Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-11-12
2001-08-07
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S309000, C568S312000, C568S323000, C549S505000, C570S190000
Reexamination Certificate
active
06271421
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to a process for the selective monodebromination of polybrominated alkyl aryl and alkyl heteroaryl ketones.
References are made in this application to various publications, the disclosures of which are hereby incorporated by reference in their entireties, in order to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
Selectively brominated alkyl aryl and alkyl heteroaryl ketones are useful as intermediates in the preparation of various pharmaceuticals. Uses include, but are not limited to, intermediates in the preparation of norepinephrine potentiators (see, e.g., Kihara et al.,
Chem. Pharm. Bull
. (1994), 42: 67—use of alpha-bromoacetophenone to prepare 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols), anti-tumor antibiotics (e.g., Ogawa et al.,
Chem. Pharm. Bull
. (1992), 40: 1315—use of alpha-bromopropiophenone to prepare guanine 7-oxides), antimicrobials (e.g., Rival et al.,
Chem. Pharm. Bull
. (1992), 40: 1170—use of alpha-bromo ketones; e.g., alpha-bromo-4-chloroacetophenone, to prepare imidazopyrimidine derivatives), antifungals (e.g., Konosu et al.,
Chem. Pharm. Bull
. (1990), 38: 2476—use of alpha-bromo-2,4,-dihalopropiophenones to prepare triazole antifungals), cyclooxygenase and 5-lipogenase dual inhibitors (e.g., Laufer et al.,
J. Med. Chem
. (1994), 37: 1894—use of phenacyl bromides to prepare pyrrolizine derivatives), and 5-HT
3
receptor antagonists (e.g., Rosen et al.,
J. Med. Chem
. (1990), 33: 3020—use of alpha-bromo-2-methoxyacetophenone to prepare imidazolylthiazole derivative).
The base-catalyzed selective alpha-bromination of alkyl aryl ketones and alkyl heteroaryl ketones is generally difficult to achieve, because the presence of an alpha-bromine atom typically enhances the rate of further bromination at the alpha position. A substantially monobrominated product can be achieved by limiting the extent of reaction (e.g., by limiting the amount of brominating agent), but this results in a product mixture containing a substantial portion of unreacted starting ketone. On the other hand, if the bromination reaction is pushed to completion by the addition of more brominating agent, an overbrominated product results in which much of the product is di- and tri-brominated in the alpha-position.
One approach to obtaining only a monobrominated or only a dibrominated ketone product has been the selective monodebromination of overbrominated product. One method for selective monodebromination (see Bull et al.,
Tetrahedron Letters
(1973), (44): 4349 and Posner et al.,
J. Amer Chem. Soc
. (1973), 95: 3076) employs lithium dimethylcuprate, but this reagent is air, moisture and temperature sensitive, so that the reaction must be carried out under an inert atmosphere and at low temperature. Another method (see Lehman et al.,
Tetrahedron Letters
(1976), 987 and Bakos et al.,
Steroids
(1993), 58, 115) employs trimethylphosphite, but this reagent is environmentally unfriendly.
SUMMARY OF THE INVENTION
The present invention is directed to a process for the selective mono-debromination of polybromoalkyl aryl or heteroaryl ketones produced during bromination reactions, to the desired dibromo- or monobrominated product. The process comprises treating the polybrominated alkyl aryl or heteroaryl ketone with an alkali metal sulfite in alkylcarboxylic acid, under conditions effective to form the desired debrominated product. The process of the invention can be conducted in a straightforward manner using mild temperatures and does not require an inert atmosphere. The alkali metal sulfite reagent employed in the process is inexpensive, commercially available and environmentally safe.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a selective mono-debromination process which comprises contacting an alpha-polybrominated ketone selected from a compound of Formula I and a compound of Formula II:
with an alkali metal sulfite in the presence of a C
2
-C
6
alkylcarboxylic acid to obtain a selectively mono-debrominated product, wherein:
Y is aryl or heteroaryl having at least one ring heteroatom selected from O and S;
R
1
is halo, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, nitro, cyano, SO
2
R
a
, or CO
2
R
a
;
R
2
is hydrogen, bromo, or C
1
-C
6
alkyl;
R
a
is C
1
-C
6
alkyl; and
p and q are each independently integers from 0 to 4.
In a first aspect of the process of the invention, the alpha-polybrominated ketone reactant is the compound of Formula I, and the mono-debrominated product comprises a compound of Formula III:
and all other variables and features are as originally set forth above.
In a second aspect of the process of the invention, the alpha-polybrominated ketone reactant is the compound of Formula II and the mono-debrominated product comprises the compound of Formula IV:
and all other variables and features are as originally set forth above.
In a third aspect of the process of the invention, Y is phenyl or a 5-6 membered aromatic heterocycle or a benzo-fused version thereof, having 1 to 3 ring heteroatoms selected from O and S; and all other variables and features are as originally set forth above or as set forth in either the first or the second aspect.
In another aspect of the process of the invention, the alkylcarboxylic acid is a C
2
-C
3
alkylcarboxylic acid; and all other variables and features are as originally set forth above or as set forth in any one of the first, second, and third aspects.
In still another aspect of the process of the invention, the alkylcarboxylic acid is acetic acid and the alkali metal sulfite is sodium sulfite; and all other variables and features are as originally set forth above or as set forth in any one of the first, second, and third aspects.
In still another aspect of the process of the invention, p is an integer from 0 to 2 (e.g., p is 0 or 1; or p is 0; or p is 1); and all other variables and features are as originally set forth above or are as set forth in any one of the preceding aspects.
In still another aspect of the process of the invention, q is an integer from 2 to 4 (e.g., q is 2 or 3; or q is 2; or q is 3) and all other variables and features are as originally set forth above or are as set forth in any one of the preceding aspects.
In one embodiment, the present invention is a process for preparing a dibromomethyl ketone of Formula V:
wherein:
Y is aryl or heteroaryl having at least one ring heteroatom selected from O and S;
R
1
is halogen, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy, nitro, cyano, SO
2
R
a
, or CO
2
R
a
;
R
a
is C
1
-C
6
alkyl; and
p is an integer from 0 to 4;
wherein the process comprises:
(A) brominating a methyl aryl or heteroaryl ketone to obtain a reaction mixture comprising di- and tri-bromomethylketones of Formulas V and VI:
(B) contacting the reaction mixture obtained in (A) with an alkali metal sulfite in the presence of a C
2
-C
6
alkylcarboxylic acid to selectively monodebrominate the tribromomethyl ketone.
In a first aspect of this embodiment of the process of the invention, Y is phenyl or a 5-6 membered aromatic heterocycle or a benzo-fused version thereof, having 1 to 3 ring heteroatoms selected from O and S; and all other variables and features are as originally set forth in this embodiment.
In another aspect of this embodiment, the alkylcarboxylic acid is a C
2
-C
3
alkylcarboxylic acid; and all other variables and features are as originally set forth in the embodiment or as set forth in the first aspect of the embodiment.
In still another aspect of this embodiment, the alkylcarboxylic acid is acetic acid and the alkali metal sulfite is sodium sulfite; and all other variables and features are as originally set forth in the embodiment, or as set forth in the first aspect of the embodiment.
In still another aspect of this embodiment, p is an integer from 0 to 2 (e.g., p is 0 or 1; or p is 0; or p is 1); and all other variables and features are as originally set forth in the embodiment or are as set forth in any one of the preceding aspec
Merck & Co. , Inc.
Padmanabhan Sreeni
Walton Kenneth R.
Winokur Melvin
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