WO2002092605A1

WO2002092605A1 - CRYSTAL OF HYDRATE OF ß-LACTAM COMPOUND

Info

Publication number: WO2002092605A1
Application number: PCT/JP2002/004595
Authority: WO
Inventors: Akihiro Shimabayashi; Shigetoshi Yaguchi
Original assignee: Otsuka Chemical Co., Ltd.; Taiho Pharmaceutical Co., Ltd.
Priority date: 2001-05-14
Filing date: 2002-05-13
Publication date: 2002-11-21
Also published as: JP2002338578A; AR034333A1

Abstract

Crystals of a hydrate of the ß-lactam compound represented by the formula. (1) The crystalline hydrate is produced by regulating an aqueous solution containing a tazobactam salt so as to have an organic-solvent content of 0.1 wt.% or lower, cooling the aqueous solution, and then adding an acid to the aqueous solution to thereby crystallize the hydrate. The crystalline ß-lactam hydrate compound has excellent storage stability.

Description

Specification

Hydrate crystals of β-lactam compounds

Technical field

The present invention relates to hydrate crystals of i9-lactam compounds.

Background technology

2 _Methyl-2-triazolylmethylpentanum-3-caprolubonic acid S, S-dioxide is an i3-lactam compound represented by the following formula (1). Called by name.

Evening zobactam has very weak antibacterial activity by itself and is not used as an antibacterial agent by itself. However, it binds irreversibly to various types of bacteria produced by] 3-lactamase, and j8-lactamase. Has the effect of inhibiting the activity of For this reason, it can be used in combination with various existing antibacterial agents inactivated by β-lactamase, and can exert the original antibacterial action of the various antibacterial agents on 3-lactamase producing bacteria.

(See the latest antibiotics handbook, 10th edition, written by Katsuharu Sakai, page 113). For example, drugs containing as active ingredients the sodium salt of zobactam and piperacillin (] —an antibacterial agent that is easily inactivated by lactamase) are commercially available and widely used. Conventionally, Yuzo Bactam has been obtained by the general formula (2) according to the method described in Japanese Patent No. 2648870.

[In the formula, R represents a benzyl group having an electron-donating group as a substituent on the phenyl ring, a diphenylmethyl group or a tert-butyl group which may have an electron-donating group on the phenyl ring. ]

It is produced by reacting an i3-lactam compound represented by the following formula with cresol. Evening zopactam is a poorly water-soluble compound, and has the property of becoming water-soluble when converted to a salt form. Utilizing this property, Zobactam is isolated and purified.

That is, according to the above-mentioned patent publication, a basic compound, water and a hydrophobic organic solvent are added to a reaction mixture containing tazopactam to be formed, and the zobactam is converted into a salt form, extracted into an aqueous layer, and then extracted with water. The desired zopactam is crystallized by making the layer acidic.

The tazobactam crystals obtained by the method described in the above patent publication have poor stability, and have a problem that when stored at room temperature for a long period of time, they are decomposed and their purity is reduced.

Even if the purity of evening zopactam is slightly reduced, it becomes out of specification as a pharmaceutical and cannot be treated. In addition, the degradation of tazopactam reduces the inhibitory activity of lactase, and the antibacterial agent used may not be able to exhibit its antibacterial effect sufficiently. In order for a combination drug of tazobactam and an antibacterial agent to be used as a medicament, it is necessary to avoid a decrease in the purity of zazobactam.

Therefore, evening zobactam produced by the above method is stored in a refrigerator and other measures are taken to avoid a decrease in purity.

Disclosure of the invention

An object of the present invention is to provide a tazopactam crystal having excellent storage stability.

The present inventor has made intensive studies to achieve the above object. As a result, in crystallizing the tazobactam crystals by the conventional method, the ratio of the organic solvent contained in the aqueous solution was adjusted to a specific level or less, and the pH of the aqueous solution was maintained while maintaining the liquid temperature of the aqueous solution at a specific temperature or lower. It has been found that by adjusting the value to a specific value or less, a tazobactam hydrate crystal having excellent storage stability can be obtained. The present invention has been completed based on such knowledge.

According to the present invention, equation (1)

A hydrate crystal of a lactam compound is provided.

The hydrate crystal of the 3-lactam compound represented by the formula (1) of the present invention] is composed of S, S-dioxide of 2-methyl-12-triazolylmethylpentanum-13-carboxylic acid, Further, it is a crystal having crystallization water. Such a hydrate crystal of a [3-lactam compound] is characterized by, for example, an X-ray diffraction spectrum obtained with copper radiation of λ = 1. It has a peak at

d (lattice spacing)

8 818-9.747

7 024-7.763

6 864-7.586

5 839-6.453

5 351 5.914

5 219 5 768

5 124 5 664

4 860 5 372

4. 810 5 317

4.374-4.835

4.116-4.550

3.985--4.405

3. 938-4.352

3. 664-4.050

3.627-4.009

3.555-3.929

3.508-3.877

3.460-3.824 3 424-3 785

3 179-3 513

2 824-3 121

2 773-3 065

2 752-3 042

Furthermore, among the hydrate crystals of the present invention having the above-mentioned X-ray diffraction spectrum peak (lattice plane spacing), the hydrate crystal has a peak at the next lattice plane spacing, and the relative intensity of the peak is as follows. Those having a diffraction spectrum are preferred.

d (Lattice spacing) Relative strength (I / I.)

8.818-9.747 0.01-0.60

7.024-7.763 0 01-0.28

6.864-7.586 0 46-1.00

5. 839-6.453 0 01-1.00

5. 351-5. 914 0 03-: L. 19

5.219 to 5.768 0 01 to 1.00

5.124-5.664 0 01-0.75

4.860〜5.372 0 01〜0.85

4.810 ~ 5.317 0 04 ~ 0.34

4. 374〜4. 835 0 01〜: L. 00

4.116-4.550 0 01-0.31

3.985-4.405 0 01-0.45

3. 938-4.352 0 03 0.23

3.664-4.050 0 07 0.35

3.627 ~ 4.009 0 12 0.54

3.555-3.929 0 01 0.24

3.508-3.877 0 02 0 26

3.460-3.824 0 01 0 26

3.424-3.785 0 05 0 57

3.179-3.513 0 09 0 29 2 8 2 3 1 2 1 0 0 2 0 3 0

2 7 7 3 3 0 6 5 0 0 2 0 2 4

2 7 5 2 3 0 4 2 0 0 1 0 2 3

In the present invention, the measurement of the X-ray diffraction spectrum was performed using an X-ray diffraction spectrometer (RINT 2000 ZPC (trade name) manufactured by Rigaku Corporation). The method for producing the hydrate crystal of the 3-lactam compound represented by the formula (1) (hydrate crystal of tazopactam) of the present invention will be described below.

The hydrate crystals of tazobactam of the present invention are prepared, for example, by adjusting the content of an organic solvent in an aqueous solution containing zopactam salt to 0.1% by weight or less, cooling the aqueous solution, and then adding an acid to the aqueous solution. It is produced by crystallization of zozobactam crystals.

An aqueous solution containing a tazopactam salt is prepared by reacting a 3-lactam compound represented by the formula (2) with cresol according to the method described in, for example, Japanese Patent No. 2,648,750. Then, a hydrophobic organic solvent such as methyl isobutyl ketone is added to the reaction mixture containing tazopactam, the mixture is cooled to 0 to 5 ° C, and a basic compound such as sodium hydrogen carbonate and water are added and mixed. It can be easily prepared by separating the aqueous layer.

Further, an aqueous solution containing a tazopactam salt is prepared by treating an evening zobactam produced according to the specification of Japanese Patent No. 2648750 with a basic conjugate to give an evening zopactam salt. It may be prepared by dissolving in water.

As the basic compound used in the present invention, known compounds can be widely used. For example, alkali metal bicarbonates such as sodium hydrogencarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and carbonate Examples thereof include alkaline earth metal carbonates such as calcium. Of these, alkali metal bicarbonates such as sodium bicarbonate are preferred. One of these basic compounds can be used alone, or two or more can be used in combination.

The evening zopactam salt of the present invention includes alkali metal salts such as sodium and potassium salts of tazopactam and earth metal salts such as calcium salts.

The concentration of the tazobactam salt contained in the aqueous solution is not limited, and can be appropriately selected from a wide range. The concentration of zobactam salt in aqueous solution Considering the crystallization efficiency and workability of the target hydrate, it is usually 1 to 50% by weight, preferably 5 to 20% by weight.

In the present invention, prior to adjusting the pH of the aqueous solution containing zobactam salt to 3 or less, it is essential to reduce the content of the organic solvent contained in the aqueous solution to 0.1% by weight or less. It is. This organic solvent includes both a hydrophobic organic solvent used in preparing the above aqueous solution and cresol, which is a raw material for producing zobactam.

In order to reduce the content of the organic solvent in the aqueous solution containing tazopactam salt to a level of 0.1% by weight or less, the aqueous solution containing zobactam salt may be treated with an adsorbent.

As the adsorbent, known ones can be widely used, and examples thereof include a synthetic resin adsorbent and activated carbon.

Examples of the synthetic resin adsorbent include a crosslinked polymer composed of styrene and divinylbenzene, and a crosslinked polymer composed of methacrylic acid ester and ethylene glycol dimethacrylate. Commercially available synthetic resin adsorbents used in the present invention include, for example, Amberlite XAD (trade name, manufactured by Rohm & Haas), Diaion HP (trade name, manufactured by Mitsubishi Chemical Corporation), and the like. .

Specific examples of the method of treating an aqueous solution containing tazopactam salt with an adsorbent include, for example, a method in which an adsorbent is packed in a column or the like, and an aqueous solution of tazobactam salt is passed once or twice or more. Examples thereof include a method of adding an adsorbent to an aqueous solution of salt and mixing the adsorbent.

The amount of the adsorbent used can be appropriately selected according to the amount of the aqueous solution of the tazopactam salt to be treated. This process is usually performed at a temperature of 20 to 30. In the next step of the present invention, an acid is added to the aqueous solution while cooling the aqueous solution in which the organic solvent content is adjusted to usually 0.1% by weight or less, preferably 0.08% by weight or less. Precipitate hydrate crystals.

In the acid addition step, the cooling temperature of the aqueous solution of zopactam salt is usually 10 ° C. or lower, preferably 0 to 5 t. If the temperature of the aqueous solution of tazopactam salt is higher than the specified temperature, then the pH was adjusted to 3 or less by adding an acid to the aqueous solution. However, the desired hydrate crystals of zopactam cannot be precipitated. In the crystallization step, the pH value of the aqueous solution containing zobactam salt is maintained at 3 or less. In consideration of the crystallization efficiency, workability, economy, etc. of the target hydrate crystal, the pH of the aqueous solution is adjusted to preferably about 0.5 to 1.5, more preferably about 0.6 to 1. Is good.

Examples of the acid used include inorganic acids such as nitric acid, hydrochloric acid, and sulfuric acid, and organic acids such as trifluoroacetic acid. Of these, inorganic acids are preferred, and hydrochloric acid is most preferred. These acids can be used alone or in combination of two or more. By the above pH adjustment, tazopactam hydrate crystals precipitate in the aqueous solution. The evening zopactam hydrate crystals can be easily isolated and purified from the reaction system by ordinary separation means such as filtration and centrifugation.

The invention's effect

The evening zopactam hydrate crystals of the present invention have excellent storage stability, and do not substantially decompose even when stored at room temperature for a long period of time.

Further, the tazobactam hydrate crystal of the present invention has an excellent property that the antibacterial agent used in combination with the crystal can sufficiently exhibit the antibacterial performance.

The tazobactam hydrate crystal of the present invention binds irreversibly to various types of 6-lactamase produced by bacteria and has an action of inhibiting the activity of lactase. Therefore, it can be used in combination with existing various antibacterial agents which are inactivated by lactamase, and can exhibit the original antibacterial action of the various antibacterial agents against 3-lactamase-producing bacteria. '

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described specifically with reference to Examples, Reference Examples, and Test Examples. According to Example 1 described in Japanese Patent No. 26488750, a crystal of 2-methyl-2-triazolylmethylpenam-13-carboxylic acid S, S-dioxide (Zobactam) was produced.

That is, while m-cresol 80 m 1 was heated to 50 to 55 ° C., 2-methyl-2-triazolylmethyl ぺ nam-1-3-carboxylic acid S, S-dioxide 1 Og of diphenyl methyl ester was added and the reaction was carried out for 2 hours while maintaining the temperature.

After completion of the reaction, 240 ml of methyl isobutyl ketone was added, and the mixture was cooled to 0 to 5 ° C. 23 ml of water and then 2.3 g of sodium hydrogen carbonate were added to perform extraction. The organic layer was separated, 12 ml of water and 0.7 g of sodium hydrogen carbonate were added to the organic layer, and extraction was performed again. The separated aqueous layers were combined, washed with 18 ml of methyl isobutyl ketone, cooled to 0 to 5 ° C, and the pH of the aqueous layer was adjusted to 1 by adding 6N-hydrochloric acid. The precipitated S, S-dioxide of 2-methyl-2-triazolylmethyl-pham-3-carboxylic acid was filtered off, washed with a small amount of cold water and dried to obtain white crystals of tazopactam.

The X-ray diffraction spectra of the tazobactam white crystals obtained above were as follows. This X-ray diffraction spectrum is an X-ray diffraction spectrum obtained with copper radiation of λ = 1.5418 A through monochromator.

d (Lattice spacing) Relative strength (IZI.)

9 2437 0 42

8 8734 0 18

8 6651 0 05

7 5317 0 19

7 2017 0 72

6 6516 0 30

6 1205 1 00

6 0130 0 44

5 9014 0 28

5 5902 0 38

5 4735 0 81

5 3681 0 36

5 1040 0 55

5 0350 0 19

4 8863 0.48 4.7513 0.11

4.5952 0.61

4.32246 0.23

4. 1796 0.57

1373 0.23

8438 0.28

8081 0 42

7355 0 17

6897 0 14

6274 0 23

5957 0 23

5037 0 15

4741 0 17

3385 0 17

2853 0 10

9665 0 25

9099 0 23

8873 0 18

7250 0 25

Example 1

In the same manner as in Reference Example 1, 80 ml of m-cresol was heated to 50 to 55 ° C, and 2-methyl-2-triazolylmethyl ぺ nam-1 3-carboxylic acid S, S-dioxide was added. 10 g of diphenyl methyl ester was added, and the reaction was carried out for 2 hours while maintaining the temperature.

After the completion of the reaction, 240 ml of methyl isobutyl ketone was added, and the mixture was cooled to 0 to 5 ° C. To this, 23 ml of water and then 2.3 g of sodium hydrogen carbonate were added to perform extraction. The organic layer was separated, 12 ml of water and 0.7 g of sodium hydrogen carbonate were added to the organic layer, and the mixture was extracted again. The separated aqueous layers were combined and washed with 18 ml of methyl isobutyl ketone. The m-cresol concentration in this aqueous solution was measured by high performance liquid chromatography and found to be about 0.84% by weight. The concentration of methyl isobutyl ketone measured by gas chromatography was about 1.3% by weight.

This aqueous solution was passed through a column filled with 10 ml of a synthetic resin adsorbent (trade name: Diaion HP-20, manufactured by Mitsubishi Chemical Corporation), and then 3 Om1 of water was passed through the column. The fractions were combined. The m_cresol concentration in this solution was measured by high performance liquid chromatography and found to be about 0.044% by weight. The concentration of methyl isobutyl ketone measured by gas chromatography was about 0.036% by weight.

After the aqueous solution was cooled to 5 ° C. or lower, hydrochloric acid was added while maintaining the temperature to adjust 1) 11 to a range of 0.5 to 1.0. The precipitated crystals were collected by filtration to obtain white crystals of hydrate of S, S-dioxide of 2-methyl-2-triazolylmethyl-p-ammonium-3-carboxylic acid.

Elemental analysis of the white crystals obtained above gave the following results, confirming that the white crystals were 1Z dihydrate crystals of zopactam.

Elemental analysis (as _{_{CioHi 2 N40 5 S · 1 /}} 2H 2 〇)

Calculated value (%) H: 4.24 C: 38.83 N: 18.11

Actual value (%) H: 4.16 C: 38.80 N:, 18.19

The X-ray diffraction spectrum of the white crystals of zobactam hydrate (X-ray diffraction spectrum obtained with a monochromator at λ = 1.5418 5 copper radiation) was as follows.

d (Lattice spacing) Relative intensity (I / I o)

9.2825 0.28

7. 3937 0 12

7. 2251 1 00

6. 1459 0 72

5. 6326 0 11

5. 4938 0 74

5. 3941 0 33 5 1157 0.35

5 0635 0, 19

4 6046 0, 52

4 3330 0, 16

4 1952 0 17

4 1449 0 13

3 8570 0 21

3 8178 0 33

3 7417 0 12

3 6927 0 14

3 6421 0 13

3 6043 0 31

3 3459 0 19

2 9723 0 16

2 9191 0 13

2 8970 0 12

Comparing the X-ray diffraction spectrum of the evening zobactam crystal obtained in Reference Example 1 with the X-ray diffraction spectrum of the tazobactam crystal obtained in Example 1, the peak number of the former spectrum was about 2 It is evident that there are many peaks at different lattice spacings, and the crystal morphology of both is clearly different.

Test example 1

Each 10 g of the evening zobactam crystals obtained in Reference Example 1 and Example 1 were placed in separate test tubes, sealed, and stored at room temperature for one year. During this time, the room temperature fluctuated between 10 and 34 ° C.

Then, when the purity of the evening zopactam crystals obtained in Reference Example 1 and Example 1 was examined, the purity of the crystals obtained in Example 1 was 99.8%, whereas the purity of the crystals obtained in Reference Example 1 was 99.8%. The purity of the obtained crystals was 95%.

From this, it has been clarified that the tazobactam hydrate crystal of the present invention is superior in storage stability to the conventional tazobactam crystal.

Claims

1. Equation (1)

/ 3—Hydrate crystals of a lactam compound.

2. X-ray contract obtained with copper radiation of λ = 1.5418 mm through a monochromator

2. The hydrate crystal according to claim 1, wherein the diffraction spectrum has a peak at the following lattice spacing.

of

d (lattice spacing)

8 818-9.747

Enclosure

7 024-7.763

6 864-7.586

5 839-6. 453

5 351-5.914

5 219-5.768

5 124-5.664

4 860-5. 372

4 810-5.317

4 374-4.835

4.116-4.550

3.985--4.405

3. 938-4. 352

3. 664-4.050

3.627-4.009

3.555-3.929

3.508-3.877

3.460-3.824

3.424-3.785

3.179-3.513

2. 824-3.12 1

2.773〜3.065

2.752-3.042

3. The hydrate according to claim 2, wherein the X-ray diffraction spectrum obtained with λ = 1.5418 mm copper radiation through a monochromator is characterized by the following lattice spacing and relative intensity: crystal.

d (Lattice spacing) Relative strength (I / "Ι ο)

8. 818 9. 747 01〜 ϋ. 60

7.024 to 7 b S 01 to ϋ. 28

6.864 ~ 7.58 D 46 ~ 1.00

5.8 S 9 to 6.453 0.01 to 1.00

5.51 ~ 5.14 Ό ϋ 3 1.19

5.1 to 5.7 b 8 0.01 to 1.00

5.D b 4 ϋ. Ϋ 1 0.75

4.8 D 0 5.S 7 Z ϋ .01 ~ ϋ .85

4.810 5.317 υ 04 34 34

4.374 4.835 0.01-1.00

4.1 16 4.550 0.01 to 0.31

3.985-4.405 0.01-1.45

3. 938-4.352 0.03 0.23

3. 664-4.050 0.07 0.35

3.627-4.009 0.12-0.54

3.555-3.929 0.01-0.24

3.508-3.877 0.02-0.26

3.460-3.824 0.01-1.26

3.424-3.785 0.05-0.57

3.179 3.513 0.09 0.29

2.824 ~ 3.12 1 0.02 ~ 0.30

2. 773 ~ 3.065 0.02 ~ 0.24

2.752 ~ 3.042 00.01 ~ 0.23

4. The hydrate crystal according to claim 3, which is a 1/2 hydrate.