Preparation of buprenorphine
Disclosed are methods for preparing buprenorphine from, for example, compounds such as nororipavine and northebaine.
1. 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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 H 2 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.
2. A method according to claim 1 , wherein Compound BnO-I-H is prepared from Compound HO-I-Me, or a salt thereof:
by a method comprising:
(i)(F) reacting Compound HO-I-Me with benzyl halide, benzyl sulfonate, or activated benzyl alcohol to provide Compound BnO-I-Me:
(ii)(E) reacting Compound BnO-I-Me with an azodicarboxylate followed by an acid or an addition salt thereof to provide Compound BnO-I-H:
3. A method according to claim 1 , wherein the demethylating agent of step (E) is a thiolate.
4. A method according to claim 1 wherein the demethylating agent of step (E) is a dodecane thiolate.
5. A method according to claim 1 , wherein step (E) is performed in a solvent comprising a polar aprotic solvent.
6. A method according to claim 1 , wherein step (E) is performed in a solvent comprising N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, propylene carbonate, or a mixture thereof.
7. A method according to claim 1 , wherein the demethylating agent of step (E) is reacted at a temperature within the range of about 50° C. to about 190° C., for a period of time within the range of about 4 hours to about 2 days.
8. A method according to claim 1 , wherein the benzyl halide of step (F) in (4) is benzyl chloride or benzyl bromide.
9. A method according to claim 1 , wherein step (F) in (4) is performed in the presence of a strong base.
10. A method according to claim 1 , wherein step (F) in (4) is performed in the presence of an alkali metal hydride.
11. A method according to claim 1 , wherein step (F) in (4) is performed in a solvent comprising a polar aprotic solvent.
12. A method according to claim 1 , wherein step (F) in (4) is performed in a solvent comprising N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, propylene carbonate, or a mixture thereof.
13. A method according to claim 2 , wherein the benzyl halide of step (F) in (4) is benzyl chloride or benzyl bromide.
14. A method according to claim 2 , wherein step (F) is performed in the presence of a strong base.
15. A method according to claim 2 , wherein step (F) is performed in the presence of an alkali metal hydride.
16. A method according to claim 2 , wherein step (F) is performed in a solvent comprising a polar aprotic solvent.
17. A method according to claim 2 , wherein step (F) is performed in a solvent comprising N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, propylene carbonate, or a mixture thereof.