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US 11,390,628 B2Granted
Preparation of buprenorphine
AssigneeRiver Stone Biotech, LLC
InventorsPatrick Roussel, Jimmy Van Wiltenburg, Marco Santella
Life of this patent
Estimating the term…
Abstract
Disclosed are methods for preparing buprenorphine from, for example, compounds such as nororipavine and northebaine.
Claims17
A method of preparing buprenorphine, or a salt thereof, (1) from Compound HO-I-H, or a salt thereof:
- comprising:
- (i)(A1) reacting Compound HO-I-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (i)(A2) reacting Compound HO-I-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (i)(A3) reacting Compound HO-I-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide Compound HO-I-MCP:
- (ii)(B) reacting Compound HO-I-MCP with methyl vinyl ketone to provide Compound HO-II-MCP:
- and either:
- (iii)(C) reacting Compound HO-II-MCP with H2 in the presence of a hydrogenation catalyst to provide Compound HO-IIIB-MCP:
- (iv)(D) reacting Compound HO-IIIB-MCP with tert-butylmagnesium halide to provide buprenorphine;
- or
- (iii)(D) reacting Compound HO-II-MCP with tert-butylmagnesium halide to provide Compound HO-IIIA-MCP:
- (iv)(C) reacting Compound HO-IIIA-MCP with H2 in the presence of a hydrogenation catalyst to provide buprenorphine;
- or
- (2) from Compound BnO-I-H, or a salt thereof:
- comprising:
- (i)(A1) reacting Compound BnO-I-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (i)(A2) reacting Compound BnO-I-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (i)(A3) reacting Compound BnO-I-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide Compound BnO-I-MCP:
- (ii)(B) reacting Compound BnO-I-MCP with methyl vinyl ketone to provide Compound BnO-II-MCP:
- (iii)(D) reacting Compound BnO-II-MCP with tert-butylmagnesium halide to provide Compound BnO-IIIA-MCP:
- (iv)(C) reacting Compound BnO-IIIA-MCP with H2 in the presence of a hydrogenation catalyst to provide buprenorphine;
- or
- (3) from Compound MeO-I-H, or a salt thereof:
- comprising:
- (i)(A1) reacting Compound MeO-I-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (i)(A2) reacting Compound MeO-I-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (i)(A3) reacting Compound MeO-I-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide Compound MeO-I-MCP:
- (ii)(B) reacting Compound MeO-I-MCP with methyl vinyl ketone to provide Compound MeO-II-MCP:
- and either:
- (iii)(C) reacting Compound MeO-II-MCP with H2 in the presence of a hydrogenation catalyst to provide Compound MeO-IIIB-MCP:
- (iv)(D) reacting Compound MeO-IIIB-MCP with tert-butylmagnesium halide to provide Compound MeO-IV-MCP:
- (v)(E) reacting a compound of Compound MeO-IV-MCP with a demethylating agent to provide buprenorphine;
- or
- (iii)(D) reacting Compound MeO-II-MCP with tert-butylmagnesium halide to provide Compound MeO-IIIA-MCP:
- (iv)(C) reacting Compound MeO-IIIA-MCP with H2 in the presence of a hydrogenation catalyst to provide a compound of Compound MeO-IV-MCP:
- (v)(E) reacting a compound of Compound MeO-IV-MCP with a demethylating agent to provide buprenorphine;
- or
- (iii)(D) reacting Compound MeO-II-MCP with tert-butylmagnesium halide to provide Compound MeO-IIIA-MCP:
- (iv)(E) reacting Compound MeO-IIIA-MCP with a demethylating agent to provide Compound HO-IIIA-MCP:
- (v)(C) reacting Compound HO-IIIA-MCP with H2 in the presence of a hydrogenation catalyst to provide buprenorphine;
- or
- (4) from Compound HO-I-H, or a salt thereof:
- comprising:
- (i)(A1) reacting Compound HO-I-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (i)(A2) reacting Compound HO-I-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (i)(A3) reacting Compound HO-I-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide Compound HO-I-MCP:
- and either:
- (ii)(B) reacting Compound HO-I-MCP with methyl vinyl ketone to provide Compound HO-II-MCP:
- (iii)(F) reacting Compound HO-II-MCP with benzyl halide, benzyl sulfonate, or activated benzyl alcohol to provide Compound BnO-II-MCP:
- (iv)(D) reacting Compound BnO-II-MCP with tert-butylmagnesium halide to provide Compound BnO-IIIA-MCP:
- (v)(C) reacting Compound BnO-IIIA-MCP with H2 in the presence of a hydrogenation catalyst to provide buprenorphine;
- or
- (ii)(F) reacting Compound HO-I-MCP with benzyl halide, benzyl sulfonate, or activated benzyl alcohol to provide Compound BnO-I-MCP:
- (iii)(B) reacting Compound BnO-I-MCP with methyl vinyl ketone to provide Compound BnO-II-MCP:
- (iv)(D) reacting Compound BnO-II-MCP with tert-butylmagnesium halide to provide Compound BnO-IIIA-MCP:
- (v)(C) reacting Compound BnO-IIIA-MCP with H2 in the presence of a hydrogenation catalyst to provide buprenorphine;
- or
- (5) from Compound HO-I-H, or a salt thereof:
- comprising:
- (i)(F) reacting Compound HO-I-H with benzyl halide, benzyl sulfonate, or activated benzyl alcohol to provide Compound BnO-I-Bn:
- (ii)(B) reacting Compound BnO-I-Bn with methyl vinyl ketone to provide Compound BnO-II-Bn:
- (iii)(D) reacting Compound BnO-II-Bn with tert-butylmagnesium halide to provide Compound BnO-IIIA-Bn:
- (iv)(C) reacting Compound BnO-IIIA-Bn with H2 in the presence of a hydrogenation catalyst to provide a compound of Compound HO-IV-H:
- (v)(A1) reacting Compound HO-IV-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (v)(A2) reacting Compound HO-IV-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (v)(A3) reacting Compound HO-IV-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide buprenorphine;
- or
- (6) from Compound HO-I-H, or a salt thereof:
- comprising:
- (i)(G) reacting Compound HO-I-H with optionally substituted benzoyl halide to provide Compound HO-I-Bz:
- (ii)(F) reacting Compound HO-I-Bz with benzyl halide, benzyl sulfonate, or activated benzyl alcohol to provide Compound BnO-I-Bz:
- (iii)(H) reacting Compound BnO-I-Bz with lithium aluminum hydride to provide Compound BnO-I-Bn:
- (iv)(B) reacting Compound BnO-I-Bn with methyl vinyl ketone to provide Compound BnO-II-Bn:
- (v)(D) reacting Compound BnO-II-Bn with tert-butylmagnesium halide to provide Compound BnO-IIIA-Bn:
- (vi)(C) reacting Compound BnO-IIIA-Bn with H2 in the presence of a hydrogenation catalyst to provide a compound of Compound HO-IV-H:
- (vii)(A1) reacting Compound HO-IV-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (vii)(A2) reacting Compound HO-IV-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (vii)(A3) reacting Compound HO-IV-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide buprenorphine;
- or
- (7) from Compound HO-I-H, or a salt thereof:
- comprising:
- (i)(G) reacting Compound HO-I-H with optionally substituted benzoyl halide to provide Compound BzO-I-Bz:
- (ii)(B) reacting Compound BzO-I-Bz with methyl vinyl ketone to provide Compound BzO-IIA-Bz:
- (iii)(D) reacting Compound BzO-IIA-Bz with tert-butylmagnesium halide to provide Compound HO-IIIA-Bz:
- (iv)(H) reacting Compound HO-IIIA-Bz with lithium aluminum hydride to provide Compound HO-IV-Bn:
- (v)(C) reacting Compound HO-IV-Bn with H2 in the presence of a hydrogenation catalyst to provide a compound of Compound HO-IV-H:
- (vi)(A1) reacting Compound HO-IV-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (vi)(A2) reacting Compound HO-IV-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (vi)(A3) reacting Compound HO-IV-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide buprenorphine;
- or
- (8) from Compound HO-I-H, or a salt thereof:
- comprising:
- (i)(G) reacting Compound HO-I-H with acyl halide to provide Compound AcO-I-Ac:
- (ii)(B) reacting Compound AcO-I-Ac with methyl vinyl ketone to provide Compound AcO-II-Ac:
- and either:
- (iii)(D) reacting Compound AcO-II-Ac with tert-butylmagnesium halide to provide Compound HO-IIIA-Ac:
- (iv)(C) reacting Compound HO-IIIA-Ac with H2 in the presence of a hydrogenation catalyst to provide a compound of Compound HO-IV-Ac:
- (v)(I) reacting Compound HO-IV-Ac with Schwartz's reagent or base to provide Compound HO-IV-H:
- (vi)(A1) reacting Compound HO-IV-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (vi)(A2) reacting Compound HO-IV-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (vi)(A3) reacting Compound HO-IV-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide buprenorphine;
- or
- (iii)(C) reacting Compound HO-IIIA-Ac with H2 in the presence of a hydrogenation catalyst to provide a compound of Compound AcO-IIIB-Ac:
- (iv)(D) reacting Compound AcO-IIIB-Ac with tert-butylmagnesium halide to provide Compound HO-IV-Ac:
- (v)(I) reacting Compound HO-IV-Ac with Schwartz's reagent or base to provide Compound HO-IV-H:
- (vi)(A1) reacting Compound HO-IV-H with cyclopropane carboxaldehyde followed by a hydride source;
- or
- (vi)(A2) reacting Compound HO-IV-H with cyclopropanecarboxylic acid halide followed by a reducing agent;
- or
- (vi)(A3) reacting Compound HO-IV-H with cyclopropylmethyl halide or activated cyclopropane methanol;
- to provide buprenorphine.
131 more elements
Dependencies are inferred from the claim text.