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US 2013/0172276 A1Published application
Processes and intermediates
AssigneeVertex Pharmaceuticals Incorporated
InventorsGERALD J. TANOURY, MINZHANG CHEN, JOHN E. COCHRAN, ADAM LOOKER, VALDAS JURKAUSKAS
Life of this patent
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Abstract
The invention relates to compounds and processes useful for the preparation of protease inhibitors, particularly serine protease inhibitors. The protease inhibitors are useful for treatment of HCV infections.
Claims46
A process for preparing a racemic mixture of cis- and trans-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of Formula 7
- comprising the step of carboxylation of an azabicyclooctane of Formula 6,
- wherein R′ is C1-5 alkyl.
A process for preparing a compound of Formula 4
- comprising the steps of:
- i) providing an N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane;
- ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane in the presence of a chelating agent;
- iii) treating the anion of step with carbon dioxide to produce a cis-/trans- mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids;
- iv) treating the mixture of step iii) with a strong base to produce an essentially pure trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid;
- v) forming a salt with an optically active amine;
- vi) crystallizing the salt;
- vii) esterifying the acid provided in step vi);
- viii) removing the N-alkoxycarbonyl group to produce (1S,3aR,6aS)-t-butyl-octahydrocyclopenta[c]pyrrole-1-carboxylate, t-butyl ester;
- ix) reacting the bicyclic aminoester of step viii) with a protected amino acid of Formula 26,
- wherein Z is an amine protecting group, in the presence of a coupling reagent, to produce an amide-ester of Formula 27;
- x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of Formula 28;
- xi) reacting the amino compound of Formula 28 with a protected amino acid of Formula 29
- in the presence of a coupling reagent to produce a tripeptide of Formula 30;
- xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31;
- xiii) reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33;
- xiv) hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34;
- xv) reacting the amide-tripeptide acid of Formula 34 with an aminohydroxy-amide of Formula 18
- in the presence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 35;
- and
- xvi) oxidizing the hydroxy group of Formula 35 to produce the compound of Formula 4.
18 more elements
A process of purifying the compound of Formula 4, comprising:
- i) dissolving the compound of Formula 4 in an organic solvent to obtain a solution of the compound of Formula 4,
- ii) adding an acid to the solution of the compound of Formula 4, and
- iii) concentrating the solution of the compound of Formula 4 to obtain the compound in a solid form.
A process of preparing a compound of Formula 8
- comprising carboxylating an azabicyclooctane of Formula 6
- to give a racemic mixture of cis and trans octahydrocyclopenta[c]pyrrol-1-carboxylic acids of Formula 7
- and
- equilibrating a trans-/cis- mixture of the compounds of Formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of Formula 8, wherein the trans-/cis- ratio in the compound of Formula 8 is greater than 80 to 20 and R′ is C1-5 alkyl.
1 more element
A process of preparing a (1S,2S,3R) trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid comprising carboxylating an azabicyclooctane of Formula 6
- to give a racemic mixture of cis and trans octahydrocyclopenta[c]pyrrol-1-carboxylic acids of Formula 7
- equilibrating a trans-/cis- mixture of the compounds of Formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of Formula 8
- wherein the trans/cis- ratio in the compound of Formula 8 is greater than 80 to 20;
- and resolving the racemic trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid mixture, wherein R′ is C1-5 alkyl.
1 more element
A process preparing a compound of Formula 1 comprising carboxylating an azabicyclooctane of Formula 6
- to give a racemic mixture of cis and trans octahydrocyclopenta[c]pyrrol-1-carboxylic acids of Formula 7
- equilibrating a trans-/cis- mixture of the compounds of Formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of Formula 8
- wherein the trans-/cis- ratio in the compound of Formula 8 is greater than 80 to 20;
- forming a salt with an optically active base;
- crystallizing the salt formed by the previous step to provide an optically active salt of Formula 9
- esterifying the carboxylic acid of Formula 9 with a compound containing the R3 group;
- and removing the —COOR′ protecting group to produce a compound of Formula 1
- wherein R′ is C1-5 alkyl and R3 is an optionally substituted alkyl or aralkyl.
5 more elements
A process for preparing a compound of Formula 4
- comprising the steps of:
- i) providing an N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane;
- ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane in the presence of a chelating agent;
- iii) treating the anion of step with carbon dioxide to produce a cis-/trans- mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids;
- iv) treating the mixture of step iii) with a strong base to produce an essentially pure trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid;
- v) forming a salt with an optically active amine;
- vi) crystallizing the salt;
- vii) esterifying the acid provided in step vi);
- viii) removing the N-alkoxycarbonyl group to produce (1S,3aR,6aS)-t-butyl-octahydrocyclopenta[c]pyrrole-1-carboxylate, t-butyl ester;
- ix) reacting the bicyclic aminoester of step viii) with a protected amino acid of Formula 26,
- wherein Z is an amine protecting group, in the presence of a coupling reagent, to produce an amide-ester of Formula 27;
- x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of Formula 28;
- xi) reacting the amino compound of Formula 28 with a protected amino acid of Formula 29
- in the presence of a coupling reagent to produce a tripeptide of Formula 30;
- xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31;
- xiii) reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33;
- xiv) hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34;
- xv) reacting the amide-tripeptide acid of Formula 34 with an aminohydroxy-amide of Formula 43
- in the presence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 36;
- and
- xvi) oxidizing the hydroxy group of Formula 36 to produce the compound of Formula 4.
18 more elements
A process for preparing a compound of Formula 4
- comprising the steps of:
- i) providing an N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane;
- ii) forming a 2-anion of the N-alkoxycarbonyl-3-azabicyclo[3.3.0]octane in the presence of a chelating agent;
- iii) treating the anion of step ii) with carbon dioxide to produce a cis-/trans- mixture of N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids;
- iv) treating the mixture of step with a strong base to produce an essentially pure trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid;
- v) forming a salt with an optically active amine;
- vi) crystallizing the salt,
- vii) esterifying the acid provided in step vi);
- viii) removing the N-alkoxycarbonyl group to produce (1S,3aR,6aS)-t-butyl-octahydrocyclopenta[c]pyrrole-1-carboxylate, t-butyl ester;
- ix) reacting the bicyclic aminoester of step viii) with a protected amino acid of Formula 26,
- wherein Z is an amine protecting group, in the presence of a coupling reagent, to produce an amide-ester of Formula 27;
- x) removing the protecting group Z from the amide-ester of step ix) to produce the amino compound of Formula 28;
- xi) reacting the amino compound of Formula 28 with a protected amino acid of Formula 29
- in the presence of a coupling reagent to produce a tripeptide of Formula 30;
- xii) removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31;
- xiii) reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33;
- xiv) hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34;
- xv) reacting the amide-tripeptide acid of Formula 34 with an aminohydroxy-amide of Formula 44
- in the presence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 45;
- and
- xvi) oxidizing the hydroxy group of Formula 45 to produce the compound of Formula 4.
18 more elements
Dependencies are inferred from the claim text.