Method for preparing 4-amino-4-phenylpiperidines

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Quick Facts

Patent No.: US 7,045,630
App. No.: 10/483,532
Granted: May 16, 2006
Kind: B2

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Abstract

The invention relates to a process for preparing a 4-amino-4-phenylpiperidine (I): in which R is hydrogen or a (C 1 –C 3 )alkyl group, characterized in that a 1-protected 4-piperidone (II): in which Pr′ represents a removable N-protecting group, is treated sequentially first with an alkali metal cyanide and then with an amine ENHPr″ (III) in which E represents a group R′=(C 1 –C 3 )alkyl, or an N-protecting group and Pr″ is an N-protecting group, the protecting group(s) being removable under the same conditions as Pr′; then the compound thus obtained (IV) is subjected to a Grignard reaction with a phenylmagnesium halide, the two or three protecting groups are removed from the compound thus obtained (V) and compound (I) is isolated or in the form of the free base, which is converted into one of its salts.

Claims (25)

1. A process for preparing a 4-amino-4-phenylpiperidine of formula (I):

in which R is hydrogen or a (C 1 –C 3 )alkyl group wherein:

(a) a 1-protected 4-piperidone of formula

in which Pr′ represents a removable N-protecting group, is treated sequentially first with an alkali metal cyanide and then, in the reaction medium containing the cyanohydrin thus obtained, with an amine of formula:

in which E represents a group R′=(C 1 –C 3 )alkyl, or an N-protecting group and Pr″ is an N-protecting group, the protecting group(s) being removable under the same conditions as Pr′;

(b) the compound thus obtained of formula:

in which Pr′, Pr″ and E are as defined above, is subjected to a Grignard reaction with a phenylmagnesium halide; and

and compound (I) is isolated either in the form of one of its salts, which is converted into the free base, or in the form of the free base, which is converted into one of its salts.

2. The process as claimed in claim 1 for the preparation of a 4-amino-4-phenylpiperidine of formula:

in which R represents a (C 1 –C 3 )alkyl group wherein in step a), treatment is performed with an amine of formula Pr″ENH in which E is a (C 1 –C 3 )alkyl group, and Pr″is as defined in claim 1 .

3. The process as claimed in claim 1 wherein the starting reagents used are a compound of formula (II) and a compound of formula (III) in which E represents a group R″=(C 1 –C 3 )alkyl and Pr′ and Pr″ represent, independently a benzyl radical, which is unsubstituted or substituted on the benzene ring with a halogen, a (C 1 –C 4 )alkyl group or a (C 1 –C 4 )alkoxy group; a benzhydryl radical; or a trityl radical.

4. The process as claimed in claim 1 wherein the starting reagent used is a compound of formula (II) in which Pr′ is a benzyl group, and a compound of formula (III) in which Pr″ is also a benzyl group.

5. The process as claimed in claim 1 wherein the compound of formula (IV) in which Pr′ and Pr″ are both a benzyl group is subjected, in step b), to a Grignard reaction with phenylmagnesium bromide.

6. The process as claimed in claim 1 wherein the starting reagent used is a compound of formula (III) in which E is a methyl group.

7. The process as claimed in claim 2 wherein the starting reagents used are a compound of formula (II) and a compound of formula (Ill) in which E represents a group R′ =(C 1 –C3)alkyl and Pr′ and Pr″ represent, independently, a benzyl radical, which is unsubstituted or substituted on the benzene ring with a halogen, a (C 1 –C4)alkyl group or a (C 1 –C4)alkoxy group; a benzhydryl radical; or a trityl radical.

8. The process as claimed in claim 2 wherein the starting reagent used is a compound of formula (II) in which Pr′ is a benzyl group, and a compound of formula (III) in which Pr″ is also a benzyl group.

9. The process as claimed in claim 3 wherein the starting reagent used is a compound of formula (II) in which Pr′ is a benzyl group, and a compound of formula (Ill) in which Pr″ is also a benzyl group.

10. The process as claimed in claim 2 wherein the compound of formula (IV) in which Pr′ and Pr″ are both a benzyl group is subjected, in step b), to a Grignard reaction with phenylmagnesium bromide.

11. The process as claimed in claim 3 wherein the compound of formula (IV) in which Pr′ and Pr″ are both a benzyl group is subjected, in step b), to a Grignard reaction with phenylmagnesium bromide.

12. The process as claimed in claim 4 wherein the compound of formula (IV) in which Pr′ and Pr″ are both a benzyl group is subjected, in step b), to a Grignard reaction with phenylmagnesium bromide.

13. The process as claimed in claim 2 wherein the starting reagent used is a compound of formula (III) in which E is a methyl group.

14. The process as claimed in claim 3 wherein the starting reagent used is a compound of formula (III) in which E is a methyl group.

15. The process as claimed in claim 4 wherein the starting reagent used is a compound of formula (III) in which E is a methyl group.

16. The process as claimed in claim 5 wherein the starting reagent used is a compound of formula (III) in which E is a methyl group.