Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-08
2003-12-09
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06660855
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to crystalline penicillin and a process for preparing the same, and more specifically to diphenylmethyl 2-methyl-2-triazolylmethylpenam-3-carboxylate crystal and a process for preparing the same.
BACKGROUND ART
Diphenylmethyl 2-methyl-2-triazolylmethylpenam-3-carboxylate (hereinafter referred to as “TMPB” where appropriate) is a compound useful as an intermediate for preparing tazobactam represented by the formula (1).
Tazobactam has a very low antibacterial activity so that it is not used as an antibiotic per se. But it exhibits a beta-lactamase inhibitory activity when irreversibly bonded to beta-lactamases produced by microorganisms. For this reason, tazobactam may be used in mixture with known antibiotics prone to be inactivated by beta-lactamase to allow them to exhibit their inherent antibacterial activity against beta-lactamase-producing microorganisms (Katsuji SAKAI, Recent Antibiotics Manual, 10
th
edition, page 113).
Tazobactam has a chemical structure of having 1,2,3-triazolylmethyl group in the 3-position. Tazobactam is prepared essentially via an intermediate for synthesis of tazobactam such as TMPB, p-nitrobenzyl 2-methyl-2-triazolylmethylpenam-3-carboxylate or the like. Using TMPB, a high-purity tazobactam can be prepared in a high yield by an industrially simple and inexpensive process.
Usually, TMPB is manufactured by the process disclosed, e.g., in Japanese Examined Patent Publication No. 121949/1995. The process comprises the steps of reacting diphenylmethyl 2-chloromethyl-2-methylpenam-3-carboxylate with 1,2,3-triazole in a solvent in the presence of a base, distilling off the solvent, extracting the mixture with methylene chloride, distilling off the methylene chloride and optionally subjecting the residue to chromatography using silica gel column or the like. Useful solvents include organic solvents such as acetone, acetonitrile and the like, and a solvent mixture of the organic solvent and water.
However, the TMPB-containing solid obtained by the process disclosed in the foregoing publication is unstable since TMPB has a 1,2,3-triazole skeleton having a nucleophilic reactivity in the molecule. For example, when stored at room temperature, the solid decomposes and degrades in properties. It is desirable that an intermediate of pharmaceutical maintains a high purity for a long time and can be stably handled without decomposition or degradation of properties under mild and economical conditions, e.g., for storage at ordinary temperature. For this reason, the TMPB-containing solid obtained by the above-mentioned process is not favorable as an intermediate of pharmaceuticals.
Japanese Unexamined Patent Publication No. 53462/1996, especially in Example 3, discloses that TMPB is produced in a yield of 87% by a process comprising reacting diphenylmethyl 2-methyl-2-aminomethylpenam-3-carboxylate with 2,2-dichloroacetoaldehyde-p-toluenesulfonyl hydrazone in methanol at room temperature, concentrating the reaction mixture, dissolving the residue in methylene chloride, filtering the solution, concentrating the filtrate, and crystallizing the residue in a solvent mixture of ethyl acetate and n-hexane (1:1).
However, the TMPB prepared by such process does not exhibit a clear X-ray powder diffraction pattern, and is in the form of amorphous powder. This TMPB amorphous powder is unstable like the foregoing TMPB-containing solid and is likely to decompose and to degenerate when stored at room temperature (e.g. 5 to 35° C.) for a long time.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a TMPB substance which is highly stable and is unlikely to decompose and to change in properties even when stored at room temperature for a long time.
Another object of the invention is to provide a process for preparing a TMPB substance which is highly stable and is unlikely to decompose and to change in properties even when stored at room temperature for a long time.
The present inventors conducted extensive research to achieve these objects, and succeeded in producing TMPB crystals which are different in properties from known TMPB-containing solid and amorphous powder. Based on this novel finding, the invention has been completed.
According to the invention, there is provided a TMPB crystal (hereinafter referred to as “crystalline penicillin”) characterized by having peaks at the following interplanar spacings in the X-ray powder diffraction pattern obtained by copper radiation of &lgr;=1.5418 angstroms through a monochromator.
d (interplanar spacing)
9.026-9.977
7.192-7.949
6.056-6.694
4.810-5.317
4.662-5.153
4.509-4.984
4.193-4.635
4.120-4.554
4.043-4.447
3.801-4.201
3.602-3.981
3.421-3.781
3.031-3.350
According to the invention, there is provided a process for preparing a crystalline penicillin, the process comprising the steps of concentrating a solution containing TMPB represented by the formula (2)
wherein Ph is a phenyl group, diluting the concentrate with acetic ester, and mixing the diluted solution with hexane or a solvent mixture of hexane and acetic ester to crystallize the TMPB out of the solution.
The crystalline penicillin of the invention, although having a 1,2,3-triazole skeleton with a nucleophilic reactivity in the crystal molecule, is stable without likelihood to decompose and to degenerate even when stored at room temperature for a period of one year or longer, and can retain the high purity, e.g. 90% or higher (especially 95% or higher). With this feature, the crystalline penicillin of the invention is very useful as an intermediate of tazobactam or like pharmaceuticals.
Using the crystalline penicillin of the invention, tazobactam having a purity of 99.9% or higher can be prepared in a yield of 91% or higher.
TMPB of the Invention
The TMPB of the invention is represented by the formula (2)
wherein Ph is as defined above.
The crystalline penicillin of the invention is composed of TMPB crystals having peaks in the above X-ray powder diffraction spectrum. An example includes the crystals having the X-ray powder diffraction spectrum shown below:
d (interplanar spacing)
Relative intensity(I/Io)
9.026-9.977
1.00
7.192-7.949
0.32-0.47
6.056-6.694
0.10-0.16
4.810-5.317
0.46-0.55
4.662-5.153
0.10-0.19
4.509-4.984
0.35-0.65
4.193-4.635
0.20-0.22
4.120-4.554
0.19-0.25
4.043-4.447
0.19-0.31
3.801-4.201
0.13-0.19
3.602-3.981
0.05-0.07
3.421-3.781
0.11-0.17
1.031-3.350
0.06-0.09
In the invention, the X-ray powder diffraction spectrum was measured with use of RINT2000/PC manufactured by Rigaku International Corporation.
Process for Preparing TMPB of the Invention
The crystalline penicillin of the invention can be prepared by concentrating a solution containing TMPB, diluting the concentrate with acetic ester, and mixing the diluted solution with hexane or a solvent mixture of hexane and acetic ester.
The TMPB-containing solution can be prepared, for example, by the known process disclosed in Japanese Examined Patent Publication No.121949/1995. For example, the TMPB-containing solution which can be used in the invention may be a reaction solution prepared by reacting diphenylmethyl 2-halomethyl-2-methylpenam-3-carboxylate with 1,2,3-triazole in a solvent or a reaction solution prepared by distilling off the solvent from the above-mentioned reaction solution and dissolving the residue in a suitable solvent such as methylene chloride, acetone, acetonitrile or the like.
The content of TMPB in the TMPB-containing solution is not limited and can be suitably selected from a wide range. Usually it is in the range of about 0.5 to about 15% by weight, preferably about 3 to about 10% by weight.
The amount of 1,2,3-triazole to be used in the reaction between diphenylmethyl 2-halomethyl-2-methylpenam-3-carboxylate and 1,2,3-triazole is in the range of about 1 to about 40 mole equivalents, preferably about 15 to about 35 mole equivalents, per mole of diphenylmethyl 2-halomethyl-2-methylpenam-3-carboxylate. Solvents useful in the reaction are organic solvents such as methylene chloride, acetone, acet
Kawahara Ichiro
Shimabayashi Akihiro
Armstrong Westerman & Hattori, LLP
Berch Mark L.
Otsuka Chemical Co. Ltd.
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