Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-07-09
2003-11-18
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06649756
ABSTRACT:
BACKGROUND OF INVENTION
The invention is concerned with an improved process for the preparation of (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]-tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, a member of the carbapenem class of compounds, which is useful as an antibacterial agent.
PRIOR ART
In general it is well known in the art that carbapenem compounds are very difficult to produce because, inter alia, their sensitivity to heat and purification procedures results in low yields and which further requires isolation by chromatography. Synthetic methods to produce carbapenems require the use of protecting groups, which when removed, produce not only the carbapenem product, but additionally unwanted contaminates. The removal of additional contaminates, produced by the removal of protecting groups often requires the use of chromatography in order to separate and purify the labile carbapenem. Typically, protecting groups such as p-nitrobenzyl (PNB) and p-nitrobenzyloxycarbonyl (PNZ) have been used in the preparation of carbapenem compounds as shown for example by Amar S. Prashad, Nancy Vlahos, Paul Fabio and Gregg B. Feigelson, Tetrahedron Letters, 39, (1998), 7035-7038 and L. D. Cama and B. G. Christensen, J. Am. Chem. Soc., 100, 8006(1978). However, following removal of protection groups (PNB) and (PNZ), chromatography is required to separate and isolate the carbapenem product, often in low yield, from contaminates. While production of carbapenems typically proceeds via removal of a single ester protecting group (PNB) in the presence of a buffer, the separation and isolation of a carbapenem from unwanted contaminates is difficult and is increasingly more difficult when two or more protecting groups, (PNB) and (PNZ) are simultaneously removed.
Japanese Kokai Application Patent No. Hei 7[1995]-70137 teaches the removal of a single (PNB) ester protecting group from 2-(mono- or disubstituted-6,7-dihydro-5H-pyrazo[1,2-a]pyrazolium-6-yl)thiocarbapenems, of the formula
by hydrogenation in the presence of palladium-on-carbon. Removal of the (PNB) group by hydrogenation is carried out in aqueous acetic acid buffer at pH 5.5, or morpholinopropanesulfonic acid-sodium hydroxide buffer solution at pH 5.5, or phosphate buffer at pH 5.5, or dipotassium phosphate, or sodium hydrogen carbonate in solvent mixtures which include tetrahydrofuran-water, tetrahydrofuran-water-ethanol, dioxane-water, dioxane-water-ethanol and butanol-water to afford the 2-(mono- or disubstituted-6,7-dihydro-5H-pyrazo[1,2-a]pyrazolium-6-yl)thiocarbapenems. The application teaches ion-exchange and chromatographic separation of the 2-(mono- or disubstituted-6,7-dihydro-5H-pyrazo[1,2-a]pyrazolium-6-yl)thiocarbapenems from organic by-products arising from the (PNB) protecting group, which include 4-methylaniline, as well as from salts or buffer salts.
An example of removing (PNB) and (PNZ) protecting groups simultaneously in the presence of buffers and requiring chromatography for purification is shown in U.S. Pat. No. 5,602,118 which teaches a method of synthesizing (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, by reaction of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)-butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate with hydrogen. The reaction proceeds in the presence of palladium-on-charcoal, palladium hydroxide, platinum oxide or the like in solvent mixtures such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether-buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like and also dioxane-water-sodium bicarbonate, dioxane-water-buffer, ethyl acetate-water-sodium bicarbonate to remove the (PNB) and/or (PNZ) protecting groups. The removal of (PNB) and/or (PNZ) groups proceeds wherein the pH is modulated by acid acceptors which includes buffers, sodium bicarbonate or potassium bicarbonate. In particular, the carbon dioxide formed from the removal of the (PNZ) protecting group is neutralized by buffers and sodium or potassium bicarbonate used in the reaction mixtures. The pH is maintained during the simultaneous removal of the (PNZ) and (PNB) blocking groups or adjusted after removal. According to U.S. Pat. No. 5,602,118 the carbapenems are isolated from the organic by-products arising from the (PNB) and/or (PNZ) protecting groups, which include 4-methylaniline, as well as from buffer salts, by chromatography.
SUMMARY OF THE INVENTION
As described in the present invention, carbapenem, (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, is advantageously prepared from 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate by deprotecting (PNB) and (PNZ) protecting groups in a biphasic solvent mixture having an organic solvent portion and a water portion and without the use of acid acceptors for pH modulation. While not being bound by theory, simultaneous removal of the (PNZ) and (PNB) protecting groups, provides spontaneous decarboxylation forming carbon dioxide. Surprisingly, the present invention, provides a process which permits the deprotection of the (PNB) and (PNZ) protecting groups in a biphasic solvent mixture, without the use of acid acceptors for pH modulation. The process advantageously does not require a specific pH or pH adjustment during or after the simultaneous removal of the (PNZ) and (PNB) protecting groups. The carbon dioxide formed in the deprotecting of the (PNZ) group is miscible in the water portion of the biphasic solvent system as is the deprotected carbapenem, (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and without further pH adjustment, the deprotected carbapenem is isolated from the separated water portion. Additionally, the 4-methylaniline formed in the deprotection of the (PNB) and (PNZ) groups is miscible in the organic solvent portion and does not interfere with the isolation of the deprotected carbapenem (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid from the separated water portion. A distinct advantage of the process of the invention is that (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid can be isolated in the absence of chromatography from the separated water portion.
The present invention provides a process for producing (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-
Li Zhong
Lin Yang-I
Mansour Tarek
Sum Phaik-Eng
Berch Mark L.
Moran Daniel B.
Szatkowski Thomas S.
Wyeth, Five Giralda Farms
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