JPH08253482A - Crystalline carbapenem compound - Google Patents

Abstract

PURPOSE: To provide new crystalline carbapenem compound consisting of a specific thiazolin-2-yl-azetidin-5-yl-thio-carbapenemcarboxylic acid compound of crystalline state, exhibiting excellent antibacterial activity and storage stability and useful e.g. as an antibacterial agent for oral administration. CONSTITUTION: This new crystalline carbapenem compound exhibiting excellent antibacterial activity and storage stability and useful e.g. as an antibacterial agent for oral administration is (1R,5S,6S)-2-[1-(thiazolin-2-yl)azetidin-3- yl]thio-6-[(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid of formula I. The compound can be produced by reacting a 2-diphenylphosphoryloxy- carbapenem compound of formula II (PNB is p-nitrobenzyl) with 3- mercapto-1-(thiazolin-2-yl)azetidine hydrochloride of formula III and removing the protecting groups of the product. The obtained amorphous compound is dissolved in water and stirred for 30min at room temperature and then for 30min under ice cooling to obtain the crystalline compound of formula I.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a carbapenem compound, and more particularly to a carbapenem compound represented by the following formula (I):

[0002]

Embedded image

(1R, 5S, 6S) -2-
It relates to various crystal forms of [1- (thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid.

[0004]

2. Description of the Related Art Various carbapenem compounds have been proposed so far, and some of them have already been clinically applied as antibacterial agents. However, all of these are used only as injections, and a carbapenem compound that can be orally administered has not yet been put to practical use. In view of such a situation, the present inventors have previously studied carbapenem compounds that can be orally administered,
Not only the compound represented by the above formula (I) having a 1- (thiazolin-2-yl) azetidin-3-ylthio group as the 2-position substituent of the carbapenem skeleton itself exhibits strong antibacterial activity, but also An ester derivative obtained by esterifying the 3-position carboxyl group with a specific ester residue has excellent absorbability from the digestive tract, and is rapidly hydrolyzed in vivo, whereby the above formula (I) is obtained again.
It was found that the ester derivative can be converted into a compound of formula (I), that is, the above-mentioned ester derivative can be a clinically superior antibacterial agent as a prodrug of the compound of formula (I), particularly an antibacterial agent for oral administration. The patent application for the ester derivative has been completed (Japanese Patent Application No. 6-170496).
issue).

On the other hand, in the case of commercializing a certain compound as a pharmaceutical product, the physical stability of the compound is an important issue from the study of formulation to the shelf life of the product. Also,
Even when a compound is used as a synthetic intermediate for another drug, it is important to improve its physical stability in order to store it as a raw material for industrial production.

INDUSTRIAL APPLICABILITY The present invention can be clinically used as a drug having excellent antibacterial activity, and is useful as a synthetic intermediate of a prodrug of an antibacterial agent which can be orally administered. It has been found that the compounds are obtained in crystalline form and are present in formula (I)
It was completed after confirming that the physical stability of the compound shown in (2) is dramatically improved and it can withstand long-term storage.

[0007]

That is, the present invention is represented by the above formula (I) in a crystalline form (1R, 5S, 6S).
-2- [1- (thiazolin-2-yl) azetidine-3
-Yl] thio-6-[(R) -hydroxyethyl] -1
-Methylcarbapene-2-em-3-carboxylic acid.

The compound represented by the formula (I) of the present invention has various crystal structures depending on the content of water in the crystal.
In particular, the following characteristic forms are possible. That is, as a specific embodiment of the crystalline form of the compound represented by the formula (I) provided by the present invention, (1) a compound represented by the above formula (I) in a crystalline form containing 4 mol of water. (2) In the powder X-ray diffraction pattern, the interplanar spacing (d) 11.
01, 9.75, 7.89, 6.26, 5.67, 4.
89, 4.76, 4.06, 3.82, 3.76, 3.
62, 3.55, 3.53, 3.41, 3.34, 3.
A compound of formula (I) in crystalline form having characteristic peaks at 29, 3.05, 2.95, 2.76 and 2.50 angstroms and comprising 4 moles of water. ) A compound represented by the above formula (I) in a crystalline form containing 1 mol of water; (4) In the powder X-ray diffraction pattern, the interplanar spacing (d) is 10.
99, 9.75, 9.07, 7.88, 7.47, 6.
25, 5.66, 5.50, 4.89, 4.75, 4.
06, 3.81, 3.75, 3.53, 3.41, 3.
33. 3.29, 2.95, 2.76 and 2.50 Angstrom characteristic peaks, and a compound of the above formula (I) in crystalline form comprising 1 mole of water. ) In the powder X-ray diffraction pattern, the interplanar spacing (d) is 10.
06, 7.48, 6.79, 6.56, 6.18, 5.
15, 5.03, 4.68, 4.41, 4.17, 4.
02, 3.74, 3.60, 3.35, 3.28, and 2.92 angstroms are characteristic peaks, and the compounds represented by the above formula (I) in a crystalline form containing no water are mentioned. be able to.

The compounds of various crystal forms represented by the formula (I) provided by the present invention are superior in physical stability to the compounds of the formula (I) existing in an amorphous form, and are long-term. It has the property of withstanding storage. In particular, the compound of formula (I) in a crystalline form containing 4 moles of water can exist extremely stably even under conditions of high temperature and high humidity. From such characteristics, the compound of formula (I) in the crystalline form of the present invention does not decompose or deteriorate in the formulation process or long-term storage when used as a drug substance itself, and has stable product. Quality can be guaranteed.
Further, even when the compound represented by the formula (I) is used as a synthetic intermediate of a prodrug which is an antibacterial agent for oral administration, it is excellent in storage stability and therefore extremely useful as a raw material for large-scale synthesis. .

The method for producing the crystalline compound of formula (I) according to the present invention will be described in detail below. First, the compound of the formula (I) can be produced, for example, according to the method shown in the production example described below, and is subjected to a commonly used purification means such as filtration, extraction, washing, solvent removal, column or thin layer chromatography. Thus, it can be isolated and purified as an amorphous powder.

The compound of formula (I) in the crystalline form provided by the present invention is obtained by crystallizing an amorphous powder of the compound of formula (I) obtained by the above-mentioned method, for example, by the following method. Can be obtained.

That is, the amorphous powder of the compound represented by the formula (I) is dissolved in purified water, and the resulting aqueous solution is left standing or cooled to precipitate crystals. Upon dissolution, it is preferable to carry out stirring at room temperature, but heating can be carried out if necessary. The concentration of the compound of formula (I) in the aqueous solution is at least about 2% (w / v) or higher, and especially 5% (w).
/ V) is preferable in order to improve the yield of crystals. In addition, a suitable organic solvent miscible with water may be added in order to precipitate crystals from the aqueous solution in good yield. Examples of such an organic solvent include acetone and acetonitrile, and acetone is more preferable.

In the method for producing the compound represented by the formula (I), the aqueous solution in which the compound represented by the formula (I) is dissolved is concentrated without taking out the final product as an amorphous powder, and the above-mentioned concentrated solution is concentrated. It is also possible to add an organic solvent and take out directly as a crystal form.

The crystalline form of formula (I) obtained by the above process
The compound represented by contains 1 mol of water with respect to 1 mol of the compound represented by the formula (I), and is shown to be in a crystalline form by observation with a polarization microscope. Interval (d) 10.99, 9.75,
9.07, 7.88, 7.47, 6.25, 5.66,
5.50, 4.89, 4.75, 4.06, 3.81,
3.75, 3.53, 3.41, 3.33, 3.29,
It is identified by having characteristic peaks at 2.95, 2.76 and 2.50 Angstroms. The detailed peak pattern in the powder X-ray diffraction pattern of this crystal form is shown in Example 1 below.

The compound of formula (I) in crystalline form comprising 1 mole of water obtained by the above process is more than the compound of formula (I) which itself exists in amorphous form. Although having excellent physical stability, the compound represented by the formula (I) in the crystal form can be converted into the compound represented by the formula (I) in the more stable crystal form by the following method. That is, the compound of the formula (I) in a crystalline form containing 1 mol of water is allowed to stand at room temperature under humidification for moisture absorption equilibrium. The humidifying condition in this case is not particularly limited, but is usually preferably about 50 to about 95% RH.

The crystalline form of formula (I) obtained by the above method
The compound represented by contains 4 mol of water per 1 mol of the compound represented by the formula (I), and is shown to be in a crystalline form by observation with a polarizing microscope. In particular, in the powder X-ray diffraction pattern, peaks clearly different from those of the compound represented by the formula (I) in a crystalline form containing 1 mole of water, that is, the interplanar spacing (d) 11.01, 9.
75, 7.89, 6.26, 5.67, 4.89, 4.
76, 4.06, 3.82, 3.76, 3.62, 3.
55, 3.53, 3.41, 3.34, 3.29, 3.
It is identified by having characteristic peaks at 05, 2.95, 2.76 and 2.50 angstroms. The detailed peak pattern in the powder X-ray diffraction pattern of this crystal form is shown in Example 4 below.

When the crystalline form of the compound of formula (I) containing water obtained by the above-mentioned method is heated and dried, the water content is lost, and the compound of formula (I) of the crystalline form containing no water is used. It is also possible to obtain the compounds shown. The water-free crystalline form of the compound of formula (I) obtained by this method also has a peak in the powder X-ray diffraction pattern which is clearly different from the other crystalline forms, ie the interplanar spacing (d).
10.06, 7.48, 6.79, 6.56, 6.1
8, 5.15, 5.03, 4.68, 4.41, 4.1
7, 4.02, 3.74, 3.60, 3.35, 3.2
It is identified by having characteristic peaks at 8 and 2.92 Angstroms.

The crystalline form of formula (I) obtained by the above method
As is clear from the results of the test examples described below, the compound represented by shows extremely excellent physical stability as compared with the amorphous powder, and can withstand long-term storage. Therefore, it is extremely useful as a drug substance or as a synthetic intermediate for other drugs, as compared with the amorphous form of the compound represented by the formula (I).

[0019]

EXAMPLES The present invention will be described in more detail below with reference to production examples, examples and test examples, but the present invention is not limited to these descriptions.

The symbols in the following description have the following meanings. Ac: Acetyl PNB: p-nitrobenzyl Production Example 1

[0021]

Embedded image

(1) 3-hydroxyazetidine hydrochloride (1) To a solution of 7.95 g of anhydrous methanol in 73 ml of anhydrous methanol, 5.09 g of potassium hydrogencarbonate was added at room temperature, and 9.67 g of 2- (methylthio) thiazoline was added dropwise. And heat to reflux for 20 hours. After returning the reaction solution to room temperature, 3.63 g of potassium hydrogen carbonate was further added, and the mixture was stirred at the same temperature for 1 hour. After the reaction was completed, the precipitate was filtered off, the solvent was distilled off under reduced pressure,
To the obtained residue, 100 ml of tetrahydrofuran is added and stirred at room temperature for 1 hour. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: chloroform-methanol) to give 3-hydroxy-1- (thiazolin-2-yl).
8.23 g of azetidine (2) as colorless crystals (yield:
71.5%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.356 (t, 2
H, J = 7.26 Hz), 3.70-4.00 (m, 4
H), 4.211 (t, 2H, J = 8.21 Hz),
4.622-4.705 (m, 1H), 4.971
(S, 1H)

(2) As another production method, a solution of 219 mg of the compound (1) in 1.5 ml of anhydrous acetonitrile was cooled to 0 ° C. under a nitrogen stream, and 0.31 ml of triethylamine and then chloroethyl isothiocyanate were added to this solution. A solution of 250 mg of anhydrous acetonitrile in 0.3 ml is added, and the mixture is stirred at the same temperature for 30 minutes and then returned to room temperature and stirred for 2 hours. Dichloromethane was added to the reaction solution, washed with a saturated aqueous solution of potassium carbonate, the dichloromethane layer was dried over magnesium sulfate and then concentrated under reduced pressure to give 3-hydroxy-1-
300 mg (yield: 95%) of (thiazolin-2-yl) azetidine (2) was obtained as colorless needle crystals. NM of this product
The R spectrum was completely in agreement with that obtained in (1) above.

Production Example 2

[0025]

[Chemical 4]

(1) To a suspension of 790 mg of the compound (2) obtained in the above Production Example 1 in 2 ml of anhydrous tetrahydrofuran was added 6 mg of N, N-dimethylaminopyridine under ice cooling.
Then, 557 mg of triethylamine and 575 mg of mesyl chloride are added dropwise under ice cooling, and the mixture is stirred at the same temperature for 40 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was extracted with a saturated aqueous sodium hydrogen carbonate solution, and this aqueous layer was further extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and the residue was subjected to silica gel column chromatography (elution solvent: chloroform-methanol) to give 3-mesyloxy-1- (thiazolin-2-yl) azetidine as colorless crystals. 995 mg (yield: 84.3%) was obtained. ¹ H-NMR (CDCl ₃ , 270 MHz, ppm)
δ: 3.07 (s, 3H), 3.39 (t, 2H, J =
7.6 Hz), 4.03 (t, 2H, J = 7.6H)
z), 4.14-4.19 (m, 2H), 4.37-
4.31 (m, 2H), 5.28-5.33 (m, 1
H)

Then, 3-mesyloxy-1- (thiazolin-2-yl) azetidine 1 obtained by the above reaction
228 mg of potassium thioacetate was added to 1 mg of a solution of 18 mg of anhydrous dimethylformamide at room temperature, and the mixture was stirred at 80 ° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added, the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was back extracted with ethyl acetate. The resulting organic layer is dried over magnesium sulfate, the solvent is evaporated under reduced pressure, and the residue is subjected to silica gel column chromatography (eluting solvent: chloroform) to give 3-acetylthio-1-.
88 mg (yield: 81.2%) of (thiazolin-2-yl) azetidine (3) was obtained as a pale yellow oily substance. ¹ H-NMR (CDCl ₃ ) δ: 2.333 (s, 3
H), 3.352 (t, 2H, J = 7.26 Hz),
3.885 (dd, 2H, J = 8.24, 5.28H
z), 4.012 (t, 2H, J = 7.26 Hz),
4.250-4.374 (m, 1H), 4.426
(T, 2H, J = 8.25 Hz)

(2) As another production method, 119 mg of the compound (2) obtained in Production Example 1 above and thioacetic acid 2
Under ice-cooling, triphenylphosphine and diethylazodicarboxylate are added to 10 ml of tetrahydrofuran solution each containing 2 molar equivalents of triphenylphosphine and diethyl azodicarboxylate, and the mixture is stirred at the same temperature for 1 hour and further at room temperature for 1 hour. The residue obtained by evaporating the solvent of the reaction solution under reduced pressure was subjected to silica gel column chromatography (eluting solvent: chloroform-ethanol) to give 3-acetylthio-1- (thiazolin-2-yl) azetidine (3). Was obtained in an amount of 107 mg (yield: 65%). The NMR spectrum of this product was completely in agreement with that obtained in (1) above.

Production Example 3

[0030]

Embedded image

Compound (3) 1 obtained in Preparation Example 2 above
2.98 g is dissolved in 58.3 ml of isopropyl alcohol, 37.3 ml of a methanol solution of potassium hydroxide (1.69N) is added to this solution under ice cooling, and the mixture is stirred for 10 minutes. Methanol solution of hydrochloric acid (2N) at the same temperature 6
6 ml was added to quench the reaction, the mixture was stirred at room temperature for 15 minutes, and then the insoluble matter was filtered off. The residue obtained by concentrating the filtrate is dissolved in 39 ml of isopropyl alcohol, the insoluble matter is filtered off, and the filtrate is concentrated. To the obtained residue, 58.5 ml of n-butanol was added and concentrated to obtain a yellowish white solid. Acetonitrile (22.8 ml) was added to this solid and the mixture was stirred at room temperature for 15 minutes to dissolve it, and then acetone (113.4 ml) was added dropwise over 30 minutes. Further, add 113.4 ml of acetone to 15
The mixture is added dropwise over a period of 1 minute, and then stirred under ice cooling for 30 minutes. The precipitated solid is collected by filtration, washed with 150 ml of acetone, and dried under reduced pressure for 1 day to give 3-mercapto-1-
10.41 g (purity 97.5) of (1,3-thiazolin-2-yl) azetidine hydrochloride (4) as colorless needle crystals.
%, Yield 80.3%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.57 (d, 1H,
J = 8.2 Hz), 3.59 (t, 2H, J = 7.4H)
z), 4.02-4.18 (m, 4H), 4.63.
(T, 2H, J = 7.4 Hz), 5.19-5.26
(M, 1H), 12.19 (s, 1H)

Production Example 4

[0033]

[Chemical 6]

(1) 3-mercapto-1- (thiazolin-2-yl) azetidine hydrochloride (4) obtained in Preparation Example 3 (4) 700 mg was dissolved in 15 ml of a mixed solvent of water, acetonitrile and chloroform, and p -Nitrobenzyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-[(R) -1-hydroxyethyl]
Add 1668 mg of -1-methyl-carbapene-2-em-3-carboxylate (5). Diisopropylethylamine 2.8 was added to this solution under nitrogen cooling in a nitrogen stream.
Add ml and stir at the same temperature for 2 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: acetone =).
1: 2), p-nitrobenzyl (1R, 5
S, 6S) -2- [1- (thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-
1339 mg of carboxylate (6) (yield: 92
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.235 (d, 3
H, J = 7.26 Hz), 1.349 (d, 3H, J =
6.27 Hz), 3.160 (quintet, 1H,
J = 7.26 Hz), 3.265 (dd, 1H, J =
2.3, 6.26 Hz), 3.367 (t, 2H, J =
7.26 Hz), 3.898 to 4.038 (m, 4
H) 4.071-4.147 (m, 1H), 4.21
2 to 4.278 (m, 2H), 4.372 (2H, J =
7.92 Hz), 5.255 and 5.517 (d (A
B), 2H, J = 13.85 Hz), 7.665 (d,
2H, J = 8.58 Hz), 8.226 (d, 2H, J
= 8.58Hz)

(2) To a solution of 1339 mg of the compound (6) obtained in the above reaction (1) in 20 ml of tetrahydrofuran was added 60 ml of 0.38 M phosphate buffer (pH 6.0) and 11.2 g of zinc powder, and 2 hours Stir vigorously. The reaction solution is filtered through celite to remove insolubles, and the filtrate is washed with ethyl acetate, and then the pH is adjusted to 5.5. The obtained solution was concentrated under reduced pressure, and this concentrated solution was added to Diaion H
Subjected to column chromatography (5% isopropyl alcohol water) by P-40 (manufactured by Mitsubishi Kasei Co., Ltd.) to give (1R, 5S, 6S) -2- [1-
(Thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid (7) was added to 86
1 mg (yield: 87%) was obtained. ¹ H-NMR (D ₂ O) δ: 1.093 (d, 3H, J
= 6.93 Hz), 1.207 (d, 3H, J = 6.2)
7 Hz), 3.05 to 3.20 (m, 1H), 3.35
7 (dd, 1H, J = 2.3, 5.94 Hz), 3.5
58 (t, 2H, J = 7.26 Hz), 3.920
(T, 2H, J = 7.26 Hz), 4.00 to 4.20
(M, 5H), 4.20-4.30 (m, 1H);
60 to 4.70 (m, 1H) IR (KBr): 1740, 1640, 1590 cm ^-1

Example 1 Amorphous compound (7) obtained in the above Production Example 4 (2)
After dissolving 5.66 g in 28 ml of water, the mixture is stirred for 30 minutes at room temperature and then for 30 minutes under ice cooling. The precipitated crystals are suction-filtered from the suspension and then washed 3 times with 5 ml of ice-cold water. The obtained crystals were air-dried for 1 hour and then dried under vacuum for 12 hours to obtain 5.41 g of colorless plate crystals of the compound (7). This crystal is 1 for compound (7).
It contained a molar equivalent of water (about 4.9%). In the powder X-ray diffraction pattern, a characteristic peak pattern as shown in Table 1 below was shown.

[0037]

[Table 1]

In the powder X-ray diffraction, Cu λ = 1.5418 was used as the X-ray source, and the plane spacing d
(Angstrom) was calculated by the following formula.

[0039]

[Equation 1]

Example 2 Amorphous compound (7) obtained in the above Production Example 4 (2)
After dissolving 0.99 g in 19 ml of water, 38 m of acetone
1 and then stirred for 45 minutes at room temperature and then for 50 minutes under ice cooling. After filtering the precipitated crystals from the suspension with suction,
Wash 5 times with 2 ml of acetone. By air-drying the obtained crystals for 1 hour and then under vacuum for 12 hours,
0.94 g of colorless plate crystals of the compound (7) were obtained. The water content of this crystal and the pattern of the powder X-ray diffraction pattern were in perfect agreement with those obtained in Example 1 above. The powder X-ray diffraction analysis was performed under the same conditions as in Example 1 above.

Example 3 4.99 g of the compound (6) obtained in the above Production Example 4 (1)
Was suspended in 100 ml of a 0.05 M phosphate buffer (pH 6.5), 100 ml of n-butanol and 2.49 g of 10% palladium carbon (50% water-containing product) were added to the suspension, and the suspension was added under a hydrogen atmosphere ( Catalytic hydrogenation is carried out for 1.5 hours at room temperature (4 atm). The residue obtained by filtering the reaction solution is washed with water 25
Wash with ml and n-butanol 25 ml, combine with the above filtrate and separate. The resulting aqueous layer is treated with n-butanol 50.
After washing with ml, the aqueous solution is concentrated under reduced pressure to 36.8 g. The obtained concentrate is used as Diaion HP-40.
(Made by Mitsubishi Kasei Co., Ltd.). The aqueous solution obtained by collecting the collected fractions is concentrated under reduced pressure to 35.2 g, 70 ml of acetone is added to this concentrated solution, and the mixture is stirred at room temperature for 15 minutes, and then ice-cooled for 30 minutes. The precipitated crystals were suction-filtered from the suspension and then washed with 10 m of acetone.
The crystals are washed 5 times with 1. The obtained crystals were air-dried for 1 hour, and then dried under vacuum for 12 hours to obtain 2.86 g of colorless plate crystals of compound (7). The NMR spectrum and IR data of the obtained crystals are shown in Production Example 4 above
It was completely the same as that obtained in (2). The water content of this crystal and the pattern of the powder X-ray diffraction pattern were completely the same as those obtained in Example 1 above. The powder X-ray diffraction analysis was performed under the same conditions as in Example 1 above.

Example 4 The crystalline form of compound (7) containing 1 molar equivalent of water obtained in Example 1 above was allowed to stand for 24 hours at 25 ° C. and 60% RH to reach a moisture absorption equilibrium. Let The obtained crystals contained 4 molar equivalents of water with respect to compound (7) (about 15.8%). In the powder X-ray diffraction pattern, a characteristic peak pattern as shown in Table 2 below was shown.

[0043]

[Table 2]

The powder X-ray diffraction analysis was carried out according to the above-mentioned Example 1.
The same conditions were used.

Example 5 The compound (7) in crystalline form containing 1 molar equivalent of water obtained in Example 1 above was heated to about 124 ° C. under a dry condition at a heating rate of 10 ° C. for 1 minute. To do. The crystals obtained by this method contained no water at all, and showed a characteristic peak pattern shown in Table 3 below in the powder X-ray diffraction pattern.

[0046]

[Table 3]

The powder X-ray diffraction analysis was carried out according to the above-mentioned Example 1.
The same conditions were used.

Test Example 1 The usefulness of the compound of formula (I) in the crystalline form of the present invention was confirmed by measuring the antibacterial activity of the compound itself. (1) Test method Japanese Society of Chemotherapy Standard Method [Chemothrapy, vol 29,76
-79 (1981)].
That is, an overnight culture of Mueller-Hinton (MH) agar liquid medium of a test bacterium at 37 ° C. is diluted with Buffered saline gelatin (BSG) solution to about 10 ⁶ cells / ml and tested using a microplanter. Approximately 5 μl of compound-containing MH agar medium was inoculated and incubated at 37 ° C for 18 hours.
tory concentration (MIC). As the test compound, the amorphous compound (7) obtained in Production Example 4 (2) above was used. A standard strain was used as the strain.

(2) Results The results of the above test are shown in Table 4 below.

[0050]

[Table 4]

From the above results, it is found that the crystalline form of the compound represented by the formula (I) provided by the present invention has an excellent antibacterial activity and is a useful compound per se as a pharmaceutical. confirmed.

Test Example 2 The physical stability of the compound of formula (I) in crystalline form according to the invention was compared with the compound of formula (I) in amorphous form. That is, 2 mg each of the amorphous compound (7) obtained in Production Example 4 (2) and the compound (7) containing 4 molar equivalents of water were placed in a glass bottle and placed at 40 ° C. It was left in a constant temperature room for 14 days. The change in appearance of each compound was observed on the 7th and 14th days of standing, and the residual amount was measured by HPLC. The result is 1 at the start of the test.
The residual rate is defined as 00% and is shown in Table 5 below.

[0053]

[Table 5]

As is clear from these results, it was found that the crystalline form of the compound of the formula (I) according to the present invention has extremely excellent storage stability.

Claims (5)

[Claims] 1. A crystalline form of formula (I): (1R, 5S, 6S) -2- [1- (thiazolin-2-yl) azetidin-3-yl] thio-6-
[(R) -Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid. 2. A compound of the above formula (I) in crystalline form comprising 4 moles of water. 3. In the powder X-ray diffraction pattern, the interplanar spacing (d) is 11.01, 9.75, 7.89, 6.26,
5.67, 4.89, 4.76, 4.06, 3.82,
3.76, 3.62, 3.55, 3.53, 3.41,
The compound of claim 2 having characteristic peaks at 3.34, 3.29, 3.05, 2.95, 2.76 and 2.50 Angstroms. 4. A compound of formula (I) above in crystalline form comprising 1 mole of water. 5. In the powder X-ray diffraction pattern, the interplanar spacing (d) is 10.99, 9.75, 9.07, 7.88,
7.47, 6.25, 5.66, 5.50, 4.89,
4.75, 4.06, 3.81, 3.75, 3.53,
The compound according to claim 4, which has characteristic peaks at 3.41, 3.33, 3.29, 2.95, 2.76 and 2.50 angstroms.