Process for the synthesis of (2S)-phenyl-3-piperidone

Details Process for the synthesis of (2S)-phenyl-3-piperidone Process for the synthesis of (2S)-phenyl-3-piperidone

2001-07-05

2002-05-14

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06388083

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of (2S)-phenyl-3-piperidone which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of (2S)-phenyl-3-piperidone which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of compounds related to (2S)-phenyl-3-piperidone employ a relatively high number of steps and require a resolution of the desired product (Calvez, et al.,
Tetrahedron Letters
, 40, 7099-7100 (1999); Tomooka, et al.,
J. Am. Chem. Soc
., 122, 408-409 (2000); Wallace, et al.,
Tetrahedron Letters
, 41, 2027-2029 (2000); EPO Patent Publication 0 528 495; PCT Patent Publication WO 97/49710). In contrast to the previously known processes, the present invention provides effective methodology for the preparation of (2S)-phenyl-3-piperidone in relatively low number of steps and without requiring resolution.
It will be appreciated that (2S)-phenyl-3-piperidone is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of (2S)-phenyl-3-piperidone which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of (2S)-phenyl-3-piperidone via a very simple, short, relatively inexpensive and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of (2S)-phenyl-3-piperidone. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula:
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of psychiatric disorders, inflammatory diseases, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of (2S)-phenyl-3-piperidone of the formula:
The general process for the preparation of (2S)-phenyl-3-piperidone may be depicted as follows:
In accordance with the present invention, the subject process provides (2S)-phenyl-3-piperidone in higher yields and in a more efficient route than the processes disclosed in the art.
In a preferred embodiment, the present invention is directed to a process for the preparation of (2S)-phenyl-3-piperidone which may be depicted as follows:
A specific embodiment of the present invention concerns a process for the preparation of (2S)-phenyl-3-piperidone of the formula:
which comprises:
reacting phenylacetylene with an organometallic base followed by 1-bromo-3-chloropropane to give a compound of the formula:
 which compound is reduced under hydrogenation conditions to give a compound of the formula:
 which compound is oxidized to give a compound of the formula:
 which compound is reacted with benzyl amine to give a compound of the formula:
 which compound is reacted with methanesulfonyl chloride in the presence of an amine base followed by reaction with a tetra-alkylammonium acetate to give a compound of the formula:
 which compound is deprotected under hydrogenation conditions followed by reaction with tert-butyloxycarbonyl anhydride to give a compound of the formula:
 which compound is hydrolysed with a base to give a compound of the formula:
 which compound is oxidized under Moffat or Swern conditions to give a compound of the formula:
 which compound is deprotected to give (2S)-phenyl-3-piperidone of the formula:
In the reaction of phenylacetylene with an organometallic base followed by 1-bromo-3-chloropropane to give a compound of the formula:
it is preferred that the reaction is conducted: in an aprotic solvents such as tetrahydrofuran, diethyl ether or dimethoxyethane; the organometallic base is and alkyl or aryl lithium reagents, such as n-butlyl, methyl, hexyl or phenyl lithium or with a Grignard reagents, such as i-propyl MgCl, Bu-MgCl, PhenylMgBr (or Cl). Alternatively, sodium amide in DMSO may be employed for deprotonation of phenyl acetylene.
In the reduction under hydrogenation conditions of the compound of the formula:
to give a compound of the formula:
it is preferred that the hydrogenation is catalytic hydrogenation, such as with a Lindlar catalyst. It is futher preferred that a catalytic poison, such as quinoline, thiophene, sulfur, lutidine or collidine is present. Appropriate solvents include ethyl acetate, MeOH, EtOH, i-propanol and IPAC.
In the oxidation of the compound of the formula:
to give a compound of the formula:
it is preferred that the oxidation is conducted under Jacobsen epoxidation conditions. Preferred oxidation agents include peracids such as N-phenylpyridine-N-oxide, mCPBA or peracetic acid. Use of the catalyst (R,R)-(−)-N,N′-bis(3,5-di-tert-butylsalicylidene)- 1.2-cyclo-hexanediarninomanganese(iii)chloride is also preferred. Preferred temperatures are below 0° C. or between 0° C. and −60° C.
In the reaction of the compound of the formula:
with benzyl amine to give a compound of the formula:
it is preferred that the solvent is acetonitrile, propionitrile or nitromethane. Sodium iodide is optionally present.
In the reaction of the compound of the formula:
with methanesulfonyl chloride in the presence of an amine base followed by reaction with a tetra-alkylammonium acetate to give a compound of the formula:
it is preferred that methanesulfonyl chloride is employed, although the N-benzyl hydroxy-pyrolidine may be converted to aziridinum halides, ie; bromide with sulfonic halides such as toluenesulfonic chloride/ bromide, bromobenzene sulfonic chloride, p-nitrobenzenesulfonic chloride in various aprotic solvents including DME, diethyl ether, methylene chloride, dichloroethane or acetonitrile. It is preferred that the tetra-alkylammonium acetate is tetra-butyl ammonium acetate or a benzoate or carboxylic acid (C
1
-C
20
) ammonium salt including alkaline metal salt, such as Li, Na, K. The temperature of the reaction mixture is preferably below −20° C.
In the deprotection of the compound of the formula:
followed by reaction with tert-butyloxycarbonyl anhydride to give a compound of the formula:
it is preferred that the deprotection is conducted under catalytic hydrogenation conditions.
In the hydrolysis of the compound of the formula:
with a base to give a compound of the formula:
it is preferred that the hydrolysis is conducted with aqueous alkaline hydroxide, such as with NaOH, LiOH, KOH, or K
2
CO
3
, Na
2
CO
3
in MeOH, EtOH or THF.
In the oxidation of the compound of the formula:
under Moffat or Swern conditions to give a compound of the formula:
it is preferred that Moffat conditions with dimethyl sulfoxide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and pyridine are employed.
In a preferred embodiment, the present invention is directed to a process for the preparation of (2S)-phenyl-3-piperidone of the formula:
which comprises:
reacting a compound of the formula:
 with methanesulfonyl chloride in the presence of an amine base followed by reaction with a tetra-alkylammonium acetate to give a compound of the formula:
 which compound is deprotected under hydrogenation conditions followed by reaction with tert-butyloxycarbonyl anhydride to give a compound of the formula:
 which compound is hydrolysed with a base to give a compound of the formula:
 which compound is oxidized under Moffat or Swern conditions to give a compound of the formula:
 which compound is deprotected to give (2S)-phenyl-3-piperidone of the formula:
An alternate embodiment of the present invention concerns a process for the pre

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