WO2006104131A1 - 1β-METHYLCARBAPENEM INTERMEDIATE IN CRYSTALLINE FORM - Google Patents

Abstract

A process for producing a crystal of an azetidinone derivative comprising subjecting an azetidinone derivative to crystallization using an organic solvent to yield the azetidinone derivative in the form of a crystal; and a crystal of the azetidinone compound. The process can provide an azetidinone compound which is useful as an intermediate for the synthesis of a 1β-methylcarbapenem compound for oral administration, in the form of a crystal which is high in purity and is easy to handle.

Description

 1 β-methylcarbapenem intermediate in crystalline form

 [0001] The present invention relates to a synthetic intermediate crystal useful for efficiently producing a 1-methylcarbapenem compound for oral administration.

 Background art

 [0002] 1 β-methylcarbapenem compounds show excellent antibacterial activity against a wide range of pathogenic bacteria

 In addition, the antibacterial agent Hitoda, which has received the most attention due to its excellent stability in vivo.

 One. For this reason, in recent years, research and development of orally administered drugs and their production methods have been energetically advanced. As an efficient method for producing 1 β-methylcarbapenem compound for oral administration, methods described in WO2004 / 43973A1 (Patent Document 1) and WO2004 / 043961A1 (Patent Document 2) are known.

 [0003] General formula (2):

 [0004] [Chemical 3]

(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, and a cyclohexane having 3 to 10 carbon atoms. An alkyl group having carbon atoms:! To 10 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. Since the compound (hereinafter referred to as Compound (2)) is a useful compound as an intermediate for producing a 1β-methylcarbapenem compound, it is desired to have particularly high purity. In general, high purity can be achieved by crystallization, but the crystalline form of the compound (2) has not been known so far. [0006] For example, in Patent Document 1, the following formula (1), which is extremely useful among the compounds (2):

[0008] (3S, 4S) _4_ [(1R) _ 1 _ (p-cyclophenylphenylcarbonyl) ethyl] -3- [(lR)-l -trimethylsilyloxetyl] _ 1 _Pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (hereinafter referred to as compound (1)) is described as a preparation, but compound (1) is handled in the form of an oil in the examples. . The oily form of the compound (1) contains about 5% of a solvent, but as a result of investigations by the inventors, this solvent cannot be removed from the form by ordinary vacuum concentration or vacuum drying. Compound (1), which is not easy, could not be obtained in crystalline form.

 [0009] Considering production on an industrial scale, since the oily form of the compound (2) has a high viscosity, it is difficult to handle when filling into the container or dispensing from the container. In order to ease handling in a high-viscosity state, using a solvent as a solution makes it relatively easy to handle during filling and dispensing operations. However, considering the distribution to the market due to the increase in capacity, it is disadvantageous because it increases the number of containers and transportation costs. In addition, when the solution of compound (2) is handled in the next step, if the solvent used in the next step is different, the solvent must be removed if the solvent is distilled off, so the oily form of compound (2) is handled as a solution. Things are disadvantageous. Furthermore, in order to purify the oily form of the compound (2) to a high purity, it is necessary to treat it with, for example, a large amount of silica gel column, which causes an increase in cost. For the reasons described above, handling as an oily form is generally disadvantageous.

[0010] For these reasons, high purity can be expected, and it has excellent storage stability that is easy to handle. It was strongly desired to obtain a crystalline form of compound (2).

 Patent Document 1: WO2004 / 043973

 Patent Document 2: W〇2004 / 043961

 Disclosure of the invention

 Problems to be solved by the invention

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

 Means for solving the problem

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

That is, the present invention is characterized in that the azetidinone derivative represented by the above formula (2) is obtained as a crystal by subjecting it to a crystallization step using an organic solvent. It relates to a manufacturing method.

 Furthermore, the present invention relates to (33,43) -4 [(11) -1-chlorophenylthiocarbonyl) ethyl] -3- [(lR) -l-trimethylsilyl represented by the above formula (1). Loxochetil] — 1-pivaloxymethyloxycarbonylmethyl-2-azetidinone. The invention's effect

 [0015] According to the present invention, the compound represented by the above formula (2), which is extremely useful in the production of various 1-methylcarbapenem compounds for oral administration, which has been actively researched and developed in recent years, is in crystalline form. Provided. 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.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0016] The crystalline form of formula (2), which is the object of the present invention: [0017] [Chemical 5]

[0018] The azetidinone derivative represented by general formula (2) 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. Hydroxyl protecting groups include ether protecting groups such as ethyl, methyl and benzyl groups described in PROT ECTIVE GROUPS IN ORGANIC SYNTHESIS THIRD EDITION (author: Theodora W. Greene and Peter GMWuts (WILEY INTERSCIENCE PUBLICATION)) Silyl protecting groups such as ethynolesilyl group, trimethylsilinole group, tert-butyldimethylsilyl group, ester protecting groups such as acetyl group, benzoyl group, benzyloxycarbonyl group, p-nitrophenoxycarbonyl group Etc. A silyl protecting group is preferred, a trimethylsilyl group and a triethylsilyl group are more preferred, and a trimethylenosilyl group is particularly preferred.

[0020] R ² represents an aryl group or a heteroaryl group, such as 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 substituted.

 [0021] Examples of aryl groups include phenyl groups, 1 to 3 chlorine atoms, bromine atoms, halognophenyl groups substituted with halogen atoms such as iodine atoms, p-nitrophenyl groups, o-nitrophenyls. Group, p-methoxyphenyl group, 1_naphthyl group, 2_naphthyl group and the like.

 [0022] Examples of the heteroaryl group include 2_pyridyl group, 3_pyridinole group, 4_pyridinole group,

2_pyrimidinole group, 2- (4, 6-dimethinole) pyrimidinole group, 2-benzothiazolyl group, 2-be Nzoimidazolyl group, 2-benzoxazolyl group, 2-chenyl group and the like.

[0023] R ² is preferably a phenyl group that is preferably an aryl group, and a halolognophenyl group that is more preferably a halognov technyl group is preferably a p-cyclophenyl group.

[0024] R ³ is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, carbon number:! To 1

A 0 alkyloxy group or a C 3 10 cycloalkyloxy group is represented.

[0025] Examples of the alkyl group having 1 to 10 carbon atoms include methinole group, ethyl group, n-propyl group, iso_propyl group, n_butyl group, iso_butyl group, sec_butyl group, tert_butyl group, n_ An octyl group, an n-decanyl group, and the like.

[0026] Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclohexyl group, and 1

-Methylcyclohexyl group, 4-methylcyclohexyl group and the like.

[0027] 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 ethyl group Propyloxy group, n xyloxy group, n-octyloxy group, n decyloxy group, etc.

[0028] Examples of the C 3 10 cycloalkyloxy group include a cyclopropyloxy group, a cyclohexyloxy group, a 1-methylcyclohexyloxy group, and a 4-methylcyclohexyloxy group.

[0029] R ³ is preferably a tert butyl group, an ethyloxy group, a 1 ethylpropyloxy group, or a cyclohexylenooxy group, and more preferably a tert butyl group.

[0030] Examples of R ⁴ include hydrogen or an alkyl group having 14 carbon atoms. Examples of the alkyl group having from 4 to 4 carbon atoms include a methylol group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec butyl group, and a tert butyl group. R ⁴ is preferably hydrogen or a methyl group, more preferably hydrogen.

 [0031] The compound (2) is preferably the following general formula (1):

[0032] [Chemical 6]

[0033] (3S, 4S) -4 — [(lR) — l— (p-phenylphenylthiocarbonyl) ethyl] -3-[(lR) -l-trimethylsilyloxetyl] — 1—Bivaloyloxymethyloxycarbonylmethyl-2-azetidinone. The crystal of the compound (1) is a novel crystal found by the present inventors, which is easy to handle when producing a 1-methylcarbapenem compound for oral administration, and has good stability. It is very useful because it is.

 [0034] Compound (2) can be produced, for example, according to the method described in WO2004Z043973. For example, an oily compound such as compound (1) produced according to the method described in Example 3 can be used, and a reaction solution (crude reaction solution) containing compound (2) can be used. Good, but can be made by other methods. Of course, the crystal 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 this crystallization step, crystallization is performed from an organic solvent solution containing compound (2) to obtain compound (2) as crystals.

[0036] The organic solvent to be used is not particularly limited. For example, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as pentane, hexane, heptane, and methylcyclohexane, dichloromethane, chlorine, and the like. Halogenated hydrocarbons such as oral benzene, dichlorobenzene, 1,2-dichloroethane, tetrahydrofuran, 1,3-dioxolan, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethers such as methyl tert-butyl ether, Esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and tert-butyl acetate can be used. A solvent may be used alone or as a mixed solvent in which two or more kinds are combined.

 [0037] When used as a mixed solvent, the mixing ratio is not limited. The organic solvent to be used is preferably benzene, toluene, hexane, heptane or dichloromethane, which is a mixed solvent thereof, more preferably benzene, toluene or a mixed solvent thereof.

 [0038] The amount of the organic solvent to be used may be appropriately set based on the solubility of the compound (2) in the organic solvent to be used as long as the solid of the compound (2) does not precipitate. Usually, the organic solvent has a weight of 0.:! To 20 times, preferably 0.:! To 10 times the weight of the compound (2) in the oily form.

 [0039] Next, a method for preparing an organic solvent solution of the 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 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 compound (2) may be a crude reaction solution of compound (2) synthesized by any method.

 [0040] The crystallization method is not particularly limited, and examples thereof include a reaction crystallization method, a cooling crystallization method, a concentrated crystallization method, a crystallization method using solvent substitution, or a crystallization by adding a poor solvent. Commonly used crystallization methods such as a crystallization method can be carried out alone or in appropriate combination. A preferred embodiment of the crystallization method will be described.

 [0041] When cooling crystallization is performed, 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, it is 20 ° C or less, and particularly preferably 10 ° C or less. The ultimate temperature is preferably 0 ° C or lower, more preferably -5 ° C or lower.

Next, the crystallization process using a poor solvent will be described. The poor solvent is not particularly limited. For example, aliphatic hydrocarbons such as pentane, n-hexane, n-heptane, and cyclohexane can be used. Among them, n-hexane or n-hexane I prefer heptane. These may be used alone or in combination of two or more. It may be used as a medium. Needless to say, an organic solvent solution containing the compound (2) may be mixed with a poor solvent to the extent that the compound (2) crystals do not precipitate.

[0043] The poor solvent is about 0.:! To about 50 times by weight, preferably about 0.5 to 25 times by weight with respect to the compound (2) in the oily form. 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) all at once, 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 should be added dropwise with stirring.

 [0044] 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) is crystallized, the state is maintained. Although it may be isolated, concentrated crystallization is preferably combined with cooling crystallization.

 [0045] 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.

 [0046] Various crystallization methods may be combined as necessary. In any of the above methods, crystallization can be promoted by adding seed crystals.

 [0047] The obtained crystal can be obtained as a dried crystal, for example, by drying under reduced pressure (vacuum drying) as necessary.

[0048] Among the crystals of compound (2) obtained as described above, the crystals of compound (1) are obtained, for example, by irradiation with copper α-rays (wavelength λ = 1.54 angstroms). Crystals showing main peaks at diffraction angles 2Θ = 7.12 °, 9.64 °, 13.34 °, 18.02 °, 20.42 °, and 21.44 ° as compared to powder X-ray diffraction As obtained. The main peak here is a peak having a relative intensity of 20 or more when the intensity of a peak showing a diffraction angle of 2Θ = 7.12 ° is taken as 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 above peak and the range based on it, but the range in which an error may occur. Can be included as a diffraction angle 2 Θ value in the crystal of the present invention. wear. The range in which such an error occurs can be easily predicted by those skilled in the art from the measurement conditions and the like. For example, the error range is ± 0.05 °.

 Example

 [0049] The present invention will be further clarified by the following examples, reference examples and test examples, but the present invention is not limited thereto.

[0050] (Participant example) (3S.4S) _4_ "(1R) _1_ (Ό-Chlorophenyldithiocarbonole) ethyl 1 -3-T (lR) -1-trimethylsilyloxetyl 1 1-Bivaloyloxime Tyroxycarbonylmethyl-2-losing the azetidinone

 Formula (3):

[0051] [Chemical 7]

で示される（3S，4S) _4_[(1R)_1_ (p—クロ口フエ二ルチオカルボニル）ェチル] -3-[(lR) -1-ヒドロキシルェチノレ]— 1—ビバロイルォキシメチルォキシカルボ二 ノレメチノレー 2 ァゼチジノン (WO2004/043973A1号参照） 29.52g(60.74m mol)をトルエン 240.00gに溶解し、この溶液を氷冷した。ついで反応液中にトリエ チノレアミン 9.93g(97.18mmol)をカロえ、塩ィ匕トリメチノレシラン 9.43g(85.04mm ol)を滴下した後、同温度で 20時間攪拌した。反応液中に水 120.00gを投入して 5 分間攪拌後、有機層を分取した。有機層を水にて再度洗浄し、 (3S,4S) -4-[(lR) — 1— (p クロ口フエ二ルチオカルボニル）ェチル]— 3 [ (1R)— 1—トリメチルシリロ キシェチル] 1ーピバロィルォキシメチルォキシカルボ二ルメチルー 2—ァゼチジノ ン（1)を含有するトノレェン溶液を得た。この溶液を濃縮し、油状形態の（3S，4S) -4 - [(1R)-1 - (p クロ口フエ二ルチオカルボニル）ェチル] 3— [ (1R)— 1 トリメチ ノレシリロキシェチル] 1 ピバロィルォキシメチルォキシカルボ二ルメチルー 2—ァ ゼチジノン（1)を 35· 56g (5%のトノレェン溶媒を含む）得た。

(3S, 4S) _4 _ [(1R) _1_ (p—Black mouth phenylthiocarbonyl) ethyl] -3-[(lR) -1-hydroxylethyleno]] — 1-Bivaloyloxymethyl Xylcarbonoremethinole 2 azetidinone (see WO2004 / 043973A1) 29.52 g (60.74 mmol) was dissolved in 240.00 g of toluene, and this solution was ice-cooled. Next, 9.93 g (97.18 mmol) of triethylenoleamine was added to the reaction solution, and 9.43 g (85.04 mmol) of salt trimethylolesilane 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-[(lR) — 1— (p-phenylphenylthiocarbonyl) ethyl] — 3 [(1R) — 1-trimethylsilyloquichetil] A tolenene solution containing 1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) was obtained. The solution was concentrated to an oily form of (3S, 4S) -4--[(1R) -1- (p-phenylphenylthiocarbonyl) ethyl] 3- [(1R) — 1 trimethyl Noresiloxychetyl] 1-pivaloyloxymethyloxycarbonylmethyl-2-azetidinone (1) was obtained in an amount of 35 · 56 g (containing 5% of toluene solvent).

[0053] (Example 1) (3S.4S) —4 1 “(1R) — 1 1 (Ό mouth opening phenylthiocarbonyl) ethyl” _ 3 _ ”(1R) _ 1 _trimethylsiloxy Loss of Shetil 1-1-Pivaloyloxymethyloxycarbonylmethyl 1-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 dropwise at 23 ° C. with stirring. _ After cooling to 5 ° C, seed crystals (0.02 g) obtained in Example 2 to be described later were added, and (3S, 4S) — 4— [(1R) — 1— (p chlorodiphenylthiocarbonyl ) Ethyl] -3-[(lR) -l-trimethylsilyloxetyl] _1_pivaloyloxymethyloxycarbonylmethyl_2-azetidinone (1) was 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. Further, NMR of the obtained crystal was as follows.

 — NMR (CDC1) δ: 0.14 (9Η, s), 1.17 (9H, s), 1.27 ~: 1.30 (6H, m), 3

 Three

 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).

[0054] Further, with respect to the powder X-ray diffraction measurement of the obtained crystal, the powder X-ray diffraction measurement was performed according to the following apparatus and measurement conditions.

 Equipment: Rotating anti-cathode X-ray diffractometer Geigerflex RAD—rA [manufactured by Rigaku Corporation]

 Measurement conditions: X-ray Cu'K wire used, X-ray intensity 40kV, 100mA, angle range 2 Θ = 3 to 80 °, running speed 2 ° apportionment, sampling interval 0.02 seconds, die purge ence slit 1 0 °, Reciprocating slit 0.6 °, Scatter slit 1.0 °

 The results are shown in Table 1.

[0055] [Table 1] Diffraction angle) Relative intensity

 7.120 100

 9.220 10

 9.640 50

 13.340 22

 14.240 16

 16.340 10

 16.920 16

 17.500 14

 18.020 42

 18.560 10

 19.360 14

 20.420 30

 21.440 38

 21.880 16

 23.040 14

 23.220 12

 24.700 10

 25.720 10

 26.980 10

 28.440 12

 31.060 10

Example 2 Crystalline Form (3S.4S) —4 1 “(1R) — 1 1 (Ό1 chlorothiophenyl) ethyl 1 3“ (1R) — 1-trimethylsilyloxiche Til 1-1—Bivaloyloxy methyloxycarbonylmethyl-2-azetidinone defeat

 (3S, 4S) 4 [(1R) — 1- (p-chlorophenylthiocarbonyl) ethyl] — 3 [(1R) — 1-trimethylsilyloxetyl] — 1-bivalloy ruo Toluene solution containing xymethyloxycarbonylmethyl 2-azetidinone (1) 11. Og was concentrated under reduced pressure and cooled at −20 ° C. overnight to obtain 1.2 g of a white-yellow mass. 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, acicular crystals with polarization were observed.

 [0057] (Example 3) (3S.4S) _4_ "(1R) _ 1 _ (O _ phenyl thiocarbonyl) ethyl] _ 3 _" (1R) _ 1 _ trimethylsilyloxy Loss of Shetil 1-1-Pivaloyloxymethyloxycarbonylmethyl 1-azetidinone

(3S, 4S) _4_ [(1R) _ 1 _ (p-chlorophenylthio) in the oily form obtained in the Reference Example Carbonyl) ethyl] -3-[(lR) -1-trimethylsilyloxetyl]-1-pivalyloxymethyloxycarbonylmethyl-2-azetidinone (1) with trace amounts of seed crystals obtained in Example 2 Added and left at room temperature (25 ° C). After 2 hours, a white mass was obtained. When the resulting mass was washed with a small amount of hexane while being crushed and then vacuum dried, a white solid was obtained, and when observed with a polarizing microscope, acicular crystals with polarization were observed.

 [0058] m A) Open Noi (ι)

 About 40 to 50 mg of the crystalline form of the compound (1) obtained in Example 1 was weighed into a glass bottle and allowed to stand at 50 ° C. for 21 days in a nitrogen gas atmosphere. The crystals obtained did not change in appearance color or 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 HPLC area percentage, and is the value for 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.

 Inertsil ODS— 2 (4.6 mm x 150 mm)

 Eluent: acetonitrile / water = 80/20 (v / v)

 Flow velocity: 1.0m min

 Detection: 220nm (UV detector)

 Temperature: 25 ° C

 The results are 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.

[0059] [Table 2] Test compound Storage conditions Residual rate

 1 曰 21 曰

 Compound in crystalline form (1) 50 ° C

Claims

Claim Formula (2):  [Chemical 1]

(Wherein R represents a protecting group for a hydroxyl group, R 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: ! ~ 1 0 Arukiruokishi group or the number of carbon atoms 3 to: represent 10 cycloalkyl O alkoxy group, R ⁴ is a Azechijinon derivative represented by an alkyl group of hydrogen or C 1 4), the organic solvent A method for producing a crystal of a compound represented by the formula (2), which is obtained as a crystal by being subjected to a crystallization step to be used. [2] The crystallization method in the crystallization process is a crystallization method performed by combining a cooling crystallization method, a concentration crystallization method and a cooling crystallization method, or a crystallization method by adding a poor solvent. The manufacturing method according to claim 1.  [3] The production method according to claim 2, wherein the crystallization method in the crystallization step is a crystallization method by adding a poor solvent.  [4] 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. The production method according to claim 13, wherein: [5] The production method according to claim 4, wherein the organic solvent is one kind selected from the group consisting of _n- xane, n-heptane, benzene, toluene, and dichloromethane, or a mixed solvent of two or more kinds. 6. The production method according to claim 3, wherein the poor solvent is one kind selected from aliphatic hydrocarbons or a mixed solvent of two or more kinds. The production method according to claim 6, wherein the poor solvent is n-hexane and / or n-heptane. The production method according to claim 1, wherein R ¹ is a silyl protecting group. The production method according to any one of claims 1 to 8, wherein R ² is a halognophenyl group. R ³ is tert_ butyl group, The process according to any one of claims 1 to 9 R ⁴ is hydrogen. Formula (1):  [Chemical 2]

(3S, 4S) _4 _ [(1R) _1_ (p—Black mouth phenylthiocarbonyl) ethyl] -3-[(lR) -l-trimethylsilyloxetyl] _ 1 _Pivaloyloxy Methyloxycarbonylmethyl _ 2 -azetidinone crystal. 12. The crystal according to claim 11, which exhibits diffraction intensity peaks at diffraction angles of 7.12 °, 9.64 °, 13.34 °, 18.02 °, 20.42 ° and 21.44 °. Use of the crystal according to claim 11 or 12 as a synthetic intermediate for the production of 1 β-methylcarbapenem compounds.