JPH04235188A - Crystal of penem compound, production thereof and antimicrobial agent - Google Patents

Abstract

PURPOSE:To obtain crystal of (+)-(5S,6S)-6-[(R)-1--hydroxyethyl]-3-(3-pyridyl)-7- oxo-4-thia-1--azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxoymethyl ester having storage stability. CONSTITUTION:New crystal of the above-mentioned ester having a X-ray diffraction pattern by powder method showing main peaks at face distance of 12.8, 8.8, 5.6, 4.44, 4.36 and 4.2 A. This crystal is produced by mixing a solution of an ester shown by the formula in a good solvent (e.g. ethanol) with a poor solvent having compatibility with the good solvent while stirring and cooling to <=30 deg.C.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to crystals of penem compounds useful as pharmaceutical antibacterial compounds and a method for producing the same.

0002

BACKGROUND OF THE INVENTION JP-A No. 62-263183 discloses certain 2-pyridyl-penem compounds, among which, in particular, the formula:

(+)-(5R,6S)-6-[(R)-1
-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester, especially , is a useful penem compound that has excellent antibacterial activity against not only Gram-negative bacteria but also Gram-positive bacteria when administered orally, and its practical application is being investigated. However, while the penem compound exhibits excellent antibacterial activity, it has so far only been obtained in an amorphous form, and this amorphous solid is insufficiently stable and changes color when stored for a long time under normal conditions. However, there is a problem that the content of the active ingredient decreases during formulation. Furthermore, there is a problem in that a complicated purification process is required to make the amorphous solid substantially pure. Therefore,
In order to solve these problems, the present inventors conducted intensive studies to obtain the penem compound exhibiting excellent antibacterial activity in a form with good storage stability, and as a result, the penem compound was obtained in the form of stable crystals. In addition, the present inventors have discovered that crystals can be easily purified by crystallization, and that crystals can be obtained from a water-ethanol system, which is advantageous as a medicine in terms of the residual solvent of the crystals, and have completed the present invention.

0003

[Means for Solving the Problems] The present invention has determined by powder X-ray diffraction that the interplanar spacings are 12.8, 8.8, 5.6, 4.44,
(+)-(5R,6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo with a diffraction pattern showing main peaks at 4.36 and 4.2 Å −
4-thia-1-azabicyclo[3.2.0]hept-2
-Ene-2-carboxylic acid pivaloyloxymethyl ester crystals are provided. The crystal is an amorphous (
+)-(5R,6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept- It is obtained by dissolving 2-ene-2-carboxylic acid pivaloyloxymethyl ester in a good solvent, then adding a poor solvent that is miscible with the solvent, stirring, and cooling to 15°C or less. , the present invention also provides a method for producing such crystals.

Amorphous (+)-(5R,6S)- used
6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[
3.2.0] hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester is disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 62-2631.
The sodium salt can be obtained by esterification with iodomethyl pivalate according to the disclosure of No. 83. Examples of good solvents for the amorphous penem compound include lower alcohols such as methanol, ethanol, propanol, and isopropanol, and esters such as ethyl acetate.
For crystallization, if necessary, the amorphous penem compound is dissolved in a good solvent by heating to a temperature of about 40°C.
The concentration of the amorphous penem compound is not particularly limited, and from the viewpoint of increasing the yield of crystals, it is desirable that the concentration be as high as possible. In the present invention, without isolating the amorphous penem compound, the reaction mixture of the esterification step in its production is diluted with the good solvent, purified, and if desired, preferably concentrated under reduced pressure. It may also be used as

Examples of poor solvents that are miscible with the good solvent include water when alcohol is used as the good solvent, and ethyl ether, n-hexane, petroleum ether and the like when ester is used as the good solvent. The amount of the poor solvent to be added may be an amount sufficient to crystallize the penem compound, and usually the volume ratio of good solvent to poor solvent may be about 1:1.5 to 10. When a mixed solution of a good solvent and a poor solvent containing the penem compound is stirred at a temperature of room temperature to 35°C (-10°C to 35°C) for 5 minutes to 2 hours, the penem compound begins to crystallize. On this occasion,
Crystallization may be promoted by rubbing the container wall in a conventional manner. Then, the temperature is 30°C or less, preferably -5°C to 15°C.
The crystallization is completed by cooling to 0.degree. C. and further stirring or standing for 30 minutes to 20 hours. The obtained crystals are washed, dried and isolated by conventional methods.

[0006] The thus obtained crystal of the present invention has a crystal size of about 95
It has a melting point of ~96°C and has a lattice spacing of 1 by powder X-ray diffraction.
2.8, 8.8, 5.6, 4.44, 4.36, 4.2
It shows a diffraction pattern with a main peak of Å. The crystals are useful as antibiotics exhibiting a broad antibacterial spectrum when administered orally, for example, against Gram-positive cocci such as Staphylococcus aureus, Staphylococcus pyogenes, Streptococcus pneumonia, Streptococcus faecalis, and Neisseria sp. and has a minimum inhibitory concentration against Gram-negative cocci of less than about 8 μg/ml. It also has a minimum inhibitory concentration of about 64 μl/ml or less against anaerobic bacteria such as Gram-negative bacilli such as Enterobacteriaceae, Haemophilus influenzae, and Pseudomonas species, and Bacteroides species. Furthermore, it exhibits an ED50 of about 0.5-15 mg/kg by oral administration in systemic infection of mice with Streptococcus aureus. Therefore, the crystals can be used as a therapeutic agent for bacterial infections, such as respiratory infections, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections in humans and other mammals. It can be used for the treatment and prevention of otorhinolaryngological infections, surgical infections, etc.

For oral administration, the crystals can be formulated into tablets or capsules in a conventional manner, and these can be formulated into tablets or capsules containing, for example, lactose,
Glucose, sucrose, mannitol, sorbitol, cellulose, diluents such as glycine, silica, talc, stearic acid or its salts, lubricants such as polyethylene glycol, magnesium aluminum silicate, starch, gelatin, gums, cellulose derivatives, polyvinyl It may contain various additives such as a binder such as pyrrolidone, a disintegrant such as starch, alginic acid or a salt thereof, a coloring agent, a flavoring agent, a sweetener, and the like. Although the dosage varies depending on the target patient and symptoms, the desired effect can usually be obtained by oral administration of about 50 mg to 1 g per day for an adult weighing 70 kg.

EXAMPLES Next, the present invention will be explained in more detail with reference to reference examples and examples, but the present invention is not limited thereto. Reference Example 2-[(3S,4R)-3-[(R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxoazetidin-1-yl]-2-triphenylphosphoranylidene acetic acid allyl ester 6.96 g of silver salt was dissolved in 110 ml of methylene chloride, and at 0°C, 3.2 ml of pyridine, 200 mg of 4-dimethylaminopyridine, and then 2.6 ml of nicotinoyl chloride hydrochloride were dissolved.
8 g was added and stirred for 20 minutes. The resulting solid was filtered off,
The filtrate was washed with sodium bicarbonate and then saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, eluted with toluene-ethyl acetate (9:1 to 3:2), and 2-[(3S,4R)-3- [(R)-1-allyloxycarbonyloxyethyl]-4-nicotinoylthio-2-oxoazetidin-1-yl]-2-triphenylphosphoranylidene acetic acid allyl ester was obtained [TL
C: Rf=0.33 (silica gel, ethyl acetate)]. 3.1 g of this ester was dissolved in 600 ml of toluene and stirred at reflux temperature for 3 hours under an argon atmosphere. The solvent was evaporated and the residue was chromatographed on silica gel using toluene-ethyl acetate (9:1 to 85:15).
) and eluted with (5R,6S)-6-[(R)-1-allyloxycarbonyloxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-asabicyclo[3.
2.0] hept-2-ene-2-carboxylic acid allyl ester was obtained [TLC: Rf=0.5 (silica gel, ethyl acetate)].

Allyl ester of penem compound obtained 1
．． 1 g was dissolved in 48 ml of tetrahydrofuran, and 111 mg of tetrakis(triphenylphosphine)palladium and 1.6 ml of tributyltin hydride were added thereto. After stirring at room temperature for 35 minutes, 0.36 ml of acetic acid was added dropwise, and the mixture was further stirred for 30 minutes and concentrated using a rotary evaporator. Water the residue
It was taken up in ethyl acetate and neutralized with sodium bicarbonate. The aqueous phase was washed twice with ethyl acetate and concentrated under vacuum. Chromatography on OptiUPC12 and elution with water gave the corresponding sodium salt [TLC: Rf
=0.61 (OptiUPC12, water)]. 62 mg of this sodium salt was dissolved in 1.5 ml of dimethylformamide, and after cooling to 0° C., 53 microliters of iodomethyl pivalate was added. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate, washed three times with saturated sodium chloride solution, dried and concentrated. The residue was subjected to silica gel column chromatography and eluted with toluene-ethyl acetate 3:1 to 1:1 to obtain the corresponding methyl pivaloyloxymethyl ester [TLC: Rf = 0.34 (
silica gel. Ethyl acetate)]. This product was a hygroscopic powder and was confirmed to be amorphous by X-ray diffraction.

Example 1 (+)-(5R,6S)-6-[ obtained in the above reference example
(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-asabicyclo[3.2
．． 0] 19.5 g of amorphous powder of hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester was dissolved in 98 ml of ethanol. This solution was heated to 31°C, 146 ml of water heated to 32°C was added, and activated carbon (Shirasagi P, manufactured by Takeda Pharmaceutical Co., Ltd.)
g and stirred for 10 minutes. The activated carbon was then filtered off and washed with a mixed solution of 20 ml of ethanol and 29 ml of water. The filtrate was stirred at 25-30°C for 1 hour, then cooled to 10°C and further stirred for 1 hour. The crystallized crystals were collected by filtration, washed successively with a mixture of 20 ml of ethanol and 39 ml of water, and 120 ml of water, and dried at 35° C. under reduced pressure for about 5 hours to obtain 16.6 g of crystals of the ester as a white powder. It was done. Melting point: 9
5-96°C Moisture (Karl Fischer method): 0.02% Ethanol content (measured by gas chromatography): 0.03% Powder X-ray diffraction pattern: The diffraction pattern is shown in the attached Figure 1.

Example 2 1.18 g of the amorphous powder of the ester obtained in Reference Example was dissolved in 12 ml of ethyl acetate, and n-
24 ml of hexane was added. This solution was heated at 25°C.
After stirring for 20 minutes, the mixture was cooled to 5° C. and allowed to stand for 1 hour. The crystallized crystals were collected by filtration, washed with 9 ml of ethyl ether, and dried under reduced pressure to give 0.8 mL of crystals of the ester.
4g was obtained. Melting point: 95.5-96°C IR (KBr method): 1766, 1714, 1320, 1
138, 1106, 982 cm-1 NMR (CDCl3): δ1.16 (9H, S),
1.38 (3H, d, J=6Hz), 3.84 (1H,
dd, J=1.5×6Hz), 4.28(1H, qui
nt. , J=6Hz), 5.66, 5.77 (2H, A
Bq, J = 5.5Hz), 5.77 (1H, d, J = 1
．． 5Hz), 7.2-8.7 (4H, m) ppm Powder X-ray diffraction pattern: Characteristic peaks similar to those obtained in Example 1 were shown.

Example 3 A diluted ethyl acetate solution containing 1530 g of the ester in Reference Example was concentrated under reduced pressure until it became a viscous oil. Add 4.5 liters of ethyl ether to this oil and
After stirring at 5°C for 30 minutes, the mixture was allowed to stand at 5°C for 16 hours. The crystallized crystals were collected by filtration, washed with 4.5 liters of ethyl ether, and dried under reduced pressure at 35° C. for about 7 hours to obtain 1131 g of crystals (first crystals) of the ester. Melting point: 96-96.5°C Concentrate the filtrate under reduced pressure, add 1.2 liters of ethyl ether to about 600 g of the obtained oil, stir at 25°C for 1.5 hours, and further stir at 5°C for 30 minutes. did. The crystals formed were collected by filtration and washed with 1.2 liters of ethyl ether.
The ester crystals (
335 g of second crystal) was obtained. Melting point: 96° C. Powder X-ray diffraction pattern: Both the first crystal and the second crystal showed characteristic peaks similar to those obtained in Example 1.

Example 4 50,000 tablets were manufactured using the formulation shown below. prescription
1 tablet (mg) 5
0000 tablets (kg) Crystals of the ester of the present invention 139
6.95 Lactose
28
1.4 Corn starch 26.4
1.32 Hydroxypropyl cellulose 6
0.3 Magnesium stearate 0.6
0.03
total
200
10 6.95 kg of crystals of the ester of the present invention, 1.4 lactose
kg and a portion of 1 kg of corn starch were placed in a fluidized granulator (FD-S-2, manufactured by Powrex) and mixed.
Next, 5 kg of 6% hydroxypropyl cellulose aqueous solution
(0.3 kg as hydroxypropyl cellulose) was sprayed and granulated. 0.32 kg of corn starch and 0.0 magnesium stearate were added to the resulting granulated powder.
After adding 3 kg and mixing well, use a rotary tablet machine (
About 5 tablets with a diameter of 8 mm (Clean Press, Kikusui Seisakusho)
0000 tablets were manufactured.

Experimental Example A crystalline powder of ester produced by the method of the present invention and an amorphous powder produced by the reference example were stored in a dark place in a sealed container at a temperature of 60° C., and the residual rate was examined. Type of powder
Storage conditions Survival rate Amorphous powder
60℃ 14 days 37.7%
Crystalline powder of Example 1 60°C 1
9 days 98.7% Crystalline powder of Example 2 60°C 14 days
98.9%

[0015]

According to the present invention, (+)-(5S,6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7- exhibits excellent antibacterial activity. Oxo-4-
Crystals of thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester with good storage stability can be obtained using a water-ethanol system which is advantageous in terms of residual solvent. These crystals are extremely useful when using the compound as a pharmaceutical preparation.

[Brief explanation of the drawing]

[Figure 1] (+)-(5S,6S)-6-[(R)-
1-hydroxyethyl]-3-(3-pyridyl)-7-
Figure 2 is a powder X-ray diffraction pattern of oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester.

Claims (3)

[Claims] Claim 1: According to powder X-ray diffraction, the interplanar spacing is 12.8.
, 8.8, 5.6, 4.44, 4.36, 4.2 Å.
S)-6-[(R)-1-hydroxyethyl]-3-(
Crystals of pivaloyloxymethyl 3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. Claim 2: (+)-(5R,6S)-6-[(R
)-1-hydroxyethyl]-3-(3-pyridyl)-
7-oxo-4-thia-1-azabicyclo[3.2.0
] A poor solvent miscible with the good solvent is added to a good solvent solution of hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester, stirred, cooled to 30°C or less, and subjected to powder X-ray diffraction. Accordingly, the surface spacing is 12.8, 8.8, 5.6, 4.4
(+)-(5R,6S)-6-[(R)-1- with a diffraction pattern showing main peaks at 4, 4.36, and 4.2 Å
Obtaining crystals of pivaloyloxymethyl hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A method for producing the crystal, characterized by: 3. An antibacterial agent comprising the crystal according to claim 1.