Preparation of substituted piperidin-4-ones

Details Preparation of substituted piperidin-4-ones Preparation of substituted piperidin-4-ones

2001-12-11

2003-03-25

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S216000, C546S219000

Reexamination Certificate

active

06538136

ABSTRACT:

The present invention provides a novel process for the preparation of substituted piperidin-4-ones useful as intermediates in the preparation of pharmaceuticals.
G. T. Katvalyan and E. A. Mistryukov,
Izv. Akad. Nauk SSSR, Ser. Khim
., 11, 2575 (2436 transl.) (1968) disclose a multistep synthesis of 1-methyl-3,3-dimethyl-piperidin-4-one starting with methylamine and isobutyraldehyde. In addition, I. V. Micovic, et al.,
J. Chem. Soc., Perkin Trans
., 1, 2041 (1996) disclose a multistep synthesis of 1-benzyl-3,3-gem-dimethyl-piperdine-4-one starting with benzylamine and methyl acrylate.
It has now been discovered that 3-substituted piperidones can be prepared simply and efficiently following the one-pot procedure of the present invention, thus obviating the traditionally lengthy syntheses such as those requiring a Dieckmann condensation.
The present invention provides a process for the preparation of a compound of formula I:
wherein R is hydrogen, C
1
-C
6
alkyl, halo(C
1
-C
6
)alkyl, phenyl, benzyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halo(C
1
-C
6
)alkyl, phenyl, NO
2
, and CN; R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are each independently hydrogen, C
1
-C
6
alkyl, halo(C
1
-C
6
)alkyl, phenyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —S(C
1
-C
6
alkyl), —S(phenyl), halo(C
1
-C
6
)alkyl, phenyl, NO
2
, and CN; or the pharmaceutically acceptable salt thereof; comprising combining a compound of formula II:
wherein R
1
, R
2
, R
3
, and R
4
are defined as above, a compound of formula III:
wherein R
5
is defined as above, and a compound of formula IV:
R—NH
2
  formula IV
wherein R is defined as above, in the presence of a suitable acid; followed by addition of a suitable base and a compound of formula V:
wherein R
6
is defined as above.
As used herein, the terms “Halo”, “Halide” or “Hal” refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein, the term “Me” refers to a methyl group, the term “Et” refers to an ethyl group, the term “Pr” refers to a propyl group, the term “iPr” refers to an isopropyl group, the term “Bu” refers to a butyl group, the term “Ph” refers to a phenyl group, the term “benzyl” refers to a —CH
2
phenyl group.
As used herein the term “C
1
-C
4
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term “C
1
-C
6
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. The term “C
1
-C
6
alkyl” includes within its scope “C
1
-C
4
alkyl”.
As used herein the term “C
1
-C
6
alkoxy” refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C
1
-C
6
alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term “C
1
-C
6
alkoxy” includes within its definition the term “C
1
-C
4
alkoxy”.
As used herein the term “—S(C
1
-C
6
alkyl)” refers to a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom such as —SCH
3
, —SCH
2
CH
3
, —SCH
2
CH
2
CH
3
, —SCH
2
CH
2
CH
2
CH
3
, and the like.
As used herein the term “halo(C
1
-C
6
)alkyl” refers to a straight or branched alkyl chain having from one to six carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C
1
-C
6
)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term “halo(C
1
-C
6
)alkyl” includes within its definition the term “halo(C
1
-C
4
)alkyl”.
This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term “pharmaceutically acceptable salt” as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenyisulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formrate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
The designation
refers to a bond that protrudes forward out of the plane of the page.
The designation
refers to a bond that protrudes backward out of the plane of the page.
As used herein, the term “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term “enantiomer” refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term “chiral center” refers to a carbon atom to which four different groups are attached. As used herein, the term “diastereomers” refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers”. The terms “racemate”, “racemic mixture” or “racemic modification” refer to a mixture of equal parts of enantiomers.
The term “enantiomeric enrichment” as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or “ee”, which is found using the following equation:
ee
=
E
1
-
E
2
E
1
+
E
2
×
100
wherein E
1
is the amount of the first enantiomer and E
2
is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:3

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