JP5016480B2 - 1β-methylcarbapenem intermediate in crystalline form - Google Patents

Description

  The present invention relates to crystals of synthetic intermediates useful for efficiently producing 1β-methylcarbapenem compounds for oral administration.

  The 1β-methylcarbapenem compound is one of the most noticeable antibacterial agents because it exhibits an excellent antibacterial action against a wide range of pathogenic bacteria and has excellent stability in vivo. Therefore, in recent years, research and development of orally administered drugs and their production methods have been energetically advanced. As an efficient method for producing a 1β-methylcarbapenem compound for oral administration, methods described in WO2004 / 43997A1 (Patent Document 1) and WO2004 / 043961A1 (Patent Document 2) are known.

  General formula (2):

(Wherein R ¹ represents a protecting group for a hydroxyl group, R ² represents an aryl group or a heteroaryl group, R ³ represents an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, or a carbon number. A compound represented by an alkyloxy group having 1 to 10 carbon atoms or a cycloalkyloxy group having 3 to 10 carbon atoms, and R ⁴ represents hydrogen or an alkyl group having 1 to 4 carbon atoms (hereinafter referred to as compound (2)) Since it is a compound useful as an intermediate for producing a 1β-methylcarbapenem compound, it is desired to have particularly high purity. Generally, high purity can be achieved by crystallization, but the crystalline form of the compound (2) has not been known so far.

  For example, in Patent Document 1, the following formula (1), which is extremely useful among the compounds (2):

(3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxy Although a method for producing methyloxycarbonylmethyl-2-azetidinone (hereinafter referred to as Compound (1)) is described, Compound (1) is handled in an oily form in the Examples. The oily form of the compound (1) contains about 5% of a solvent, however, as a result of investigation by the inventors, this solvent can be easily removed from the form by ordinary vacuum concentration or vacuum drying. However, compound (1) could not be obtained in crystalline form.

  Considering production on an industrial scale, since the oily form of the compound (2) has a high viscosity, it is difficult to handle at the time of filling or dispensing from the container. In order to ease the handling in a high-viscosity state, a solution with a solvent makes it relatively easy to handle during filling and dispensing operations. However, since the capacity increases, considering the distribution to the market, the number of containers and transportation costs are increased, which is disadvantageous. In addition, when the solution of the compound (2) is handled in the next step, when the solvent used in the next step is different, it is necessary to evaporate the solvent or replace the solvent. It is disadvantageous. Furthermore, in order to purify the oily form of the compound (2) to a high purity, it is necessary to treat with, for example, a large amount of silica gel column, which causes an increase in cost. For the reasons as described above, handling as an oily form is generally disadvantageous.

For these reasons, it has been strongly desired to obtain a crystalline form of the compound (2) that can be expected to be highly purified, easy to handle, and excellent in storage stability.
WO2004 / 043953 WO2004 / 043961

  An object of the present invention is to provide a compound (2) in a crystalline form that is an intermediate of a useful 1β-methylcarbapenem compound, is easy to handle, and is excellent in terms of quality and storage stability.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor treated the compound represented by the oily form of the compound (2) in an appropriate organic solvent to obtain the crystalline form of the compound (2). And the compound was found to be a stable compound over a long period of time. The present invention has been completed based on such findings.

  That is, this invention relates to the manufacturing method of the crystal | crystallization of a compound (2) characterized by attaching | subjecting the azetidinone derivative represented by said Formula (2) to the crystallization process using an organic solvent, and obtaining as a crystal | crystallization.

  Furthermore, the present invention relates to (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyl represented by the above formula (1). Roxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone.

  According to the present invention, a compound represented by the above formula (2), which is extremely useful in producing various 1β-methylcarbapenem compounds for oral administration which have been actively researched and developed in recent years, is provided as a crystalline form. Since the crystalline form of the compound (2) is of high quality, has excellent storage stability, and is excellent in handleability, the present invention is very useful industrially.

  The crystalline form of formula (2), which is the object of the present invention:

The azetidinone derivative represented by can be obtained by subjecting compound (2) to a crystallization step using an organic solvent.

In the compound (2), R ¹ represents a hydroxyl-protecting group. As protecting groups for hydroxyl groups, ether-based protecting groups such as ethyl, methyl and benzyl groups described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS THIRD EDITION (author: Theodora W. Greene and Peter GMWuts (WILEY INTERSCIENCE PUBLICATION)), triethylsilyl Groups, silyl protecting groups such as trimethylsilyl group and tert-butyldimethylsilyl group, and ester protecting groups such as acetyl group, benzoyl group, benzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group. Preferred are silyl-based protecting groups, more preferred are trimethylsilyl group and triethylsilyl group, and particularly preferred is trimethylsilyl group.

R ² represents an aryl group or a heteroaryl group, and is substituted by a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a nitro group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or the like. May be.

  Examples of the aryl group include a phenyl group, a halogenophenyl group substituted with a halogen atom such as 1 to 3 chlorine atoms, a bromine atom, and an iodine atom, a p-nitrophenyl group, an o-nitrophenyl group, and a p-methoxy group. Examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  Examples of the heteroaryl group include 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidyl group, 2- (4,6-dimethyl) pyrimidyl group, 2-benzothiazolyl group, 2-benzoimidazolyl group, 2 -A benzoxazolyl group, 2-thienyl group, etc. are mention | raise | lifted.

R ² is preferably an aryl group, more preferably a phenyl group or a halogenophenyl group, and the halogenophenyl group is preferably a p-chlorophenyl group.

R ³ represents an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkyloxy group having 1 to 10 carbon atoms, or a cycloalkyloxy group having 3 to 10 carbon atoms.

  Examples of the alkyl group having 1 to 10 carbon atoms include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, and n-octyl group. Group, n-decanyl group and the like.

  Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclohexyl group, a 1-methylcyclohexyl group, and a 4-methylcyclohexyl group.

  Examples of the alkyloxy group having 1 to 10 carbon atoms include methyloxy group, ethyloxy group, n-propyloxy group, iso-propyloxy group, n-butyloxy group, iso-butyloxy group, sec-butyloxy group, tert-butyloxy group 1-ethylpropyloxy group, n-hexyloxy group, n-octyloxy group, n-decyloxy group and the like.

  Examples of the cycloalkyloxy group having 3 to 10 carbon atoms include a cyclopropyloxy group, a cyclohexyloxy group, a 1-methylcyclohexyloxy group, and a 4-methylcyclohexyloxy group.

R ³ is preferably a tert-butyl group, an ethyloxy group, a 1-ethylpropyloxy group or a cyclohexyloxy group, more preferably a tert-butyl group.

R ⁴ is hydrogen or an alkyl group having 1 to 4 carbon atoms. Examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, and tert-butyl group. . R ⁴ is preferably hydrogen or a methyl group, more preferably hydrogen.

  The compound (2) is preferably the following general formula (1):

(3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxy Methyloxycarbonylmethyl-2-azetidinone. The crystal of the compound (1) is a novel crystal found by the present inventors and is easy to handle and has good stability when producing a 1β-methylcarbapenem compound for oral administration. Very useful from.

  Compound (2) can be produced, for example, according to the method described in WO2004 / 043953. For example, it may be an oily compound such as compound (1) produced according to the method described in Example 3, or a reaction solution (crude reaction solution) containing compound (2) itself. It may be manufactured by the above method. Of course, the crystals obtained by this method may be used again in order to further increase the purity or to make the crystal shape easier to handle. Hereinafter, the crystallization process will be specifically described.

  In the crystallization step, crystallization is performed from an organic solvent solution containing the compound (2) to obtain the compound (2) as crystals.

  Although it does not specifically limit as an organic solvent to be used, For example, aromatic hydrocarbons, such as benzene, toluene, xylene, aliphatic hydrocarbons, such as pentane, hexane, heptane, methylcyclohexane, dichloromethane, chlorobenzene, dichlorobenzene, 1, Halogenated hydrocarbons such as 2-dichloroethane, ethers such as tetrahydrofuran, 1,3-dioxolane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, acetic acid Esters such as n-butyl and tert-butyl acetate can be used, and these organic solvents may be used alone or as a mixed solvent in which two or more kinds are combined.

  When used as a mixed solvent, the mixing ratio is not limited. The organic solvent to be used is preferably benzene, toluene, hexane, heptane, dichloromethane, or a mixed solvent thereof, and more preferably benzene, toluene, or a mixed solvent thereof.

  What is necessary is just to set the usage-amount of the organic solvent to be used suitably based on the solubility of the compound (2) with respect to the organic solvent to be used, as long as the solid of the compound (2) does not precipitate. Usually, the organic solvent is 0.1 to 20 times by weight, preferably 0.1 to 10 times by weight with respect to the oily form of the compound (2).

  Next, a method for preparing an organic solvent solution of compound (2) will be described. An organic solvent solution of the compound (2) can be prepared by adding an organic solvent to the oily form of the compound (2). The addition of the organic solvent can be carried out at any temperature, but it may be once heated as necessary. The heating temperature is not particularly limited, but may be any temperature below the boiling point of the organic solvent to be used. Needless to say, the organic solvent solution of the compound (2) may be a crude reaction solution of the compound (2) synthesized by any method.

  The crystallization method is not particularly limited. For example, a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, or a crystallization method by adding a poor solvent is generally used. These crystallization methods can be carried out alone or in appropriate combination. A preferred embodiment of the crystallization method will be described.

  When performing cooling crystallization, it is preferable to crystallize by cooling with stirring. The cooling rate is not particularly limited, and the cooling temperature is not particularly limited as long as it is not higher than the organic solvent solution temperature of the compound (2) prepared by the above-described method, but is preferably 30 ° C. or lower, more preferably 20 ° C. Or less, particularly preferably 10 ° C. or less. The ultimate temperature is preferably 0 ° C. or lower, more preferably −5 ° C. or lower.

  Next, a crystallization process using a poor solvent will be described. Although it does not specifically limit as a poor solvent, For example, aliphatic hydrocarbons, such as a pentane, n-hexane, n-heptane, a cyclohexane, can be used, and n-hexane or n-heptane is preferable among these. These may be used alone or as a mixed solvent in which two or more kinds are combined. Needless to say, an organic solvent solution containing the compound (2) may be mixed with a poor solvent to the extent that crystals of the compound (2) do not precipitate.

  The poor solvent is about 0.1 to 50 times by weight, preferably about 0.5 to 25 times by weight with respect to the oily form of the compound (2). The poor solvent is preferably used in an amount of 0.5 to 5 times the weight of the organic solvent. The poor solvent may be added to the organic solvent solution containing the compound (2) in a lump, sequentially, or dividedly. Of course, an organic solvent solution may be added to the poor solvent to take the reverse addition form. Preferably, sequential addition is performed. The addition time of the poor solvent is usually about 5 minutes to 20 hours, preferably about 30 minutes to 5 hours. The poor solvent is preferably added dropwise with stirring.

  Concentrated crystallization includes a method in which an organic solvent is removed from an organic solvent solution containing the compound (2) by stirring under reduced pressure or the like. If the compound (2) crystallizes, it may be isolated as it is. However, the concentrated crystallization is preferably performed in combination with the cooling crystallization.

  Preferred examples of the crystallization method include a cooling crystallization method, a crystallization method by adding a poor solvent, a concentrated crystallization method, and a cooling crystallization method. Among the above crystallization methods, a crystallization method using a poor solvent is more preferable.

  Various crystallization methods may be combined as necessary. In any of the above methods, crystallization can be promoted by adding seed crystals.

  The obtained crystal can be obtained as a dry crystal, for example, by drying under reduced pressure (vacuum drying) as necessary.

  Among the crystals of compound (2) obtained as described above, the crystal of compound (1) is, for example, powder X-ray diffraction obtained by irradiation with copper Kα radiation (wavelength λ = 1.54 Å). In this case, the crystals are obtained as crystals having main peaks at diffraction angles 2θ = 7.12 °, 9.64 °, 13.34 °, 18.02 °, 20.42 °, and 21.44 °. The main peak here is a peak having a relative intensity of 20 or more when the intensity of the peak showing the diffraction angle 2θ = 7.12 ° is 100. In this specification, when the crystal is defined by the position of the diffraction peak, the value of the diffraction angle 2θ is not limited to the value indicated as having the peak and the range based thereon, The diffraction angle 2θ value in the crystal of the present invention can be included. The range in which such an error occurs can be easily predicted by those skilled in the art based on the measurement conditions and the like. For example, the error range is ± 0.05 °.

  The present invention will be further clarified by the following examples, reference examples and test examples, but the present invention is not limited thereto.

(Reference Example) (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1-pi Formula for obtaining Valoyloxymethyloxycarbonylmethyl-2-azetidinone (3):

(3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-hydroxylethyl] -1-pivaloyloxymethyloxycarbonyl 29.52 g (60.74 mmol) of methyl-2-azetidinone (see WO2004 / 043953A1) was dissolved in 240.00 g of toluene, and this solution was ice-cooled. Next, 9.93 g (97.18 mmol) of triethylamine was added to the reaction solution, and 9.43 g (85.04 mmol) of trimethylsilane chloride was added dropwise, followed by stirring at the same temperature for 20 hours. After adding 120.00 g of water to the reaction solution and stirring for 5 minutes, the organic layer was separated. The organic layer was washed again with water, and (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl]- A toluene solution containing 1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) was obtained. The solution is concentrated to an oily form of (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1 -35.56 g (including 5% toluene solvent) of pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) was obtained.

Example 1 Crystalline (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1- Acquisition of pivaloyloxymethyloxycarbonylmethyl-2-azetidinone 17.82 g of the oily form compound (1) obtained in Reference Example was dissolved in 20.80 g of toluene, and 30.50 g of hexane was added at 23 ° C. with stirring. It was dripped. After cooling to −5 ° C., seed crystals (0.02 g) obtained in Example 2 described later were added, and (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl was added. ] -3-[(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) precipitated as crystals. The precipitated crystals were collected by filtration, washed with a small amount of hexane, and then vacuum dried for 18 hours to obtain 13.7 g of compound (1) in the form of white crystals. The obtained crystal was a needle-like crystal having polarization as observed with a polarizing microscope. Melting point: 64 ° C. Moreover, NMR of the obtained crystal was as follows.
¹ H-NMR (CDCl ₃ ) δ: 0.14 (9H, s), 1.17 (9H, s), 1.27 to 1.30 (6H, m), 3.05 to 3.16 (2H m), 3.85 (1H, d, J = 18.3 Hz), 4.10 (1H, dd, J = 2.7, 5.4 Hz), 4.14 to 4.20 (1H, m) 4.32 (1H, d, J = 18.3 Hz), 5.75 (2H, s), 7.30 (2H, d, J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz).

Moreover, about the powder X-ray-diffraction measurement of the obtained crystal | crystallization, the powder X-ray-diffraction measurement was performed according to the following apparatus and measurement conditions.
Apparatus: Rotating anti-cathode X-ray diffractometer Geiger Flex RAD-rA [manufactured by Rigaku Corporation]
Measurement conditions: X-ray Cu / Kα ray used, X-ray intensity 40 kV, 100 mA, angle range 2θ = 3 to 80 °, scanning speed 2 ° / min, sampling interval 0.02 seconds, divergence slit 1.0 °, receiving Slit 0.6 °, Scatter slit 1.0 °
The results are shown in Table 1.

Example 2 Crystalline (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1- (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3 obtained by the same method as in Reference Example for Acquisition of Pivaloyloxymethyloxycarbonylmethyl-2-azetidinone 11.0 g of a toluene solution containing-[(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) was concentrated under reduced pressure and cooled at -20 ° C overnight. As a result, 1.2 g of a white-yellow mass was obtained. When this lump was crushed, washed with a small amount of hexane and then vacuum-dried, a white solid was obtained, and when observed with a polarizing microscope, needle-like crystals with polarization were observed.

Example 3 (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1- Acquisition of pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3- in oil form obtained in Reference Example [(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) was added with a very small amount of the seed crystal obtained in Example 2 at room temperature (25 ° C. ). After 2 hours, a white mass was obtained. When the resulting mass was crushed and washed with a small amount of hexane and then vacuum-dried, a white solid was obtained, and when observed with a polarizing microscope, needle-like crystals with polarization were observed.

(Example 4) Storage stability test of compound (1) in crystalline form About 40 to 50 mg of compound (1) in crystalline form obtained in Example 1 was weighed into a glass bottle, and then 21 at 50 ° C in a nitrogen gas atmosphere. Left for days. The obtained crystal had no change in appearance color and shape. Further, the residual ratio of the obtained crystals was measured by high performance liquid chromatography (HPLC) with the residual ratio of the compound (1) in the crystalline form on the first day as 100%. The residual ratio here is based on the area percentage of HPLC and is a value relative to the area percentage of the compound (1) on the first day.
[HPLC analysis conditions]
Model: LC-10A series manufactured by Shimadzu Corporation Column: ODS column manufactured by GL Sciences Inc. Silts ODS-2 (4.6 mm × 150 mm)
Eluent: acetonitrile / water = 80/20 (v / v)
Flow rate: 1.0 ml / min
Detection: 220 nm (UV detector)
Temperature: 25 ° C
The results are as shown in Table 2. It was found that the stability of the compound of formula (1) in the crystalline form of the present invention was good.

Claims (9)

Formula (1):

(3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxy In a powder X-ray diffraction pattern, methyloxycarbonylmethyl-2-azetidinone is subjected to a crystallization step using an organic solvent and obtained as a crystal. In a powder X-ray diffraction pattern, diffraction angles are 7.12 °, 9.64 °, The manufacturing method of the crystal | crystallization of the compound represented by said Formula (1) which shows the peak of diffraction intensity at 13.34 degrees, 18.02 degrees, 20.42 degrees, and 21.44 degrees . The crystallization method in the crystallization step is a crystallization method implemented by combining a cooling crystallization method, a concentrated crystallization method and a cooling crystallization method, or a crystallization method by adding a poor solvent. Production method. The production method according to claim 2, wherein the crystallization method in the crystallization step is a crystallization method by adding a poor solvent. The organic solvent to be used is one single solvent selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, and esters, or a mixed solvent of two or more. Item 4. The production method according to any one of Items 1 to 3. The production method according to claim 4, wherein the organic solvent is one kind selected from the group consisting of n-hexane, n-heptane, benzene, toluene, and dichloromethane, or a mixed solvent of two or more kinds. The production method according to claim 3, wherein the poor solvent is a single solvent selected from aliphatic hydrocarbons or a mixed solvent of two or more. The production method according to claim 6, wherein the poor solvent is n-hexane and / or n-heptane. In the powder X-ray diffraction pattern, diffraction intensity peaks are shown at diffraction angles of 7.12 °, 9.64 °, 13.34 °, 18.02 °, 20.42 °, and 21.44 °. ):

(3S, 4S) -4-[(1R) -1- (p-chlorophenylthiocarbonyl) ethyl] -3-[(1R) -1-trimethylsilyloxyethyl] -1-pivaloyloxy Crystal of methyloxycarbonylmethyl-2-azetidinone. Use of the crystals according to claim 8 as a synthetic intermediate for the production of 1β-methylcarbapenem compounds.