Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-18
2001-09-11
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S226000, C540S227000
Reexamination Certificate
active
06288223
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel process for producing selectively and in a high yield the Z-isomer (cis-isomer) of a cephalosporin antibiotic having a 2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl group as the 3-substituent, or the Z-isomer (cis-isomer) of such a 7-amino-3-[2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or a protected derivative thereof which is utilizable as an intermediate for the synthesis of the said cephalosporin antibiotic. This invention also relates to a novel process for producing efficiently and in a facile way a highly pure Z-isomer (cis-isomer)of a 7-[2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetamido]-3-[2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid, or a 7-amino-3-[2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or a protected derivative thereof.
BACKGROUND ART
Japanese Patent Publication No. Hei 3-64503 (Japanese Patent No. 1698887), U.S. Pat. No. 4,839,350 or European Patent No. 0175610 specification discloses 7-[2-methoxyimino-2-(2-amino-thiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer) represented by the following formula (A)
This compound is an excellent cephalosporin antibiotic called as “Cefditoren”. The excellent antibacterial activity of Cefditoren against gram-negative bacteria is attributable to the fact that the Cefditoren compound has the Z-configuration such that the cephem ring and the 4-methylthiazol-5-yl group of Cefditoren are connected in the cis-configuration to the carbon-carbon double bond of the 3-vinyl group of the Cefditoren molecule.
7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (syn-isomer, cis-isomer), which is derived by esterifying the 4-cartboxyl group of the above-mentioned Cefditoren compound with pivaloyloxymethyl group, is represented by the following formula (B)
and is a pro-drug known as a general name “Cefditoren pivoxil” (refer to “Merck Index” 12th Edition, Page 317). In cases of the 3-(2-substituted-vinyl)-cephalosporin antibiotics, it is generally known that the Z-isomer (cis-isomer) is superior to the E-isomer (trans-isomer) in the various properties of the antibiotics.
The above-mentioned 3-(2-substituted-vinyl)-cephalosporin antibiotics including Cefditoren, or intermediates usable for the synthesis of said antibiotics may be prepared by various processes. As one of the processes available for the production of these antibiotics, there is known a process using Wittig's reaction. Such a process for the preparation of the 3-(2-substituted-vinyl)-cephalosporin antibiotics or the intermediates for their synthesis which comprises using Wittig's reaction is disclosed, for example, in Japanese Patent Application first publication KOKAI Hei-3-264590 or the corresponding U.S. Pat. No. 5,233,035 or European Patent Application Publication No. 0175610A2; the “Journal of Antibiotics” XLIII, No. 8, pages 1047-1050 (1990), “Chem. Pharm. Bull.” Vol. 39, No. 9, pages 2433-2436(1991), and international Publication No. W095/09171 (published on Apr. 6, 1995) of PCT Application No.PCT/JP94/01618 or the corresponding European Patent Application Publication No. 0734965A1 specification. By conducting the Wittig's reaction step in accordance with the prior art processes, the resultant reaction product has always been given in the form of a mixture of the Z-isomer and E-isomer of the produced compound.
For example, the “Journal of Antibiotics” XLIII, No. 8, pages 1047-1050 and “Chem. Pharm. Bull.” Vol. 39, No. 9, pages 2433-2436 mentioned above disclose a process for the preparation of such 4-methoxybenzyl ester of 7-&bgr;-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid, which may be used for the synthesis of the aforesaid 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyirnino-acetamido]-3-(Z)-(4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylic acid. In this process, there are carried out the steps of treating p-methoxybenzyl ester of 7-&bgr;-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid with sodium iodide in acetone to produce the corresponding 3-iodomethyl derivative; treating this derivative with triphenylphosphine to produce the corresponding triphenylphosphonium iodide derivative; and reacting this triphenylphosphonium iodide derivative with 5-formyl-4-methylthiazol by the Wittig's reaction at room temperature in a heterogeneous reaction medium comprising dichloromethane (i.e. methylene chloride) and water in the presence of sodium hydrogen carbonate, thereby to produce the 4-methoxybenzyl ester of 7-&bgr;-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid.
The above-mentioned process may be expressed by the following reaction scheme:
In the above-mentioned process, there is produced, as an intermediate product, 4-methoxybenzyl ester of 7-&bgr;-phenylacetamido-3- [(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylic acid of formula (F) above, which is then reacted with 5-formyl-4-methylthiazole by the Wittig's reaction to produce 4-methoxybenzyl ester of 7-&bgr;-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid of formula (H). The reaction product of formula (H) is described in the above-mentioned literature to have been obtained in the form of a mixture of the Z-isomer (cis-isomer) and E-isomer (trans-isomer) of the compound (H) at a mix ratio of 4.7:1.
The above literature “Journal of Antibiotics” describes that the mixed Z-isomer and E-isomer of the compound of formula (H) is difficult to be isolated from each other even by treating with a column chromatographic technique. Then, said literature further discloses that the Z-isomer of the target product could be isolated only by effecting amethod comprising removing the 7-phenylacetyl group fro:m the compound of formula (H) by a deprotection technique, condensing the 7-position of the deprotected product with 2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetic acid, subjecting the resulting condensation product to a deprotection reaction, then subjecting the resulting deprotected product to a column chromatography with a non-ionic porous resin, and further subjecting the resulting product so purified to a fractional crystallization. Thus, the yield of the desired Z-isomer as finally harvested was necessarily low to a considerable extent.
Further, Japanese Patent Application First Publication KOKAI Hei-7-188250 or the corresponding U.S. Pat. No. 5,616, 703 or European Patent Application Publication No. 658558A1 specification discloses that the reaction product, which comprised 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or a derivative thereof having the following formula (J)
where R is a protecting group of silyl type or a hydrogen atom and which was produced by the Witting's reaction, is a mixture of the Z-isomer and E-isomer. The Japanese Patent Application First Publication KOKAI Hei-7-188250 specification also discloses a method for the isolation of the Z-isomer which comprises converting the Z/E mixture of 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]3-cephem-4-carboxylic acid into a corresponding amine salt and subjecting the amine salt so obtained to a recrystallization step. This Publication further discloses that when the said Z/E mixture is subjected to a chromatography, there can be obtained the Z-isomer from which the E-isomer of a lower activity has been removed as much as possible.
Further, the above-mentioned PCT International Publication No. WO95/09171 discloses a process which comprises the steps of treating a phosphonium halide compound represented by the following formula (K)
where X is CH or N, R
11
is an amino group or a protected amino group, R
12
is a hydrogen atom or a hydroxyimino-prote
Iinuma Katsuharu
Iwasawa Hiroyuki
Murai Yasushi
Okada Yumiko
Sukegawa Masamichi
Berch Mark L.
Larson & Taylor PLC
Meiji Seika Kaisha Ltd.
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