JP2014122164A - Method for producing olanzapine ii type crystal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for obtaining a II type crystal of 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine (general name:olanzapine) at a high recovery rate, which crystal is useful as an antipsychotic drug.SOLUTION: A method for producing the olanzapine II type crystal comprises the steps of: using water-containing ethyl acetate as a recrystallization solvent when a crude material of the olanzapine is re-crystallized; dissolving the crude material of the olanzapine in the water-containing ethyl acetate; adjusting the amount of the water within 1.5-4.5 moles based on 1 mole of the dissolved olanzapine; precipitating crystals to obtain a new olanzapine hydrate crystal having characteristic peaks at such positions that 2θ is 8.9±0.2°, 9.4±0.2°, 17.1±0.2°, 18.2±0.2°, 18.6±0.2°, 20.2±0.2°, 20.5±0.2°, 20.8±0.2°, 21.7±0.2°, and 26.4±0.2° when X-ray diffraction measurement is performed by using a Cu-Kα ray; and drying the obtained olanzapine hydrate crystal.

Description

  The present invention relates to a novel method for producing olanzapine type II crystals useful as an active pharmaceutical ingredient.

  2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine represented by the following formula (1) is called olanzapine by a general name. It is a drug substance compound. The compound has been used in antipsychotic drugs for treatment of schizophrenia or bipolar disorder epilepsy (see Patent Document 1).

  This olanzapine is known to have a crystalline polymorph. Here, having crystal polymorphism means that there are a plurality of crystal forms having different crystal structures in the same molecule. The characteristics related to pharmaceutical quality such as solubility, bioavailability, and stability are often different between crystal forms in crystal polymorphs. Generally, a desired crystal form (crystal form) is specified for use. In olanzapine, physical properties such as melting point and stability are preferable, and because the appearance color is bright yellow and gives a good impression, the crystal form called type II is considered most desirable for use as a drug substance (See Patent Document 1).

  The following methods are known as methods for producing olanzapine type II crystals. That is, (1) a method in which olanzapine is heated and dissolved in anhydrous ethyl acetate and then cooled and crystallized (see Patent Document 1) and (2) a dihydrate crystal of olanzapine is used as an intermediate, and the crystal is cooled to 50 ° C. A method of obtaining olanzapine type II crystals by drying as described above (see Patent Document 2) is known. According to these methods, it is said that a pure type II crystal free from other crystal forms can be stably produced.

  Olanzapine hydrate also has a polymorphic form. In addition to the dihydrate crystals B, D and E disclosed in Patent Document 2, there is a crystal form called J1 type dihydrate. It is known to exist (see Patent Document 3).

Japanese National Patent Publication No. 11-502535 Special table 2001-500787 gazette Special table 2009-530267

  The methods described in Patent Documents 1 and 2 are excellent in that a pure olanzapine type II crystal can be stably produced. However, in the method described in Patent Document 1, it is necessary to perform recrystallization under anhydrous conditions, and not only the control of the atmosphere is complicated, but the isolation yield in recrystallization is about 70 to 75%. It is not so expensive.

  On the other hand, according to the method described in Patent Document 2, type II crystals can be obtained by a simple operation of heat-drying olanzapine dihydrate. There is no need to be careful. However, in this method, in order to obtain a particularly preferred dihydrate B, D or E, the olanzapine crude product is suspended in water for a long time or the olanzapine crude product is suspended in a specific solvent (ethyl acetate, toluene and It is necessary to precipitate and recover the dihydrate crystals after being dissolved in a mixed solvent comprising water). From the viewpoint of the time required for production, it seems that it is preferable to employ the latter method industrially. However, as shown in Comparative Example 2 described later in this specification, the dihydrate crystals at this time The recovery rate (olanzapine standard) was found to be as low as about 60%.

  The inventors of the present invention have made extensive studies to solve the above-described problems. As a result, when the olanzapine crude product is recrystallized under specific conditions, it is possible to obtain olanzapine hydrate crystals with a high recovery rate, and by drying the hydrate crystals obtained at this time. The inventors have found that a high-purity olanzapine type II crystal can be obtained and that the hydrate crystal is a novel one that has not been known so far, and the present invention has been completed.

  That is, according to the first aspect of the present invention, in X-ray diffraction using Cu-Kα rays, 2θ is 8.9 ± 0.2 °, 9.4 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 18.6 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 20.8 ± 0.2 °, 21.7 ± 0 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [2,3-b] with characteristic peaks at 2 ° and 26.4 ± 0.2 ° 1,5] benzodiazepine hydrate crystals, 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine This is a method for producing a type II crystal.

  The second aspect of the present invention is the X-ray diffraction using Cu-Kα ray, wherein 2θ is 8.9 ± 0.2 °, 9.4 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 18.6 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 20.8 ± 0.2 °, 21.7 ± 0 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [2,3-b] with characteristic peaks at 2 ° and 26.4 ± 0.2 ° 1,5] Benzodiazepine hydrate crystals.

  Further, the third aspect of the present invention relates to the 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine water of the second aspect of the present invention. A method for producing a hydrate crystal comprising 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine, water and ethyl acetate. The amount of water contained in the solution is such that the amount of dissolved 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5 ] A method comprising a step of preparing a solution of 1.5 mol to 4.5 mol with respect to 1 mol of benzodiazepine and a step of precipitating the hydrate crystals from the solution.

  According to the present invention, an olanzapine type II crystal useful as an antipsychotic is efficiently produced as a pure crystal that does not contain other crystal forms or quasi-crystal forms such as hydrates, with high recovery. Can do.

  The reason why such an excellent effect is obtained by the present invention is not necessarily clear, but is estimated as follows. That is, when olanzapine is crystallized and precipitated from a solution of olanzapine in ethyl acetate, hydrate crystals will precipitate if water is present in the solution, but the crystal form of the hydrate that precipitates is This is because it changes depending on the amount of water in the solution and other organic solvents that coexist, and the stability of the precipitated hydrate crystals and the solubility in the recrystallization solvent also change depending on the type of hydrate crystals. Estimated.

  For example, in Patent Document 2, the dihydrate E was recrystallized using a crude olanzapine type II crystal (industrial grade olanzapine) using ethyl acetate containing specific amounts of toluene and water as recrystallization solvents. Although sometimes obtained, the dihydrate E crystal is highly purified during precipitation and has the feature that it can be easily converted into type II crystal by heating and drying, while it is a recrystallization solvent. The recovery rate is considered to be low because of its relatively high solubility. The J1 type dihydrate crystal described in Patent Document 3 is recrystallized using a mixed solution of ethyl acetate and water (water content: m / c = 3.8%) as a recrystallization solvent. The J1 type dihydrate crystal is obtained when it is carried out, but the recovery rate in recrystallization is high, but the stability as a hydrate crystal is high, and the olanzapine II type crystal even when heated and dried (See Comparative Example 3 in this specification).

  In contrast, the novel olanzapine hydrate crystals obtained by the method of the third invention of the present application are less likely to contain impurities during the crystallization process, and further have low solubility in the recrystallization solvent. It is thought that it was obtained with high purity and high recovery. Further, since the hydrate crystals are unstable and have a property of easily taking water of crystallization, it is considered that olanzapine II type crystals could be easily obtained by drying.

This figure is a powder X-ray diffraction chart of the olanzapine hydrate crystal of the present invention obtained in Example 1. This figure is a powder X-ray diffraction chart of the olanzapine II type crystal obtained in Example 1. This figure is a powder X-ray diffraction chart of the olanzapine II type crystal obtained in Comparative Example 1. This figure is a powder X-ray diffraction chart of J1-type dihydrate crystals obtained in Comparative Example 3.

  The first aspect of the present invention is a method for producing olanzapine type II crystal, which is a novel olanzapine hydrate crystal according to the second aspect of the present invention (hereinafter also referred to as “olanzapine hydrate crystal of the present invention”). It is characterized by drying. First, the olanzapine hydrate crystal of the present invention and the production method thereof will be described.

  The olanzapine hydrate crystal of the present invention is a crystal comprising a hydrate of 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine. In X-ray diffraction using Cu-Kα rays, 2θ is 8.9 ± 0.2 °, 9.4 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0. 2 °, 18.6 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 20.8 ± 0.2 °, 21.7 ± 0.2 ° and 26. It has a characteristic peak at a position of 4 ± 0.2 °. Among these peaks, the peak intensity when 2θ is 9.4 ± 0.2 ° is the strongest, and the relative intensity of each peak when the peak intensity of the peak is 100% is, for example, as follows.

  Olanzapine hydrate crystals show low intensity peaks (relative intensity of less than 10%) in addition to the above-mentioned characteristic peaks in X-ray diffraction measurement. However, olanzapine hydrate crystals have been known to have the above-mentioned characteristic peaks. It can be clearly distinguished from hydrate crystals. Regarding the relative intensity of the peak, there is generally a possibility that a difference of about ± 10% may occur depending on the apparatus used for the measurement and the prepared sample. Therefore, the above relative intensity is only a guide value.

  Moreover, it can be easily confirmed that the olanzapine hydrate crystal is an olanzapine hydrate crystal by measuring the amount of water contained in the crystal as crystal water by a thermal analysis method or a Karl Fischershire method. . According to these analysis results, the molar ratio of olanzapine and water (crystal water) contained in the crystal was about 1 to 1.3. This suggests that the olanzapine hydrate crystal of the present invention is probably a monohydrate. For example, when three molecules of water are hydrated with respect to two molecules of olanzapine, The stoichiometric composition ratio of olanzapine and water in the hydrate crystal may not be an integer. Therefore, the stoichiometric composition ratio in the olanzapine hydrate crystal of the present invention is considered to be in the range of olanzapine: water = 1.0 to 1.5.

  The olanzapine hydrate crystal of the present invention has a feature that it is easily converted into an olanzapine II type crystal by a drying operation.

  The olanzapine hydrate crystal of the present invention can be preferably produced by the following method. A solution comprising 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine, water and ethyl acetate, The amount of water contained in the solution was 1. with respect to 1 mol of 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine dissolved. Suitable for a method comprising a step of preparing a solution of 5 mol or more and 4.5 mol or less (solution preparation step) and a step of precipitating the olanzapine hydrate crystal of the present invention from the solution (crystallization step) Can be manufactured.

  Since 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine (olanzapine) used in the above method is once in solution, The crystal form is not particularly limited, and for example, type I, type II, amorphous or a mixture thereof can be used. Further, the purity of olanzapine is not particularly limited. Even when the raw material olanzapine containing impurities (crude body) is used, it is purified in the crystal precipitation step in the above method, and a high-purity hydrate crystal can be obtained. That is, the above method is also useful as a method for purifying olanzapine. When the above method is used as a purification step for olanzapine, the crude product of olanzapine, which is the product to be purified, contains 0.1 to 2.0% by mass of impurities such as olanzapine hydrolyzate and oxides. Preferably used. Such a crude olanzapine is obtained by, for example, a method disclosed in Patent Document 1, specifically, 4-amino-2-methyl-10H-thieno [2,3-b] [1,5 The benzodiazepine hydrochloride and N-methylpiperazine were reacted in a mixed solvent of dimethyl sulfoxide and toluene under a nitrogen atmosphere at a reflux temperature, the reaction mixture was cooled, and water was added at around 50 ° C. Further, it is cooled to around 5 ° C. and stirred to precipitate olanzapine crystals. The precipitated crystals are filtered off, washed with acetonitrile, and then dried.

  As another method for producing a crude olanzapine, 4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine is methylated with dimethyl sulfate, etc. Can be mentioned.

  In the solution preparation step in the method for producing olanzapine hydrate crystals of the present invention, the solution comprises olanzapine, water and ethyl acetate, and the amount of water contained in the solution is 1 mol of olanzapine to be dissolved. A solution that is 1.5 mol or more and 4.5 mol or less is prepared. As ethyl acetate to be used at this time, those available as reagents or industrial use can be used without any limitation. The amount used is not particularly limited as long as it can dissolve olanzapine. Normally, when 5 ml or more of ethyl acetate is used per 1 g of olanzapine, heating is performed regardless of the crystal form or purity of olanzapine (crude). By doing so, olanzapine can be easily dissolved. However, the recovery rate of olanzapine tends to increase as the amount of ethyl acetate used decreases if the amount of water contained in ethyl acetate is constant. Is preferred. From the viewpoint of ease of dissolution of olanzapine and high recovery efficiency, the amount of ethyl acetate used is more preferably from 6 ml to 25 ml, most preferably from 7 ml to 20 ml, based on 1 g of olanzapine.

  In the method for producing olanzapine hydrate crystals of the present invention, the amount of water contained in the solution prepared in the solution preparation step is 1.5 mol to 4.5 mol with respect to 1.0 mol of olanzapine. Is extremely important. When the amount of water is less than 1.5 moles based on the above criteria, when crystallization is performed from the above solution, the olanzapine hydrate crystals of the present invention are not precipitated but the anhydrous olanzapine crystals are precipitated. In the case of exceeding 5 mol, in addition to the olanzapine hydrate crystal of the present invention, a hydrate crystal having a crystal form different from the olanzapine hydrate crystal of the present invention such as J1 type dihydrate is precipitated. Resulting in. From the viewpoint of the purity of the olanzapine hydrate crystals of the present invention obtained, the amount of water contained in the solution is 1.7 mol or more and 4.3 mol or less, particularly 2.0 mol or more and 4.2 mol or less based on the above criteria. It is preferable that From the viewpoint of the purity and recovery rate of the olanzapine hydrate crystals of the present invention obtained, ethyl acetate containing 2.0 mol or more and 4.2 mol or less of water based on the above criteria is used in an amount of 7 ml or more and 20 ml or less with respect to 1 g of olanzapine. Most preferably.

  The solution is preferably composed only of olanzapine (crude), ethyl acetate and water, but not more than 5 parts by mass, preferably not more than 1 part by mass with respect to 100 parts by mass of ethyl acetate and water. Organic solvents other than ethyl acetate can be included. Organic solvents that can be included at this time include alcohols such as methanol and ethanol, nitriles such as acetonitrile, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as toluene and xylene, dichlorometa and chloroform, etc. Examples thereof include halogenated aliphatic hydrocarbons, esters such as isopropyl acetate and butyl acetate, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone.

  In preparing the solution, it is preferable to adjust the amount of water after dissolving olanzapine (crude) in a predetermined amount of ethyl acetate or a mixed solvent of ethyl acetate and the other organic solvent. In order to dissolve olanzapine (crude body) in ethyl acetate, both may be mixed and stirred in a container. As a container used at this time, a glass container, a stainless steel container, a fluororesin container, a glass lining container, or the like can be used without particular limitation. The container is preferably equipped with a thermometer or a temperature sensor. Stirring can be performed using a mechanical stirrer, a magnetic stirrer, or the like. The temperature at which olanzapine is dissolved may be appropriately determined depending on the amount of ethyl acetate used, but is usually 30 ° C. or higher and reflux temperature or lower, preferably 40 ° C. or higher and lower than reflux temperature.

  In order to adjust the amount of water contained in the olanzapine (crude) ethyl acetate solution thus prepared, first, the amount of water contained in the solution is measured using an automatic moisture measuring device (Karl Fischer). If measurement is performed and the amount of water is within a predetermined range, the adjustment operation is not particularly necessary, and the crystallization step may be performed subsequently. On the other hand, if the amount of water contained in the solution is outside the above range, the amount of water may be adjusted by the following method. That is, when the amount of water contained in the olanzapine solution is less than 1.5 mol with respect to 1 mol of olanzapine, water may be added to the solution so as to obtain a predetermined amount of water. Normally used olanzapine (crude body) has a water content of about 0.3% by mass, and commercially available ethyl acetate has a water content of about 0.03% by mass. Therefore, in many cases, the amount of water contained in the obtained olanzapine solution is less than 1.5 mol with respect to 1 mol of olanzapine. Therefore, in such a case, a necessary amount of water may be added so that the amount of water is in the range of 1.5 mol or more and 4.5 mol or less on the basis of the above. As water to be added at this time, tap water can be used, but ion-exchanged water, pure water or ultrapure water is preferably used. The method for adding water is not particularly limited, and may be added directly into the container using a metering pump, a dropping funnel or the like. In addition, when the amount of water contained in olanzapine (crude) and ethyl acetate to be used is known in advance, it is not particularly necessary to measure the water content of the solution. For example, before the solution is formed, that is, olanzapine (crude) A necessary amount of water may be added in a state suspended in ethyl acetate or before mixing the crude olanzapine and ethyl acetate.

  On the other hand, when the amount of water contained in the olanzapine solution exceeds 4.5 mol with respect to 1 mol of olanzapine, water may be removed from the solution until a predetermined amount of water is obtained. As described above, in the normally produced olanzapine solution, the amount of water contained in the olanzapine solution is less than 1.5 mol. For example, before the crystallization process, the solution is washed with water for the purpose of removing water-soluble impurities. In such a case, the amount of water contained therein may exceed 4.5 moles per mole of olanzapine. In such a case, a process for removing moisture from the solution may be performed. Examples of the water removal treatment method include solvent distillation (concentration), dehydration treatment using a dehydrating agent such as magnesium sulfate, sodium sulfate, and molecular sieve. When performing treatment with a dehydrating agent, it is necessary to remove the dehydrating agent from the olanzapine solution by filtration, etc. At that time, crystals may precipitate from the olanzapine solution. It is preferable to do. Since ethyl acetate azeotropes with water, water can be removed by distilling off the solvent. In order to distill off the solvent, the solution may be heated under normal pressure or reduced pressure. The heating temperature is usually in the range of 30 ° C. to reflux temperature, but from the viewpoint of water removal efficiency, it is particularly preferable to heat to around 73 ° C., which is the azeotropic temperature of ethyl acetate and water under normal pressure. The dehydration by distilling off (concentrating) the solvent is preferably performed in the presence of air or an inert gas such as nitrogen or argon. In addition, when adjusting the amount of water by distilling off the solvent (concentration), crystallization occurs in the process, and the hydrate crystals precipitated in the crystallization step include J1 type dihydrate. Undesirable hydrates may be included. For this reason, it is preferable to add ethyl acetate substantially free of water after the concentration operation and redissolve the precipitated crystals.

  In the crystallization step, the olanzapine hydrate crystals are precipitated from the olanzapine solution obtained as described above. As a method for precipitating crystals, it is preferable to employ a method of cooling the solution. At this time, if the cooling rate of the solution is too fast, the purity of the crystal tends to decrease, and if it is too slow, it is not efficient. Therefore, it is preferably 1 ° C./hour or more and 100 ° C./hour or less, preferably 5 ° C./hour. It is particularly preferably 50 ° C./hour or less, more preferably 5 ° C./hour or more and 30 ° C./hour or less. Further, it is preferable to stir the solution during cooling.

  The target temperature for cooling (the temperature reached at the time of cooling) is usually −5 ° C. or more and 50 ° C. or less, but the recovery rate tends to decrease if the temperature is high, and the purity tends to decrease if the temperature is too low. Therefore, it is preferable that the temperature be 0 ° C. or higher and 30 ° C. or lower, particularly 0 ° C. or higher and 10 ° C. or lower. Although it varies somewhat depending on conditions, normally, if stirring is continued for about several minutes to 5 hours after reaching the target temperature, crystals are sufficiently precipitated, and olanzapine can be recovered as hydrate crystals at a high recovery rate.

  The olanzapine hydrate crystals thus precipitated are separated into solid and liquid by vacuum filtration, pressure filtration, centrifugation, etc., and washed with an organic solvent such as water or ethyl acetate to sufficiently remove the mother liquor. Is isolated.

  The olanzapine hydrate crystal of the present invention thus obtained is dried to easily remove water (crystal water) forming a solvate with olanzapine and convert it into olanzapine. The temperature for drying the olanzapine hydrate is 0 ° C. or higher and 100 ° C. or lower, preferably 20 ° C. or higher and 90 ° C. or lower, more preferably 30 ° C. or higher and 80 ° C. or lower. Drying can be carried out under reduced pressure or normal pressure, and can be more effectively dried by passing an inert gas such as nitrogen or argon.

  The time required for drying varies depending on the drying temperature, pressure, and the like, and thus cannot be generally defined, but can usually be sufficiently dried within 24 hours. In addition, when drying, it is preferable to confirm the disappearance of the peak derived from the olanzapine hydrate crystal of the present invention by sampling appropriately and measuring by powder X-ray diffraction measurement or the like.

  By such a drying operation, a high-purity olanzapine type II crystal containing almost no hydrate can be obtained. At this time, the conversion of the olanzapine II type crystal from the olanzapine hydrate crystal of the present invention proceeds almost quantitatively, so that a highly pure olanzapine II type crystal can be obtained efficiently.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not restrict | limited at all by these Examples. In addition, the powder X-ray diffraction measurement of the crystal | crystallization in an Example and a comparative example, the measurement of the quantity of water, and the measurement of olanzapine purity were performed by the method shown below.

(Powder X-ray diffraction measurement of crystals of olanzapine and its hydrate)
Using CuKα radiation having a wavelength of 1.541858 angstroms, the following apparatus was used under the following conditions.
Equipment: Rigaku RINT1200 X-ray powder diffractometer Voltage: 40 kV
Current: 30mA
Sampling width: 0.050 °
Scan speed: 2.0 ° / min
Scan range: Start angle is 5 °, end angle is 35 °.

(Measurement of olanzapine, its hydrates and the amount of water in these solutions)
It was measured by the Karl Fischer method. The apparatus used for the measurement and the measurement conditions are as follows. In addition, the amount of water contained in the crystal was expressed by mass% based on the total mass of the crystal as the mass of the detected water. Incidentally, the theoretical water content of olanzapine monohydrate and dihydrate is 5.4 mass% and 10.3 mass%. Moreover, the amount of water in the solution was expressed as a molar ratio obtained by converting the detected amount of water in moles and dividing by the number of moles of dissolved olanzapine.
Apparatus: Automatic moisture measuring device CA-100 manufactured by Mitsubishi Chemical Corporation
Method: Karl Fischer volumetric titration system Titration reagent: Aquamicron titrant SS-Z 3 mg manufactured by Mitsubishi Chemical
Solvent: anhydrous methanol.

(Evaluation of olanzapine purity)
The purity of olanzapine was measured by high performance liquid chromatography (HPLC). The apparatus used for the HPLC measurement and the measurement conditions are as follows. The purity of olanzapine is a value expressed as a percentage of the peak area value of olanzapine in the obtained chromatogram with respect to the sum of all peak area values. In the HPLC analysis under the above conditions, the detection limit is 0.003%, and the retention time of olanzapine is around 13.5 minutes.
Apparatus: 2695 manufactured by Waters
Detector: Ultraviolet absorptiometer (Waters 2489)
Detection wavelength: 220 nm
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Mobile phase A: a mixed solvent containing a buffer solution and acetonitrile at 52% by volume and 48% by volume as 100% by volume of the mixed solution, respectively.
Mobile phase B: A mixed solvent containing 100% by volume of a mixed solution and 30% by volume and 70% by volume of a buffer solution and acetonitrile, respectively.
Buffer solution: A solution prepared by dissolving 13 g of sodium dodecyl sulfate and 5 mL of phosphoric acid in 1500 mL of distilled water and adjusting the pH to 2.5 using an aqueous sodium hydroxide solution.
Transfer of mobile phase: Concentration control is performed by changing the mixing ratio of mobile phases A and B as shown in Table 2.
Flow rate: 1.5 mL per minute
Column temperature: constant temperature around 35 ° C

Example 1
In a 200 mL three-necked flask equipped with a stirring blade and a thermometer, 2-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride 20.0 g (75.3 mmol) And 60.3 g (602.0 mmol) of N-methylpiperazine were added and stirred. The resulting mixture was warmed little by little and allowed to react at 120 ° C. for 5 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to around 70 ° C., and 30 ml of acetonitrile was added. Subsequently, 20 ml of water was added so that the internal temperature became 70 to 75 ° C., and the mixture was stirred at around 70 ° C. for 10 minutes. When 20 ml of water was further added twice by the same operation and stirred, yellow crystals were precipitated.

Subsequently, the solution was gradually cooled to around 5 ° C. and stirred at around 5 ° C. for 2 hours. Crystals precipitated by vacuum filtration were separated by filtration, and the crystals separated by filtration were washed twice with 40 ml of acetonitrile. The obtained yellow crystals were dried under reduced pressure at 60 ° C. for 14 hours to obtain 17.9 g (57.4 mmol) of crude olanzapine as yellow crystals. (Yield 76.2%, HPLC purity 99.89%, water content: 0.3% by mass)
To a 100 ml three-necked flask equipped with a stirring blade and a thermometer, 5.0 g (16.0 mmol) of the obtained crude olanzapine was added, and then 50 ml of ethyl acetate having a water content of 0.03% by mass was added. Stir. The resulting mixture was warmed little by little and stirred at reflux temperature for 15 minutes to dissolve all the crude olanzapine. When the amount of water contained in the obtained olanzapine solution was measured, it was 0.029 g (1.6 mmol), and was 0.1 mol with respect to 1 mol of olanzapine. Therefore, 0.55 g (30.4 mmol) of water was added, and the amount of water contained in the solution was adjusted to 2 mol with respect to 1 mol of olanzapine. Subsequently, the obtained solution was cooled to about 5 ° C. at a rate of about 30 ° C. per hour. After stirring at around 5 ° C. for 2 hours, yellow crystals precipitated by filtration under reduced pressure were filtered off, and the crystals separated by filtration were washed once with 5 ml of ethyl acetate.

  When measured with an automatic moisture measuring device, the water content of this crystal was 5.8% by mass, and the molar ratio of olanzapine to water was 1. Therefore, this crystal is considered to be a monohydrate of olanzapine. Further, when powder X-ray diffraction measurement was performed using the crystal as a sample, the X-ray diffraction chart shown in FIG. 1 was obtained. As shown in FIG. 1, a diffraction peak different from that of J1 type dihydrate shown in FIG. 4 was confirmed.

  For reference, Table 3 summarizes the position (2θ) and relative intensity of each peak observed in the X-ray diffraction chart shown in FIG.

  The olanzapine hydrate was dried under reduced pressure at 60 ° C. for 5 hours to obtain 4.2 g (13.4 mmol) of olanzapine as yellow crystals (yield 83.8% (based on olanzapine), HPLC purity 99.95. %).

  Since the water content of olanzapine measured by an automatic moisture measuring device was 0.3% by mass and the molar ratio of olanzapine to water was 0.05, it was found not to be a hydrate of olanzapine. Further, when powder X-ray diffraction measurement was performed using this olanzapine as a sample, an X-ray diffraction chart shown in FIG. 2 was obtained. As shown in FIG. 2, the same diffraction peak as that of the type II crystal obtained by the method described in Patent Document 1 shown in FIG. 3 was confirmed.

  For reference, Table 4 summarizes the position (2θ) and relative intensity of each peak observed in the X-ray diffraction chart shown in FIG.

Examples 2-7
In Example 1, the same procedure was performed except that the amount of ethyl acetate, the amount of water added to the olanzapine solution, and the drying time and temperature were changed. The results are shown in Table 5.

Comparative Example 1 (refer to Patent Document 1)
In Example 1, yellow was similarly added except that 0.51 g of water was not added to the olanzapine solution, and the amount of water contained in the solution was adjusted to 0.1 mol with respect to 1 mol of olanzapine. As a crystal, 3.5 g (11.2 mmol) of olanzapine type II crystal was obtained. (Yield 70.1% (olanzapine standard), HPLC purity 99.95%, water content: 0.3% by mass)
When powder X-ray diffraction measurement was performed using this olanzapine as a sample, the X-ray diffraction chart shown in FIG. 3 was obtained.

  As a reference, Table 6 summarizes the position (2θ) and relative intensity of each peak observed in the X-ray diffraction chart shown in FIG.

Comparative Example 2 (refer to Patent Document 2)
To a 100 mL three-necked flask equipped with a stirring blade and a thermometer, 5.0 g (16.0 mmol) of the crude olanzapine obtained in Example 1 was added, and then 100 ml of ethyl acetate, 5 ml of toluene, and 10 ml of water. And stirred. The resulting mixture was warmed little by little and stirred at reflux temperature for 15 minutes to dissolve all the crude olanzapine. When the amount of water contained in the obtained solution was measured, it was 10.5 g (581.4 mmol), and was 36.3 mol with respect to 1 mol of olanzapine. Subsequently, the obtained solution was cooled to about 5 ° C. at a rate of about 30 ° C. per hour. After stirring at around 5 ° C. for 2 hours, the yellow crystals precipitated by filtration under reduced pressure were filtered off, and the filtered crystals were washed once with 5 mL of ethyl acetate.

  The crystals were dried under reduced pressure at 60 ° C. for 14 hours to obtain 3.1 g (9.8 mmol) of olanzapine as yellow crystals (yield 61.3% (based on olanzapine), HPLC purity 99.90%, moisture content) : 0.4 mass%).

Comparative Example 3 (refer to Patent Document 3)
The same as in Comparative Example 1 except that ethyl acetate having a water content of 3.8% by mass was used and the amount of water contained in the olanzapine solution was adjusted to 6.0 mol per mol of olanzapine. As a result, 3.5 g (11.2 mmol) of olanzapine J1 type dihydrate was obtained as yellow crystals (yield 84.8% (based on olanzapine), HPLC purity 99.91%, water content: 10.5). mass%).

  When the powder X-ray diffraction measurement was performed using this olanzapine as a sample, the X-ray diffraction chart shown in FIG. 4 was obtained.

  As a reference, Table 7 summarizes the position (2θ) and relative intensity of each peak observed in the X-ray diffraction chart shown in FIG.

Comparative Example 4
In Example 1, the amount of water added to the olanzapine solution was 0.26 g (14.4 mmol), and the amount of water contained in the olanzapine solution was adjusted to be 1.0 mol with respect to 1 mol of olanzapine. In the same manner, 3.4 g (10.8 mmol) of olanzapine was obtained as yellow crystals (yield 67.7% (based on olanzapine), HPLC purity 99.95%, water content: 0.3% by mass).

Claims (5)

In X-ray diffraction using Cu-Kα ray, 2θ is 8.9 ± 0.2 °, 9.4 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 18.6 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 20.8 ± 0.2 °, 21.7 ± 0.2 ° and 26.4 ± 0 2-Methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine hydrate with a characteristic peak at a 2θ position of 2 ° A method for producing 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine type II crystal, wherein the crystal is dried. The step of obtaining the hydrate crystals includes 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine, water and ethyl acetate. 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine in which the amount of water contained in the solution dissolves In the step of preparing a solution of 1.5 mol to 4.5 mol with respect to 1 mol and X-ray diffraction using Cu-Kα ray from the solution, 8.9 ± 0.2 °, 9. 4 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 18.6 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 2-methyl-4 with characteristic peaks at 2θ positions of 20.8 ± 0.2 °, 21.7 ± 0.2 ° and 26.4 ± 0.2 ° (4-methylpiperazin-1-yl)-10H-thieno [2,3-b] [1,5] further comprising the step of precipitating the benzodiazepine hydrate crystal The method of claim 1. The method according to claim 1 or 2, wherein the drying is performed under reduced pressure at a temperature of 30 ° C to 80 ° C. In X-ray diffraction using Cu—Kα ray, 8.9 ± 0.2 °, 9.4 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 18. 6 ± 0.2 °, 20.2 ± 0.2 °, 20.5 ± 0.2 °, 20.8 ± 0.2 °, 21.7 ± 0.2 ° and 26.4 ± 0.2 2-Methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine hydrate crystals having a characteristic peak at the 2θ position of °. A method for producing a 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine hydrate crystal according to claim 4. A solution comprising 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine, water and ethyl acetate, 1.5 mol per 1 mol of 2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine in which the amount of water contained is dissolved A method comprising the steps of preparing a solution of 4.5 mol or less and the step of precipitating the hydrate crystals from the solution.

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