Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-31
2001-05-29
Oswecki, Jane C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S243000, C549S028000, C560S009000, C560S030000
Reexamination Certificate
active
06239283
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is a process for the preparation of cyclic-sulfur fluorine containing oxazolidinone antibacterial agents.
2. Description of the Related Art
Many processes are known for producing pharmaceutically antibacterial oxazolidinones, see for example, International Publication WO97/37980. However, when the the oxazolidinone contains an o-halogen substituted phenyl ring, decomposition of the metallated benzene to a reactive benzyne is a known undesirable side reaction, see “Dehydrobenzene and Cycloalkynes” by R. W. Hoffmann, Academic Press, N.Y., 1967. The process of the present invention produces a tetrahydrothiopyran-o-fluorinated oxazolidinones intermediate (IV) which is useful in producing antibacterially active oxazolidinones (XIV), (XIX) and N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran4-yl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide.
International Publication WO97/09328 discloses tetrahydrothiopyran-o-fluorinated oxaxolidinones which are produced by a process which requires much colder temperatures, than the claimed invention.
International Publication WO97/30995 discloses tetrahydrothiopyran-o-fluorinated oxaxolidinones which are produced by a process different that that of the present invention
SUMMARY OF INVENTION
Disclosed are tetrahydrothiopyran-o-fluorinated compounds of formula (IV)
where R
ester
is selected from the group consisting of:
(I) C
1
-C
10
alkyl optionally substituted with:
(A) phenyl,
(B) 1 thru 3 C
1
-C
3
alkoxy,
(II) C
2
-C
5
alkenyl optionally substituted with:
(A) phenyl,
(B) C
3
-C
7
cycloalkyl,
(III) phenyl and optionally substituted with one thru three C
1
-C
3
alkyl
(IV) naphthyl optionally substituted with one thru three C
1
-C
3
alkyl.
Also disclosed are the compounds of EXAMPLES 1, 7 thru 10 and 12 thru 15.
Further disclosed is a process of preparing a tetrahydrothiopyran-o-fluorinated carbamate of formula (IV) where R
ester
is as defined above which comprises:
(1) contacting a 4-bromo-3-fluorinated carbamate of formula (II)
where R
ester
is as defined above, with a Grignard reagent of the formula R—Mg—X where R is C
1
-C
4
alkyl, CH
2
═CH—, CH
2
═CH—CH
2
—, cyclohexyl or phenyl and where X is —Br, —Cl or —I;
(2) contacting the product of step (1) with an alkyl lithium base and
(3) contacting the product of step (2) with tetrahydrothiopyran-4-one (III).
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is the reaction of the 4-bromo-3-fluorinated carbamate (II) with tetrahydrothiopyran-4-one (III) to produce a tetrahydrothiopyran-o-fluorinated compound (IV). The tetrahydrothiopyran-o-fluorinated compound (IV) is a key intermediate to making oxazolidinone antibacterial agents which contain the tetrahydrothiopyran-o-fluorinated group.
The process starts with a 4-bromo-3-fluorinated carbamate (II). Operable R
ester
groups include:
(I) C
1
-C
10
alkyl optionally substituted with:
(A) phenyl,
(B) 1 thru 3 C
1
-C
3
alkoxy,
(II) C
2
-C
5
alkenyl optionally substituted with:
(A) phenyl,
(B) C
3
-C
7
cycloalkyl,
(III) phenyl and optionally substituted with one thru three C
1
-C
3
alkyl and
(IV) naphthyl optionally substituted with one thru three C
1
-C
3
alkyl.
It is preferred that R
ester
be C
1
-C
6
alkyl or —CH
2
—&phgr;; it is more preferred that R
ester
be i-butyl.
The first step of the process requires that the 4-bromo-3-fluorinated carbamate (II) be reacted with a Grignard reagent of the formula R—Mg—X where R is C
1
-C
4
alkyl, CH
2
═CH—, CH
2
═CH—CH
2
—, cyclohexyl or phenyl and where X is —Br, —Cl or —I. It is preferred that R is C
1
-C
3
alkyl or phenyl; it is more preferred that R be ethyl. It is preferred that X be —Br. This reaction is performed in the usual manner for Grignard reactions which is well known to those skilled in the art.
Step (2) is the reaction of the mixture from step (1) with an alkyl lithium base. It is preferred that the alkyl lithium base is selected from the group consisting of methyllithium, n-butyllithium, s-butyllithium and t-butyllithium. Step (2) should be performed at a temperature of less than about −15°; it is preferred that step (2) be performed at a temperature range of about −15 to about −35°, more preferably in the range of about −20 to about −35°. It is preferred that both step (1) and step (2) be performed in the presence of 3 equivalents of N,N,N′,N′-tetramethylethylenediamine.
Step (3) of the process is contacting the product of step (2) with the tetrahydrothiopyran-4-one (III) to produce the desired tetrahydrothiopyran-o-fluorinated compound (IV).
It is preferred where the product of step (2) is contacted with a compound of the formula MgQ
2
prior to contacting with the tetrahydrothiopyran-4-one (III), where Q is —Cl, —Br or —I and where the two Qs can be the same or different prior to performing step (3). It is preferred that the two Qs be different and be —Cl and —Br.
The tetrahydrothiopyran-o-fluorinated compound (IV) is then converted to the following pharmaceutically useful antibacterial agents;
[4(S)-cis]-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-ox-5-oxazolidinyl]methyl]acetamide (IX) by the process of EXAMPLEs 3 thru 6,
[1&agr;,4&bgr;(S)]-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanamide monohydrate (XIV) by the process of EXAMPLEs 7 thru 11 and to
4(S)-N-[[3-[fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolinyl]methyl]acetamide (XIX) by the process of EXAMPLEs 12 thru 16.
These three antibacterially active oxazolidinones are useful as pharmaceutical agents to treat various bacterial infections and/or diseases. For [4(S)-cis]-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (IX) see U.S. Patent application Ser. No. 60/100,185 (filed Sep. 14, 1998), Ser. No. 60/075,247 (filed Feb. 19, 1998) and Ser. No. 60/088,283 (filed Jun. 5, 1998). For [1&agr;,4&bgr;(S)]-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanamide monohydrate (XIV) see U.S. patent application Ser. No. 08/696,313 (filed Aug. 13, 1996). For 4(S)-N-[[3-[fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolinyl]methyl]acetamide (XIX) see U.S. patent application Ser. No. 60/100,185.
DEFINITIONS AND CONVENTIONS
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
I. Conventions for Formulas and Definition of Variables
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as “C
1
-C
4
”, where both “1” and “4” are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, “C
1
-C
4
alkyl” represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C
2
-C
4
alkoxycarbonyl describes a group CH
3
—(CH
2
)
n
—O—CO— where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the “C
i
-C
j
” designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C
1
-C
3
)alkoxycarbonyl has the same meaning as C
2
-C
4
alkoxy-carbonyl because the “C
1
-C
3
” refers only to the carbon atom content of the alkoxy group. Similarly whil
Oswecki Jane C.
Pharmacia & Upjohn Company
Stein Bruce
LandOfFree
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