Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2002-04-15
2004-08-10
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S060000, C564S305000
Reexamination Certificate
active
06774231
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for the production of N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide or its pharmaceutically acceptable salt.
BACKGROUND OF THE INVENTION
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, gram-negative aerobic bacteria such as
H. influenzae
and
M. catarrahlis
, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium.
The present invention provides a novel method for the production of N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide. This compound has broad coverage against Gram-positive organisms. In particular, it demonstrates beneficial efficacy for treating infections caused by resistant pathogens. In addition, the present invention provides novel intermediates useful for the preparation of N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,880,118 discloses substituted oxazine and thiazine oxazolidinone antimicrobials.
U.S. Pat. No. 6,968,962 discloses phenyloxazolidinones having a C—C bond to 4-8 membered heterocyclic rings.
U.S. Pat. No. 5,981,528 discloses antibiotic oxazolidinone derivatives.
U.S. Pat. application Serial No. 60/236595 discloses N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide.
J. Chem. Soc.
1949, 2433-2440 and U.S. Pat. No. 3,585,182 discloses the formation of thiomorpholine, 1,1-dioxide from vinyl sulfone and aniline. Due to the sluggishness of the double Michael addition, excess aniline is needed to achieve reasonable yield. The present invention uses a Lewis acid as a catalyst to form a compound of structure (4) as shown below wherein the reaction needs only equal equivalence of vinyl sulfone and aniline.
DETAILED DESCRIPTION OF THE INVENTION
The N-({(5S)-3-[4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide is prepared according to Scheme I and examples described herein below.
In Scheme 1, each R
1
is independently hydrogen, fluorine, chlorine or bromine atom. Preferably both R
1
are fluorine atoms. R
2
is a straight and branched alkyl group having one to twelve carbon atoms, which may be substituted by a phenyl group. As shown in step one, a Lewis-acid such as aluminum chloride mediates a double Michael addition between vinyl sulfone and an aniline of structure 1 to form a compound of structure 4 via compounds of structures 2 and 3. The reaction occurs at a temperature in a range of from 40° C. to 170° C., preferably at between 100° C. and 110° C. for reactions using solvents, at between 140-160° C. for reactions with no solvents. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably is halogenated aliphatics, halogenated aromatics or hydrocarbon aromatics, and more preferably is 1,2-dichloroethane, chlorobenzene or toluene. Lewis acids of the present invention includes, but not limits, strong acids and lanthanide triflates, preferably is AlCl
3
, FeCl
3
, BiCl
3
, SnCl
2
, ZnCl
2
, TfOH, Yb(OTf)
3
, and more preferably is AlCl
3
, TfOH or Yb(OTf)
3
. The double Michael addition can also be mediated with weak acids, such as AcOH, H
3
PO
4
or trfluoroacetic acid. The preferred weak acids is H
3
PO
4
. The reaction temperature can be between 60-180° C., but preferably at 110-150° C.
Transformation of 4 to 5 can be accomplished by a procedures well known to one skilled in the art. For example, a number of standard nitration conditions, such as nitric acid, a mixture of acetyl chloride and silver nitrate, or nitric acid with a Lewis acid as a catalyst may be utilized. However, economically efficient nitric acid based conditions and nitric acid alone as a nitration agent are preferred reaction routes. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably carboxylic acid, carboxylic anhydride and halogenated aliphatics, and more preferably acetic acid. The equivalents of nitric acid can be between 1-20, but preferably between 5-10. The reaction temperature can be between 0-60° C., but preferably between 10-30° C.
Transformation of 5 to 6 can be accomplished by a procedures well known to one skilled in the art. For example, a number of reduction conditions, such as hydrogenation with metal catalysts, reduction with iron and iron (II) sulfate may be utilized. However, hydrogenation with metal catalysts, and hydrogenation with Ni-based catalysts are preferred reaction routes. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably halogenated aliphatics, alcohols, aliphatic esters and THF, and more preferably THF. The equivalents of Ni-based catalyst can be between 5-40%, but preferably between 10-20%. The reaction temperature can be between 0-100° C., but preferably between 35-45° C.
Ttransformation or 6 to 7 can be accomplished by a procedures well known to one skilled in the art. For example, a number of carbamate formation conditions, such as haloalkylformate with trialkyl amine as base, haloalkylformate with aqueous metal carbonate as base, or dialkylcarbonate with base may be utilized. However, haloalkylformate with base, and haloalkylformate with aqueous potassium carbonate as base are preferred routes. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably halogenated aliphatics, alcohols, aliphatic esters and THF, and more preferably THF. The equivalents of potassium carbonate can be between 1-10, but preferably between 2-3. The equivalents of haloalkylformate can be between 1-4, but preferably between 1.2-2.0. The reaction temperature can be between 0-100° C., but preferably between 45-55° C.
Finally, reacting 7 with an (S)-chloroacetamidoacetoxypropane in the presence of a base, a lithium cation, a nucleophile and a solevnt provides compound 8.
Alternatively, the compound of structure may be prepared according to the procedures illustrated in Scheme II.
In Scheme II, X refers to a chlorine, bromine or iodine atom. Each R
1
is the same as defined above.
In equation (1): In step 1, the reaction occurs in the presence of a base and in a solvent system. The bases can be any bases that neutralize HF, but preferably trialkylamine, and more preferably is triethylamine. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably is halogenated aliphatics, and more preferably is methylene chloride. In step 2, the conversion requires an oxidant and in the presence of a solvent system. The oxidants can be any oxidants that oxidize sulfide to sulfone, but preferably oxone. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably is halogenated aliphatics mixed with water, and more preferably is methylene chloride mixed with water.
In equation (2): The reaction occurs in the presence of a base, a catalyst, and a solvent system. The Pd-based catalysts can be any catalysts that facilitate the formation of a nitrogen and carbon bond, but preferably Pd[O] or Pd[II] catalysts, and more preferably is Pd(OAc)
2
. The ligand can be any ligands that assist Pd catalyst for the formation of a nitrogen and carbon bond, but preferably phosphorus based catalysts, and more preferably is 2-(dicyclohexylphosphino)biphenyl and 2-(di-t-butylphosphino)biphenyl. The reaction solvent can be any solvent that does not adversely affect the reaction, but preferably is hydrocarbon aromatics, and more pref
Chen Jiong Jack
Lu Cuong V.
Berch Mark L.
Habte Kahsay
Pharmacia & Upjohn Company
Yang Lucy X.
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