INTERMEDIATES FOR THE PREPARATION OF REMIFENTANIL HYDROCHLORIDE

• US 20200131127A1
• Filed: 10/25/2019
• Published: 04/30/2020
• Est. Priority Date: 10/26/2018
• Status: Active Grant

• Current Assignee: Hameln Pharma GmbH
• Original Assignee: Hameln Pharma Plus Gmbh (Siegfried Holding AG)
• Inventors: Valachovic, Pavol, Kralova, Janka, Slizik, Lubos, Varga, Norbert
• Granted Patent: US 10,844,014 B2
• Time in Patent Office: Days
• CPC Class Codes: C07D 211/66 having a hetero atom as the second substituent in position 4
• CPC Class Codes: C07D 211/98 Nitrogen atom

Abstract

A new intermediate for synthesizing 1-substituted-4-[phenyl(propanoyl)amino]piperidine-4-carbonitrile derivatives is laid open. Specifically set out is a method for use of this intermediate in the preparation of remifentanil. The enclosed shorter process offers a greater yield of products with higher purity as compared to methods reported in the prior art.

Claims

1. A compound of formula 20 or a salt thereof:

2. A method for synthesizing Remifentanil (1) or a salt thereof, the method selected from the group consisting of Method A and Method B, wherein Method A comprises reacting the compound of claim 1 or a salt thereof with an acylating agent, optionally in the presence of an acid scavenger, to produce a compound of formula (21), and reacting the compound of formula (21) with methanol under acidic conditions, and Method B comprises hydrolyzing the compound of claim 1 or a salt thereof with an acid, esterifying the hydrolyzed product with an alcohol to produce a compound of formula (12), and reacting the compound of formula (12) with an acylating agent, whereby Remifentanil (1) or a salt thereof is synthesized

3. The method of claim 2, wherein the compound of formula (20) is first converted to a compound of formula (21)

4. The method of claim 3, wherein the acylating agent is propionic anhydride or propionyl chloride.

5. method of claim 4, wherein the acid scavenger is selected from the group consisting of triethylamine, morpholine, piperidine, and pyridine.

9. A method for preparing a compound of claim 1, the method comprising reacting a compound of formula (19) with phenylamine in the presence of a cyanide compound to produce a compound of formula (20).

10. The method of claim 9, wherein the cyanide compound is sodium cyanide.

11. The method of claim 9, further comprising preparing the compound of formula (19) by alkylating 4-piperidone monohydrate hydrochloride with an appropriate alkylating agent in the presence of a basic catalyst, whereby a compound of formula (19) is prepared.

12. The method of claim 11, wherein the appropriate alkylating agent is selected from the group consisting of 3-chloropropionitrile, 3-bromopropionitrile, 3-iodopropionitrile, 2-cyanoethyl methanesulfonate, and 2-cyanoethyl 4-methyl benzenesulfonate,

13. The method of claim 12, wherein the basic catalyst is selected from the group consisting of sodium or potassium carbonate, sodium hydrogen carbonate, sodium or potassium hydroxide, sodium amide, potassium terc-butoxide, and sodium ethoxide.

14. The method of claim 11, wherein the alkylating is performed in the presence of a solvent, optionally wherein the solvent is selected from the group consisting of acetone, methyl ethyl ketone, isopropanol, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, and 2-methyl tetrahydrofuran.

6-8. -8. (canceled)

15. A method for synthesizing remifentanil hydrochloride, wherein the method is according to the following scheme: