfluoroalkane-1-sulfonate of Formula 4:
- where n is 0, 1, 2, 3 or 4, which process comprises:
- (a) reducing an alkyl 3-cyclopropyl-2,2-difluoropropanoate of Formula 5:
- where R3 is hydrogen or alkyl having 1 to 5 carbon atoms, to give 3-cyclopropyl-2,2-difluoropropan-1-ol and
- (b) reacting the 3-cyclopropyl-2,2-difluoropropan-1-ol with a perfluoroalkyl sulfonyl halide or a perfluoroalkyl sulfonic anhydride having the formula CF3(CF2)nSO2X or (CF3(CF2)nSO2)2O, respectively, where n is 0, 1, 2, 3 or 4 and X is chloro or fluoro.
A compound of Formula 4:
- where n is 1, 2 or 3.
A process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises reacting ethyl 2,2-difluoropent-4-enoate with diiodomethane in the presence of trifluoroacetic acid and diethylzinc or a zinc/copper couple.
A process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises reacting the ethyl 3-cyclopropyl-2-oxopropanoate with a fluorinating agent.
Dependencies are inferred from the claim text.