JP2005097278A - Crystal of 1-methylcarbapenem compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a crystal of a 1-methylcarbapenem compound which has excellent antimicrobial activity and preservative stability, high productivity and easy manipulability, and a medicine especially an antibacterial agent which effectively comprises the crystal. <P>SOLUTION: The crystal of a 1-methylcarbapenem compound represented by formula (I) which characteristically shows a certain main peak in powder X-ray diffractometry by copper K<SB>α</SB>radiation, or its pharmacologically permissible salt, are provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a crystal of 1-methylcarbapenem compound having excellent antibacterial activity and storage stability, and having high productivity or easy handling, and a medicament containing the crystal as an active ingredient, particularly an antibacterial agent. .

  Patent Document 1 and Patent Document 2 include a formula

The 1-methylcarbapenem compound represented by these is disclosed. This compound (I) exhibits excellent antibacterial activity not only against gram-negative bacteria but also against gram-positive bacteria, and can be expected to be useful as an antibacterial agent.

Patent Documents 3 and 4 disclose specific crystals of the present compound (I) or a pharmacologically acceptable salt thereof. The crystal is superior in storage stability and easy to handle as compared with freeze-dried powder, but it cannot be said that there is no problem in terms of productivity and storage stability.
JP-A-10-204086 JP 11-71277 A Japanese Patent No. 2001-72681 JP 2002-161034 A

  As a result of various studies to solve these problems, the inventors have succeeded in obtaining specific new crystals. These crystals have improved productivity and storage stability compared to the crystals described in Examples of JP-A No. 2001-72681, and crystals that are practically extremely useful as pharmaceuticals, particularly antibacterial agents. As a result, the present invention was completed.

  Specifically, the crystal 1 described later can be produced with high yield and simple operation, does not require special drying conditions in the drying process, and has improved storage stability under drying conditions. is there. Crystal 2 to be described later can be produced by a simple operation, does not require a drying step, or may be a short time, and is easy to handle because it is stable in storage under normal humidity or high humidity conditions. Crystal 3 to be described later containing a specific amount of water can be produced in a high yield and with a simple operation, does not require a drying step or requires a short time, and is stable in storage under normal humidity or high humidity conditions. Therefore, the crystal is easy to handle.

The present invention
(1) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 7.60,6.69,6.33,6.14,5.15,4.58 and 4.48 A crystal of a 1-methylcarbapenem compound represented by the above formula (1) or a pharmacologically acceptable salt thereof (hereinafter, referred to as crystal 1), which has a main peak in FIG.
(2) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 7.60,6.69,6.33,6.14,5.15,4.58 and 4.48 Is the main peak

A crystal of 1-methylcarbapenem compound / ethanol solvate represented by:
(3) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 11.68,8.79,7.53,6.57,5.58,5.37,3.99 And a crystal of a 1-methylcarbapenem compound represented by the above formula (1) or a pharmacologically acceptable salt thereof (hereinafter, referred to as crystal 2), which has a main peak at 3.09;
(4) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 11.68,8.79,7.53,6.57,5.58,5.37,3.99 And 3.09 showing the main peak

1-methylcarbapenem compound represented by the formula: tetrahydrate crystal;
(5) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, characterized by showing a main peak in the lattice distance d = 6.65,5.68,4.86,4.57 and 4.03 The expression

1-methylcarbapenem compound / ethanol hydrate / trihydrate crystal (described in JP-A No. 2001-72681, hereinafter referred to as crystal 3) represented by Method for producing crystal 1;
(6) Method for producing crystal 3 by absorbing crystal 1;
(7) Crystal 1 having a water content of 0.5 to 2% by mass;
(8) Crystal 2 having a water content of 8 to 10% by mass; and (9) A pharmaceutical, particularly an antibacterial agent, containing the crystal as an active ingredient.

In the above,
The 1-methylcarbapenem compound represented by the formula (I) is a compound disclosed in JP-A-10-204086 and JP-A-11-071277, and is effective against a wide range of bacteria from gram-positive bacteria to gram-negative bacteria. It is a compound having strong antibacterial activity.

  Compound (I) may be a pharmacologically acceptable salt. Here, the pharmacologically acceptable salt refers to a salt that can be used as a medicine.

  Since compound (I) has a tertiary amino group and a guanidino group as basic groups in the molecule, it can be converted into a corresponding pharmacologically acceptable acid addition salt by treating with an acid according to a conventional method. Examples of such acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates; carbonates, acetates, benzoates, oxalates, maleates, Examples thereof include organic acid salts such as fumarate, tartrate and citrate; or sulfonates such as methanesulfonate, benzenesulfonate and p-toluenesulfonate.

  Since compound (I) has a carboxyl group which is an acidic group in the molecule, it can be converted into a corresponding pharmacologically acceptable base addition salt by treating with a base according to a conventional method. Examples of such base addition salts include: alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts, iron salts, zinc salts, copper Metal salts such as salts, nickel salts and cobalt salts; or ammonium quaternary salts such as ammonium salts.

  In addition, Compound (I) or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the atmosphere. A certain solvent may be absorbed to form a solvate, and such a hydrate or solvate is also encompassed in the present compound (I) and a pharmacologically acceptable salt thereof.

  Such salts, hydrates and solvates are preferably sodium salts, hydrochlorides, sulfates, carbonates, hydrates or ethanol solvates, more preferably hydrates or solvates. Ethanol solvate.

  The compound represented by formula (I-1) is an ethanolate of compound (I), and the compound represented by formula (I-2) is a tetrahydrate of compound (I).

  The crystal of the present invention refers to a solid whose internal structure is composed of regularly repeated constituent atoms (or a group thereof) in a three-dimensional manner, and is distinguished from an amorphous solid that does not have such a regular internal structure. .

  Even crystals of the same compound may produce crystals having a plurality of different internal structures and physicochemical properties depending on the crystallization conditions. The crystal of the present invention is in any of these crystal forms. It may be a mixture of two or more crystal forms.

  The crystal of the 1-methylcarbapenem compound represented by the formula (I-1) has an interplanar spacing d = 7.60 in powder X-ray diffraction obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å). , 6.69, 6.33, 6.14, 5.15, 4.58 and 4.48.

  The crystal of the 1-methylcarbapenem compound represented by the formula (I-2) has an interplanar distance d = 11.68 in powder X-ray diffraction obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å). , 8.79, 7.53, 6.57, 5.58, 5.37, 3.99 and 3.09.

  The crystal of the present invention has improved productivity or storage stability among the crystals of compound (I) or a pharmacologically acceptable salt thereof, and is useful in industrial production.

  The 1-methylcarbapenem compound represented by the formula (I) can be produced according to the method disclosed in JP-A-10-204086 and JP-A-11-071277 or a method analogous thereto.

  The crystal of the present invention is prepared, for example, by dissolving Compound (I) or a pharmacologically acceptable salt thereof in a suitable solvent (good solvent), concentrating as necessary, adding a poor solvent as necessary, and The reaction is achieved by, for example, cooling the compound (I) or a pharmacologically acceptable salt thereof to a supersaturated state, precipitating crystals, and then isolating and drying the precipitated crystals.

  Crystal precipitation can be initiated spontaneously in the reaction vessel, but can also be initiated or promoted by applying mechanical stimuli such as seed crystal inoculation, ultrasonic stimulation, or rubbing the reactor surface.

  The pharmacologically acceptable salt of compound (I) is preferably a hydrochloride, sulfate, or carbonate. The pharmacologically acceptable salt can be produced by adding a necessary amount of an acid or base that forms a desired salt to the solution of compound (I).

  When handling a solution of compound (I) or a pharmacologically acceptable salt thereof, in order to suppress decomposition of compound (I), it is usually handled at a temperature of 0 ° C. to 60 ° C., preferably at 0 ° C. to 25 ° C.

  The cooling temperature for crystallization is preferably 0 ° C. to 10 ° C.

  As a method of concentrating the solution of compound (I) or a pharmacologically acceptable salt thereof, for example, a method of concentrating by evaporating the solvent while heating under normal pressure or reduced pressure using a rotary evaporator or the like, reverse osmosis There is a method of concentration using a membrane. The reverse osmosis membrane used for concentration of the aqueous solution can be selected from, for example, a polyacrylonitrile membrane, a polyvinyl alcohol membrane, a polyamide membrane, and a cellulose acetate membrane.

  Examples of the good solvent for the compound (I) or a pharmacologically acceptable salt thereof include water, dimethyl sulfoxide, dimethylformamide, and methanol, with water being preferred.

  Examples of the poor solvent for compound (I) or a pharmacologically acceptable salt thereof include alcohols having 2 to 4 carbon atoms such as ethanol, propanol and butanol; ketones such as acetone and methyl ethyl ketone; diethyl ether; Examples include ethers such as tetrahydrofuran; esters such as methyl acetate and ethyl acetate. Ethanol or acetone is preferable, and ethanol is most preferable.

  The starting material compound (I) may be one that has already been isolated as a lyophilized powder, but can also be purified by crystallization, so a solution of the crude product of the synthetic reaction containing compound (I) is used. It can also be used.

  The supersaturated state is obtained by, for example, concentrating an aqueous solution of compound (I) to a saturated state under heating at 30 ° C. to 60 ° C. and gradually cooling to 0 ° C. to 10 ° C. It can be obtained by gradually adding a poor solvent such as ethanol or acetone and cooling as necessary.

  The crystal of the present invention is preferably precipitated by concentrating an aqueous solution containing Compound (I) or a pharmacologically acceptable salt thereof, adding a poor solvent as necessary, and cooling as necessary.

  More preferably, the aqueous solution containing the compound (I) or a pharmacologically acceptable salt thereof is concentrated, ethanol or acetone is added as necessary, and precipitation is carried out as necessary.

  Most preferably, crystal 1 is precipitated by concentrating an aqueous solution of compound (I), adding sodium bicarbonate and ethanol and cooling; crystal 2 cooling an aqueous solution of compound (I) It precipitates by adding sodium and acetone and cooling, or precipitates by cooling the aqueous solution of compound (I).

  The precipitated crystals can be isolated, for example, by filtration, centrifugation, or gradient methods. The isolated crystal may be washed with a suitable solvent as necessary. Washing is preferably performed with the solvent used for crystallization.

  The isolated crystal 1 is dried usually at a temperature of 10 ° C. to 50 ° C., preferably at a temperature of 20 ° C. to 30 ° C., until the weight becomes substantially constant. If necessary, the crystal 1 can be dried in the presence of a desiccant such as silica gel or calcium chloride, or under reduced pressure.

  Crystal 2 is obtained by drying under reduced pressure, usually at a temperature of 10 ° C. to 60 ° C., preferably at a temperature of 20 ° C. to 30 ° C., usually at a humidity of 30% or more, preferably 70 to 90%. It can be obtained by standing at a humidity of usually 30 minutes to 2 days, preferably 6 hours to 1 day.

  The crystal 1 thus obtained is a crystal with improved storage stability under dry conditions, and the crystal 2 is a crystal that is easy to handle because it is storage stable under normal humidity or high humidity conditions. It is.

  The crystal 1 of the present invention can be converted to the crystal 3 described in JP-A No. 2001-72681 by humidification. Conversely, crystal 3 can be converted to crystal 1 by drying.

  When converting the crystal 1 to the crystal 3, for example, at a temperature of 10 ° C. to 60 ° C., preferably at a temperature of 20 ° C. to 30 ° C., at a humidity of 30% or more, preferably at a humidity of 50% to 70%, This is achieved by allowing to stand for 30 minutes to 2 days, preferably 6 hours to 1 day.

  In the case of converting the crystal 3 into the crystal 1, for example, drying under reduced pressure at a temperature of 10 ° C. to 60 ° C., preferably at a temperature of 15 ° C. to 25 ° C., for 2 hours to 2 days, preferably 12 hours to 1 day, Or at a temperature of 10 ° C. to 60 ° C., preferably at a temperature of 20 ° C. to 30 ° C., at a humidity of 20% or less, preferably at a humidity of 10% or less, for 2 hours to 2 days, preferably 6 hours to 1 Achieved by standing for days.

  As described above, the crystal 1 and the crystal 3 may have different moisture absorption levels depending on the environment. However, even if the moisture absorption level is different, the crystal 1 and the crystal 3 may each have the same powder X-ray analysis pattern as the crystal 1 or the crystal 3 Included in Crystal 1 or Crystal 3 of the invention. The degree of moisture absorption can be measured and determined by a conventional method such as Karl Fischer's method, and can be expressed by, for example, the amount of moisture. A suitable moisture content in the crystal 1 is 0.5% to 2%, and if the moisture content is less than this range, it is considered that severe drying conditions are required and the production cost is increased. If the amount is large, the risk of changing to crystal 3 increases. In addition, the preferable amount of water in the crystal 3 is 3% to 12%, more preferably 8% to 10%. If the amount of water is smaller than this range, the risk of changing to the crystal 1 increases. If the amount of water is larger than this range, the crystals may be difficult to handle. Thus, when the moisture content of crystal 1 and crystal 3 is within this range, the mixture is particularly excellent in storage stability, and there is no quality fluctuation at normal temperature and humidity. It is a crystal suitable for practical use as an antibacterial agent.

  The crystal 3 containing a specific amount of water as described above is a crystal that is easy to handle because it is stable in storage under normal humidity or high humidity conditions.

  The crystal of the present invention exhibits a broad antibacterial spectrum and a strong antibacterial activity against gram positive bacteria, gram negative bacteria and anaerobic bacteria, including cephalosporinase producing bacteria. When the antibacterial activity was measured by the agar plate dilution method, for example, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, pneumococci, enterococci, and other Gram-positive bacteria, It showed strong antibacterial activity against a wide range of pathogens including Gram negative bacteria such as Bacter, Pseudomonas aeruginosa and anaerobic bacteria such as Bacteroides fragilis. Furthermore, it showed strong antibacterial activity against Helicobacter pylori, which is detected at high rates in chronic gastritis and peptic ulcer.

  When the crystals of the present invention were dissolved in an appropriate solvent and administered to mice, they showed a longer half-life in blood concentration and higher urinary recovery than conventional related drugs.

  In addition, the crystal of the present invention showed an excellent infection treatment effect by subcutaneous administration in systemic infection of mice by Staphylococcus aureus, pneumococci, Escherichia coli or Pseudomonas aeruginosa. Therefore, the crystal of the present invention is useful as a medicine (particularly, an antibacterial agent) and a bulk powder for production thereof.

  When the crystal of the present invention is used as a medicine (particularly an antibacterial agent), it is mixed with itself or appropriate pharmacologically acceptable excipients, diluents, tablets, capsules and granules. Orally by powder or syrup, etc., parenterally by injection or the like, or locally by ointment or the like.

  These preparations are made of excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose , Low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate Silicate derivatives such as: Phosphate derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate Body, etc.), binders (eg, the aforementioned excipients; gelatin; polyvinylpyrrolidone; macrogol, etc.), disintegrants (eg, the aforementioned excipients; croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone Such as chemically modified starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; stearic acid metal salts such as calcium stearate, magnesium stearate; colloidal silica; bee gum; beeswax, gay wax, etc. Waxes; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; sodium lauryl sulfate and magnesium lauryl sulfate Lauryl sulfur Acid salts; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients, stabilizers (for example, paraoxybenzoic acid esters such as methylparaben and propylbaraben; chlorobutanol and benzyl alcohol) Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid and the like; and flavoring agents (eg, commonly used sweeteners, acidulants) , Fragrances, etc.), suspending agents (eg, polysorbate 80, sodium carboxymethyl cellulose, etc.), diluents, solvents for preparation (eg, water, ethanol, glycerin, etc.), solubilizers (nonionic surfactants, anions) Surfactants), local anesthetics (lidocaine hydrochloride, mebivacaine hydrochloride, etc.) It is prepared in a known manner by using additives and the like.

  Examples of the dosage form suitable for oral administration include solid preparations such as tablets, coating agents, capsules, troches, powders, fine granules, granules, dry syrups, and liquid preparations such as syrups. Can do. Examples of dosage forms suitable for parenteral administration include injections, drops, suppositories and the like. Examples of dosage forms suitable for topical administration include ointments, tinctures, creams, and gels. These preparations can be prepared by methods known per se in the field of pharmaceutics.

  The crystalline 1-methylcarbapenem compound of the present invention is preferably administered parenterally, particularly in the form of injections or drops. The dose varies depending on age, weight, and symptoms, but it is usually divided into 1 to 4 times at a lower limit of 10 mg (preferably 50 mg) and an upper limit of 6000 mg (preferably 4000 mg) per day for adults. Can be administered.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples and Formulation Examples. In the nuclear magnetic resonance spectra of the examples, tetramethylsilane was used as an internal standard substance in measurement in heavy water.

(Example 1)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid / ethanol solvate (crystal 1)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- [2- [2,3-bis] obtained by the method described in JP-A No. 2001-72681 (4-Nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1- 7.5% palladium-carbon (3.13 g) was added to a 33% aqueous tetrahydrofuran solution (120 mL) of carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (10.0 g), and the suspension was added. Was stirred at 20 ° C. for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was extracted and washed with ethyl acetate. Activated carbon (4.3 g) was added to the aqueous layer and stirred at room temperature for 30 minutes. After the activated carbon was filtered off, the filtrate was concentrated under reduced pressure. Sodium bicarbonate (100 mg) and ethanol (240 mL) were added to the concentrated solution, and the resulting suspension was allowed to stand at 0 ° C. for 16 hours. The suspension was then stirred for 1 hour, and the precipitated crystals were collected by filtration, washed with an ethanol: water (3: 1) solution, and dried under reduced pressure to give the title ethanol hydrate crystals (4.35 g). It was.
Melting point: 225-240 ° C (decomposition).
Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm: 1.17-1.94 (6H, m), 1.31 (3H, d, J = 6.4 Hz), 1.56-1.74 (1H, m), 1.94-2.12 (1H , m), 2.19-2.29 (1H, m), 2.28, 2.29 (3H, s × 2), 2.72-2.88 (2H, m), 3.08 (1H, d, J = 10.5 Hz), 3.29-3.74 (8H , m), 3.74-3.94 (2H, m), 4.01 (2H, s), 4.17-4.28 (2H, m), 4.39-4.54 (1H, m).
Infrared absorption spectrum (KBr) νmax (cm ^-1 ): 3335, 2970, 1755, 1651, 1452, 1387, 1251.
Powder X-ray (Cu K _a , λ = 1.54 angstroms) d (angstroms): 7.60, 6.69, 6.33, 6.14, 5.15, 4.58, 4.48.

(Example 2)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid tetrahydrate (crystal 2)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidine-] obtained by the method described in JP-A No. 2001-72681 1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid (5.50 g) Was added to water (14 mL) and the suspension was stirred at 0 ° C. for 1 h. The obtained crystals were collected by filtration and dried under reduced pressure to obtain anhydrous crystals. The anhydrous crystals were allowed to stand in an atmosphere of 25 ° C. and 80% humidity for 1 day to obtain crystals of the title tetrahydrate (5.28 g).
Melting point: 235-250 ° C. (decomposition).
Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm: 1.34 (3H, dd, J = 7.1, 1.9Hz), 1.44 (3H, d, J = 6.4 Hz), 1.58-1.68 (1H, m), 1.96-2.13 (1H, m), 2.18-2.34 (1H, m), 2.27, 2.28 (3H, s × 2), 2.69-2.89 (2H, m), 3.07 (1H, d, J = 10.7Hz), 3.29-3.74 (6H, m), 3.75-3.94 (2H, m), 4.00 (2H, s), 4.16-4.31 (2H, m), 4.37-4.49 (1H, m).
Infrared absorption spectrum (KBr) νmax (cm ^-1 ): 3336, 2967, 1753, 1628, 1576, 1451, 1384, 1285, 1182.
X-ray powder (Cu K _a , λ = 1.54 angstrom) d (angstrom): 11.68, 8.79, 7.53, 6.57, 5.58, 5.37, 3.99, 3.09.

(Example 3)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid / ethanol solvate (crystal 1)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidine-] obtained by the method described in JP-A No. 2001-72681 1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid / ethanol solvate Trihydrate (which is erroneously written as “1/2 carbonate · 1/2 ethanol” in JP-A No. 2001-72681. 4.76 g) was dried under reduced pressure at 20 ° C. for 6 hours to give the title ethanol. A Japanese product (2.55 g) was obtained.

Example 4
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid / ethanol hydrate / trihydrate (crystal 3)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1- obtained in Example 1 Methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid / ethanol solvate (42.89 g) at 25 ° C. The product was placed in a container with a humidity of 60% and allowed to stand for 1 day to obtain the title ethanol hydrate / trihydrate (45.46 g).
Melting point: 228-233 ° C. (decomposition).
Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm: 1.13-1.24 (4.5H, m), 1.30 (3H, d, J = 6.4 Hz), 1.57-1.72 (1H, m), 1.93-2.10 ( 1H, m), 2.15-2.35 (1H, m), 2.27, 2.29 (3H, s × 2), 2.68-2.88 (2H, m), 3.09 (1H, d, J = 10.6 Hz), 3.29-3.73 ( 7H, m), 3.75-3.93 (2H, m), 4.01 (2H, s), 4.12-4.30 (2H, m), 4.38-4.50 (1H, m).
Infrared absorption spectrum (KBr) νmax (cm ⁻¹ ): 3331, 2968, 2875, 2791, 1755, 1669, 1637, 1453, 1386, 1339, 1312, 1283, 1254.

(Example 5)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid tetrahydrate (crystal 2)
(1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- [2- [2,3-bis] obtained by the method described in JP-A No. 2001-72681 (4-Nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1- Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (3.00 g) was dissolved in 33% aqueous tetrahydrofuran (36 mL), and 7.5% palladium-carbon (850 mg) was added to the solution. The suspension was stirred at 20 ° C. for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was extracted and washed with ethyl acetate. Activated carbon (1.29 g) was added to the obtained aqueous layer and stirred at room temperature for 30 minutes. After the activated carbon was filtered off from the reaction solution, the obtained filtrate was concentrated under reduced pressure, sodium bicarbonate (30 mg) and acetone (72 mL) were added to the concentrate, and the suspension was allowed to stand at 0 ° C. for 16 hours. . Thereafter, the suspension was stirred for 1 hour, and the precipitated crystals were collected by filtration and washed with a mixed solution of acetone: water (3: 1) to obtain crystals of the title tetrahydrate (1.31 g). .

  The melting point, nuclear magnetic resonance spectrum, infrared absorption spectrum and powder X-ray of the obtained crystal were the same as those of the crystal obtained in Example 2.

(Formulation example 1)
Injection: 250 mg of crystals of the compound of Example 1 are aseptically filled into a vial and sealed. If necessary, a known pharmaceutical additive such as a local anesthetic such as lidocaine hydrochloride can be added to this preparation. This preparation is used after being dissolved in a solvent such as distilled water for injection at the time of administration.

  The crystal of the present invention has improved productivity or storage stability, and is extremely useful practically as a medicine, particularly as an antibacterial agent.

FIG. 1 shows (1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine- 4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid / ethanol hydrate (I-1) It is a powder X-ray diffraction pattern obtained by irradiation with a line (wavelength λ = 1.54 Å). The vertical axis of the powder X-ray diffraction pattern indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ. FIG. 2 shows (1R, 5S, 6S) -2-[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine- 4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylic acid tetrahydrate (I-2) It is a powder X-ray diffraction pattern obtained by irradiation with Kα rays (wavelength λ = 1.54 Å). The vertical axis of the powder X-ray diffraction pattern indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ.

Claims (8)

In the powder X-ray diffraction obtained by irradiating the copper K _alpha ray, a main peak at lattice distance d = 7.60,6.69,6.33,6.14,5.15,4.58 and 4.48 An expression characterized by

A crystal of a 1-methylcarbapenem compound represented by the formula or a pharmacologically acceptable salt thereof. In the powder X-ray diffraction obtained by irradiating the copper K _alpha ray, a main peak at lattice distance d = 7.60,6.69,6.33,6.14,5.15,4.58 and 4.48 An expression characterized by

A crystal of 1-methylcarbapenem compound / ethanol solvate represented by In the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 11.68,8.79,7.53,6.57,5.58,5.37,3.99 and 3. An expression characterized by a main peak at 09

A crystal of a 1-methylcarbapenem compound represented by the formula or a pharmacologically acceptable salt thereof. In the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 11.68,8.79,7.53,6.57,5.58,5.37,3.99 and 3. An expression characterized by a main peak at 09

A crystal of 1-methylcarbapenem compound tetrahydrate represented by the formula: In the powder X-ray diffraction obtained by irradiating the copper K _alpha line, wherein, characterized in that shows the main peak at lattice distance d = 6.65,5.68,4.86,4.57 and 4.03

The manufacturing method of the crystal | crystallization of Claim 1 by drying the crystal | crystallization of 1-methylcarbapenem compound, ethanol hydrate, and trihydrate represented by these at normal temperature. Due to to hygroscopic crystals according to claim 1, in a powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 6.65,5.68,4.86,4.57 and 4 .03 is the main peak

The manufacturing method of the crystal | crystallization of 1-methyl carbapenem compound, ethanol hydrate, and trihydrate represented by these.   The crystal according to claim 1, wherein the water content is 0.5 to 2% by mass. Water content is 8-10 wt%, in a powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 6.65,5.68,4.86,4.57 and 4.03 Is the main peak

A crystal of 1-methylcarbapenem compound / ethanol hydrate / trihydrate represented by

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