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Details for Patent: 4,650,873

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Details for Patent: 4,650,873

Title: Process for the preparation of a derivative of piperidine
Abstract:Processes for the preparation of the antiarrhythmic agent 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Inventor(s): Leir; Charles M. (New Richmond, WI)
Assignee: Riker Laboratories (St. Paul, MN)
Filing Date:May 01, 1986
Application Number:06/857,966
Claims:1. A method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide which comprises:

(a) contacting 1,4-dibromobenzene with alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol, whereby 1,4-bis(2,2,2-trifluoroethoxy)benzene is formed;

(b) in the presence of a Lewis acid catalysts, treating said 1,4-bis(2,2,2-trifluoroethoxy)benzene with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone:

(c) substituting two of the three hydrogens on the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone to yield first the alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(d) in the presence of a buffering base, substituting the third hydrogen of said alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone to yield alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(e) contacting the resultant alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with 2-aminomethylpyridine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide;

(f) treating said 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)-benzamide with an agent capable of hydrogenation of the aromatic bond in the heterocyclic ring, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.

2. A method of claim 1 wherein said 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is recovered in the form of its acetate.

3. A method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide which comprises:

(a) contacting 1,4-dibromobenzene with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous of cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene;

(b) in the presence of a Lewis acid catalyst, treating said 1,4-bis(2,2,2-trifluoroethoxy)benzene with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(c) substituting two of the three hydrogens on the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone to yield first the alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(d) in the presence of a buffering base, substituting the third hydrogen of said alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone to yield alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(e) contacting the resultant alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.

4. A method of claim 3 wherein said 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is recovered in the form of its acetate.

5. A method of preparing 1,4-bis(2,2,2-trifluoroethoxy)benzene comprising contacting 1,4-dibromobenzene with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to provide said 1,4-bis(2,2,2-trifluoroethoxy)benzene.

6. A method of preparing 2,5-bis(2,2,2-trifluoroethoxy)acetophenone comprising:

(a) contacting 1,4-dibromobenzene with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion in a strongly polar solvent comprising 2,2,2-trifluoroethanol to provide 1,4-bis(2,2,2-trifluoroethoxy)benzene; and

(b) treating said 1,4-bis(2,2,2-trifluoroethoxy)benzene, in the presence of a Lewis acid catalyst, with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone.

7. A method of preparing alpha,alpha,dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone comprising:

(a) contacting 1,4-dibromobenzene with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion in a strongly polar solvent comprising 2,2,2-trifluoroethanol to provide 1,4-bis(2,2,2-trifluoroethoxy)benzene;

(b) treating said 1,4-bis(2,2,2-trifluoroethoxy)benzene, in the presence of a Lewis acid catalyst, with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone; and

(c) reacting said bis(2,2,2-trifluoroethoxy)acetophenone by substituting two of the three hydrogens on the acetophenone function to yield alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone.

8. A method of preparing alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone comprising:

(a) contacting 1,4-dibromobenzene with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion in a strongly polar solvent comprising 2,2,2-trifluoroethanol to provide 1,4-bis(2,2,2-trifluoroethoxy)benzene;

(b) treating said 1,4-bis(2,2,2-trifluoroethoxy)benzene, in the presence of a Lewis acid catalyst, with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(c) reacting said bis(2,2,2-trifluoroethoxy)acetophenone by substituting two of the three hydrogens on the acetophenone function to yield alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone; and

(d) substituting the third hydrogen of said alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenon e in the presence of a buffering base to yield alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone.

9. A method of preparing 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide comprising:

(a) contacting 1,4-dibromobenzene with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion in a strongly polar solvent comprising 2,2,2-trifluoroethanol to provide 1,4-bis(2,2,2-trifluoroethoxy)benzene;

(b) treating said 1,4-bis(2,2,2-trifluoroethoxy)benzene, in the presence of a Lewis acid catalyst, with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(c) reacting said bis(2,2,2-trifluoroethoxy)acetophenone by substituting two of the three hydrogens on the acetophenone function to yield alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone;

(d) substituting the third hydrogen of said alpha,alpha-dichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenon e in the presence of a buffering base to yield alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone; and

(e) reacting said alpha,alpha,alpha-trichloro-substituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with 2-aminomethylpyridine to yield said 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide.
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