Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-14
2003-11-04
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S225000, C540S227000, C540S228000, C540S314000, C540S328000, C540S350000
Reexamination Certificate
active
06642377
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel and industrially-excellent process for producing a basic antibiotic.inorganic acid salt. For example, herein described is an industrially-excellent production process for producing an inorganic acid salt of an excellent antimicrobial agent having strong antimicrobial action on gram-positive bacteria and gram-negative bacteria, disclosed in JP-A 8-73462. More specifically, it relates to an industrially-excellent production process for producing, for example, (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylic acid.hydrochloride, a novel oxalate useful as a production intermediate, and a process for producing it.
PRIOR ART
In order to produce a basic antibiotic.inorganic acid salt, it is generally known to produce a free form, purify by column chromatography etc., and react the product with an inorganic acid.
For example, in the process disclosed in JP-A 8-73462, WO96/01261 or Example 9 of EP-A 773222 as a process for producing (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylic acid.hydrochloride etc., the objective product is obtained by subjecting a p-nitrobenzyl ester compound to catalytic reduction, purifying by reversed-phase silica gel chromatography, converting the product to a hydrochloride, and subjecting it to freeze-drying.
In the above-mentioned process in the prior art, the purification by chromatography is performed. Thus, a solvent is used in a large amount. Therefore, costs for the production rise to a considerable degree. Additionally, many problems as follows arise: difficulty in industrial processing in large amounts, the possibility of generating thermal cruelty (thermal decomposition) at the time of concentrating fractions, solvent remaining in the final product, disposal of waste liquid and environment pollution due to transpiration of the solvent. Thus, it cannot be said that the process is suitable for industry.
Moreover, it is necessary to perform subtle adjustment of pH when the free form is produced (neutralized) or converted to the hydrochloride. Thus, the process requires much labor and cost in industrial production. Moreover, freeze-drying is required in the last step, and results additional problems as follows: a further rise in the production costs, unsuitability thereof for processing in large amount and necessity of much
DISCLOSURE OF THE INVENTION
Thus, the present inventors made eager investigations to pursue a novel production process excellent in viewpoints such as production costs, operability (workability, safety and non-toxicity), the purity of final products, and the protection of the environment.
As a result, they have found out that the above-mentioned problems can be overcome at a stroke by using a novel oxalate (which will be in detail described below) as a production intermediate, and subjecting the oxalate to salt-exchange with an alkali earth metal salt an inorganic acid. Thus, they have accomplished the present invention.
Therefore, an object of the present invention is to provide a novel production process useful for producing a basic antibiotic.inorganic acid salt industrially, and a novel production intermediate useful for producing antimicrobial agents, and a process for producing it.
In one embodiment, the present invention is a process for producing a basic antibiotic.inorganic acid salt (I), which comprises subjecting a basic antibiotic.oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid.
wherein the ring A means the basic antibiotic; R
10
means a protected functional group used in organic synthesis; Ak—E means the alkali earth metal; and B means the inorganic acid.
In another embodiment, the present invention is a process for producing a basic antibiotic.inorganic acid salt (I), which comprises subjecting a basic antibiotic protector.oxalate (VI) to deprotection reaction; and then subjecting to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. The present invention is also a process for producing a basic antibiotic.inorganic acid salt (I), which comprises subjecting a basic antibiotic protector.oxalate (VI) to deprotection reaction; then subjecting to salt-exchange with an alkali earth metal salt (III) of an inorganic acid; and then crystallizing the resultant or resulting compound by adding a poor solvent thereto.
The present invention is also a process for producing (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylic acid.hydrochloride (VIII) represented by the following formula:
which comprises subjecting p-nitrobenzyl(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylate.oxalate (VII) represented by the following formula:
(wherein PNB represents p-nitrobenzyl group) to deprotection reaction; then subjecting to salt-exchange with calcium chloride; and then crystallizing the resulting compound by adding methanol and/or isopropanol thereto.
The present invention is a process for producing a basic antibiotic.inorganic acid salt (I), in which the oxalate (II-I) of a carbapenem compound represented by the following formula is a basic antibiotic.oxalate (II), and which comprises subjecting the basic antibiotic.oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid.
The ring A represents a 3- to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R
6
; R
1
represents hydrogen or methyl group; R
2
and R
5
are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R
3
represents a carboxyl-protecting group; R
4
represents hydrogen, a lower alkyl group or an amino-protecting group; R
6
represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:
(wherein R
7
and R
8
are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1.
The present invention is an oxalate (II-I) of a carbapenem compound represented by the following formula:
wherein the ring A represents a 3- to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R
6
; R
1
represents hydrogen or methyl group; R
2
and R
5
are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R
3
represents a carboxyl-protecting group; R
4
represents hydrogen, a lower alkyl group or an amino-protecting group; R
6
represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:
(wherein R
7
and R
8
are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1.
Further, the present invention is a process for producing p-nitrobenzyl(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3-carboxylate.oxalate (II-III), which comprises reacting p-nitrobenzyl(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate-2-active compound (XIV) represented by the following formula:
(wherein PNB has the same meaning as describ
Chiba Hiroyuki
Ishizuka Hiroyuki
Kayano Akio
Komatsu Yuuki
Nakamura Taiju
Berch Mark L.
Birch & Stewart Kolasch & Birch, LLP
Eisai Co. Ltd.
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