JP2013194017A - 4-amino-2-methyl-10h-thieno[2,3-b][1,5]benzodiazepine hydrochloride salt hydrate having crystalline structure and method of producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride salt hydrate having high solubility to an alcohol solvent such as ethanol.SOLUTION: There is provided a 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride salt hydrate having a crystalline structure which gives characteristic peaks in the vicinity of at least 2θ=7.4°, 8.4°, 16.5°, 17.3° according to X-ray diffraction using Cu-Kα ray.

Description

  The present invention relates to 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate having a novel crystal structure and a method for producing the same.

  Following formula (1)

で示される２−メチル-４−（４−メチルピペラジン−１−イル）−１０Ｈ−チエノ〔２、３−ｂ〕〔１、５〕 ベンゾジアゼピン（ 以下、オランザピンともいう）は、抗精神病薬として、統合失調症に対する治療、双極性障害の躁状態の治療に使用されており、非常に有用な化合物である。
このオランザピンは、以下に示すフローチャートに従って、合成される。（特許文献１参照）

2-methyl-4- (4-methylpiperazin-1-yl) -10H-thieno [2,3-b] [1,5] benzodiazepine (hereinafter also referred to as olanzapine) is an antipsychotic agent, It is used for the treatment of schizophrenia, the treatment of manic state of bipolar disorder, and is a very useful compound.
This olanzapine is synthesized according to the flowchart shown below. (See Patent Document 1)

前記フローチャートにおいて、下記式（２）

In the flowchart, the following formula (2)

で示される２−（２−ニトロアニリノ）−５−メチル−チオフェン−３−カルボニトリル（以下、ＯＺ−０３ともいう）を、エタノールと水の混合溶媒中で塩化スズ（ＩＩ）及び塩化水素を用いて還元、閉環し、次いで、減圧濃縮を行い、５℃において熟成を行い、下記式（３）

2- (2-nitroanilino) -5-methyl-thiophene-3-carbonitrile (hereinafter also referred to as OZ-03) represented by the following formula using tin (II) chloride and hydrogen chloride in a mixed solvent of ethanol and water: Reduction, ring closure, concentration under reduced pressure, aging at 5 ° C., and the following formula (3)

で示される４−アミノ−２−メチル−１０Ｈ−チエノ〔２，３−ｂ〕〔１，５〕ベンゾジアゼピン塩酸塩の結晶（以下、Ｉ型結晶ＯＺ−０４ともいう）を得ている。次に、下記式（４）

4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride crystals (hereinafter also referred to as I-type crystals OZ-04). Next, the following formula (4)

で示されるＮ−メチルピペラジン（以下、ＯＺ−０５ともいう）とＩ型結晶ＯＺ−０４を反応させることにより、オランザピン粗体が合成される。

A crude olanzapine is synthesized by reacting N-methylpiperazine (hereinafter also referred to as OZ-05) represented by the formula I with crystal IZ OZ-04.

Japanese Patent Application Laid-Open No. 7-089965

However, in the step of synthesizing the I-type crystal OZ-04, the following formula (5)

2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepin-4 [5H] -one (hereinafter also referred to as OZP-RCB), which is an olanzapine analog represented by It was found that it was produced as a by-product by hydrolysis of -04, and remained as an impurity in the olanzapine crude product without being removed in the synthesis step subsequent to the step of synthesizing the olanzapine crude product. Therefore, in order to produce high-purity olanzapine, it is important to reduce the OZP-RCB content in the type I crystal OZ-04.

  The present inventors have studied a purification method by recrystallization in order to reduce the amount of impurities in the I-type crystal OZ-04. However, since type I crystal OZ-04 has low solubility in alcohols such as ethanol, it is necessary to use a large amount of ethanol in a purification process by recrystallization using ethanol, which is disadvantageous in industrial production. It turns out that.

  The inventors of the present invention have intensively studied the above problems. As a result, after the synthesis reaction of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride, the temperature of the reaction solution was adjusted to a specific temperature and moderately stirred. The present inventors have found that the precipitated crystals have a crystal form different from that of the conventional type I crystal and are a substance having high purity and high solubility in a solvent of alcohols such as ethanol, and the present invention has been completed.

  That is, the present invention provides a crystal structure that gives a characteristic peak at least in the vicinity of 2θ = 7.4 °, 8.4 °, 16.5 °, and 17.3 ° by X-ray diffraction using Cu—Kα ray. 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate (hereinafter also referred to as type II crystal OZ-04).

  Further, the present invention provides a reaction solution in which 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride is dissolved at a temperature of 60 ° C. or higher and 67 ° C. or lower, and a chip speed. Is a method of precipitating type II crystal OZ-04 while stirring at 0.7 m / s to 2.0 m / s.

  The type II crystal OZ-04 of the present invention has a novel crystal structure, and the content of OZP-RCB is significantly less than that of the conventional type I crystal OZ-04. Furthermore, the type II crystal OZ-04 has better solubility in alcohol solvents such as ethanol than the conventional type I crystal OZ-04, and in particular, when the solvent is ethanol, a small amount of ethanol. Can be dissolved. Therefore, the high-purity type II crystal OZ-04 obtained by the present invention can be suitably used as a raw material for high-purity olanzapine, and is optimally used as an intermediate for pharmaceuticals and the like that particularly require purity. I can do it.

X-ray diffraction of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate (type II crystal OZ-04) prepared in Example 1 according to the present invention It is a chart. 4 is an X-ray diffraction chart of a conventional 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (type I crystal OZ-04) produced in Comparative Example 1. .

The present invention will be described in detail below.
(Type II crystal OZ-04)
The type II crystal OZ-04 of the present invention has characteristic peaks at least in the vicinity of 2θ = 7.4 °, 8.4 °, 16.5 °, 17.3 ° by X-ray diffraction using Cu—Kα ray. It is a compound which has this. In this case, the measurement error of the X-ray diffraction angle is allowed to about ± 0.2 °. The X-ray diffraction measurement result of this type II crystal OZ-04 is shown in FIG.

  The type II crystal OZ-04 will be described in detail in the following examples. Compared with the type I crystal OZ-04, which is a conventional crystal form obtained by the method disclosed in Patent Document 1, OZP -The content of RCB is small, and further the solubility in alcohol solvents such as ethanol is improved. Specifically, at room temperature, type II crystal OZ-04 can be dissolved approximately 1.6 times in the same amount of ethanol as type I crystal OZ-04.

  From the thermogravimetric analysis result, the type II crystal OZ-04 of the present invention contains 0.5 to 1 mol of hydration water with respect to 1 mol of OZ-04.

  The II-type crystal OZ-04 has a lower melting point than the conventional I-type crystal OZ-04, and the melting point of the II-type crystal OZ-04 is 316 ° C. Is 233 ° C.

(Method for producing type II crystal OZ-04)
The production method of the type II crystal OZ-04 is not particularly limited, but is preferably produced by the following method. Specifically, the temperature of the reaction solution in which crystals of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride is dissolved is 60 ° C. or higher and 67 ° C. or lower, This is a method for precipitating type II crystal OZ-04 while stirring at a speed of 0.7 m / s or more and 2.0 m / s or less. In the following, description will be given in order.

  In the method for producing type II crystal OZ-04 of the present invention, crystals of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride are synthesized from OZ-03. The method can be synthesized by a known method, for example, the method described in Patent Document 1. Specifically, reduction and ring opening are simultaneously performed using tin (II) chloride and hydrogen chloride, and 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine. Hydrochloride crystals are synthesized. As the organic solvent used as the solvent for the synthesis reaction, alcohols are usually used, and among these, ethanol is particularly preferable because of its low toxicity and low boiling point. The amount of ethanol used is usually preferably 5 ml to 15 ml with respect to 1 g of OZ-03, and more preferably 7 to 10 ml considering the batch yield.

  In this way, a reaction solution in which crystals of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride is dissolved can be obtained. For example, after obtaining the I-type crystal OZ-04 by the production method described in Patent Document 1, the I-type crystal OZ-04 is dissolved in an alcohol solvent such as ethanol to obtain 4-amino-2-methyl. A reaction solution in which crystals of -10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride is dissolved may be obtained.

  In the production method of the present invention, the greatest feature is that the temperature of the reaction solution obtained by the above-described method is maintained at 60 ° C. or more and 67 ° C. or less, and the chip speed is 0.7 m / s or more and 2.0 m / s or less. The purpose is to precipitate type II crystal OZ-04. Here, the tip speed is the speed of the tip of the stirring blade having the maximum diameter during stirring, and is a value obtained by multiplying the circumference length drawn by the stirring blade and the number of rotations per second. . Crystals precipitated under these conditions are type II crystals OZ-04.

  If the temperature of the reaction solution exceeds 67 ° C, type I crystal OZ-04 is precipitated, which is not preferable. Further, the lower the temperature of the reaction solution, the higher the yield of the II-type crystal OZ-04 can be expected. On the other hand, the incorporation of impurities is promoted, and the purity of the precipitated II-type crystal OZ-04 is expected. Therefore, the temperature of the reaction solution is 60 ° C. or higher and 67 ° C. or lower.

  On the other hand, the precipitation of type II crystal OZ-04 depends not only on the reaction temperature but also on the stirring efficiency at the time of precipitation. It is not preferable to perform the precipitation operation at a tip speed of less than 0.7 m / s, which is an index of stirring efficiency, because the conventional type I crystal OZ-04 is precipitated. The upper limit of the chip speed is not particularly limited, but is preferably 2.0 m / s or less in view of industrial production. Therefore, the tip speed for precipitating the type II crystal OZ-04 is 0.7 m / s or more and 2.0 m / s or less.

  The time required for the precipitation of type II crystal OZ-04 is a predetermined condition in which the temperature of the reaction solution is in the range of 60 ° C. to 67 ° C. and the tip speed is in the range of 0.7 m / s to 2.0 m / s. It is preferable to maintain the predetermined conditions for about 30 minutes to 1 hour after reaching the above, but the above conditions are not particularly limited, and the reaction solution is kept at room temperature for 1 hour to 12 hours for the purpose of improving the yield. It may be aged for about time to precipitate and recover type II crystal OZ-04.

  In the present invention, the type II crystal OZ-04 precipitated by the above method can be separated by a known method, a solid-liquid separation method such as filtration or centrifugation. Moreover, it can also dry by natural drying, ventilation drying, vacuum drying, etc. as needed.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

First, an evaluation method, an analysis method, and a purity measurement method of the type II crystal OZ-04 will be described.
(1) Solubility Evaluation of Type II Crystal OZ-04 100 mg of Type II crystal OZ-04 was placed in an eggplant flask, and an appropriate amount of ethanol was added at room temperature, followed by stirring for 3 hours. Thereafter, the amount of type II crystalline OZ-04 in the saturated solution was quantified using high performance liquid chromatography (HPLC).

(2) Crystal analysis method (2) -1 X-ray powder diffraction analysis measurement X-ray powder diffraction analysis was performed on a RINT1200 X-ray powder diffractometer manufactured by Rigaku using CuKα radiation having a wavelength of 1.541858 angstroms. Carried out. The voltage was set to 40 kV and the current was set to 40 mA. The sampling width was set to 0.020, and the scan speed was set to 1.0 ° / min. The measurement was performed in the range of a start angle of 10 ° and an end angle of 35 °. The sample was prepared for analysis by pressing it uniformly into the holder.
(2) -2 Purity measurement of type II crystal OZ-04 Purity measurement of type II crystal OZ-04 is performed by liquid chromatography, column: ZORBAX RX-C8 manufactured by Agilent Technologies (inner diameter 4.6 mm, length 250 mm). Measurement was performed using a detection wavelength of 220 nm.
(2) -3 Melting point measurement of type II crystal OZ-04 Melting point measurement of type II crystal OZ-04 was carried out in a B-540 melting point measuring instrument manufactured by BUCHI. The temperature increase rate was set to 1.0 ° C./min, and measurement was performed in a temperature range of a start temperature of 210 ° C. and an end temperature of 255 ° C.
(2) -4 Thermogravimetric analysis (TG)
TG-DTA measurement was performed in a differential thermogravimetric analyzer manufactured by SII Nanotechnology. Measurement was performed in a temperature range of a start temperature of 30 ° C. and an end temperature of 400 ° C. with a temperature increase rate of 10 ° C./min.
(2) -5 Moisture content measurement The moisture content was measured with an automatic moisture measuring device (Karl Fischer moisture measuring device) manufactured by Mitsubishi Chemical Corporation.

Example 1
(Method for producing type II crystal OZ-04)
In a 200 mL four-necked flask, 28.8 g of tin (II) chloride dihydrate and 50 mL of concentrated hydrochloric acid were added and dissolved. Ethanol (75 mL) was added thereto, and then 2- (2-nitroanilino) -5-methyl-thiophene-3-carbonitrile (10 g) was added, the chip speed was 0.5 m / s, and the mixture was reacted under reflux for 2 hours. . After the reaction, the chip speed was set to 0.9 m / s, and then the reaction solution was rapidly cooled to 65 ° C. and held at 65 ° C. for 30 minutes to precipitate type II crystal OZ-04. The reaction solution was filtered, and the cake was washed with 10 mL of ethanol to obtain type II crystal OZ-04. At this time, the physical properties of Type II crystal OZ-04 were 99.93% purity, 0.04% OZP-RCB content, and 75.0% yield.

When the powder X-ray diffraction measurement is performed using this crystal as a sample, the X-ray diffraction chart shown in FIG. 1 is obtained. This crystal has 2θ = 7.4 °, 8.4 °, 16.5 °, 17.3. It was found to be a compound having a crystal structure that gives a characteristic peak at °. The melting point was 233 ° C. From these results, this crystal has a novel crystal form of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate (type II crystal OZ-04) It turns out that.
(Solubility evaluation)
It was 7.8 mg / ml when the solubility of the obtained type II crystal OZ-04 in ethanol was evaluated by the above method.
(Water content evaluation)
The obtained type II crystal OZ-04 was dried at 40 ° C. under reduced pressure to evaporate water adsorbed on the type II crystal OZ-04, and then the water content of the type II crystal OZ-04 was evaluated. As a result, the weight loss by thermogravimetric analysis was 4.2%, and the moisture content measurement result by Karl Fischer moisture measuring device was 4.6%.

Here, assuming that 1 mol of OZ-04, that is, 265.76 g, hydrated water is present in x mol, that is, 18 × xg,

(Moisture%) = (Weight of hydrated water) / (Weight of pure OZ-04 + Weight of hydrated water) × 100 = (18 × x) / (265.76 + 18 × x) × 100

Is given by

  Therefore, when calculated from a weight loss of 4.2% by TG, it is calculated that 0.65 mol of hydration water is hydrated with respect to 1 mol of OZ-04, and measurement result 4 by Karl Fischer moisture measurement When calculated from 0.6%, it was calculated that 0.71 mol of hydration water was hydrated with respect to 1 mol of OZ-04.

  Since the weight loss due to TG and the weight loss due to Karl Fischer moisture measurement were almost the same, it is considered that the moisture adsorbed on the type II crystal OZ-04 was removed by the pre-treatment reduced-pressure drying. The hydration water calculated from the above results is the hydration water taken into the type II crystal OZ-04.

Example 2
The same operation as in Example 1 was performed to obtain a reaction solution in which crystals of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride were dissolved, and then the chip speed Was set to 1.5 m / s, and II type crystal OZ-04 was precipitated in the same manner as in Example 1 except that the reaction solution was rapidly cooled to 62 ° C.

  When the obtained type II crystal OZ-04 was subjected to powder X-ray diffraction measurement, solubility evaluation, and water content evaluation, the same results as in Example 1 were obtained.

Example 3
The same operation as in Example 1 was performed to obtain a reaction solution in which crystals of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride were dissolved, and then the chip speed Was set to 1.7 m / s, and then the type II crystal OZ-04 was precipitated in the same manner as in Example 1 except that the reaction solution was rapidly cooled to 65 ° C.

  When the obtained type II crystal OZ-04 was subjected to powder X-ray diffraction measurement, solubility evaluation, and water content evaluation, the same results as in Example 1 were obtained.

Comparative Example 1
(Production of type I crystal by the method described in Patent Document 1)
In a 200 mL four-necked flask, 28.8 g of tin (II) chloride dihydrate and 50 mL of concentrated hydrochloric acid were added and dissolved. Ethanol (75 mL) was added thereto, and then 2- (2-nitroanilino) -5-methyl-thiophene-3-carbonitrile (10 g) was added, the chip speed was 0.5 m / s, and the mixture was reacted under reflux for 2 hours. . After the reaction, the temperature of the reaction solution was maintained at 24 ° C. with an ice bath while maintaining the tip speed at 0.5 m / s, and the same as in Example 1 except that I-type crystal OZ-04 was precipitated. Was performed. Regarding the physical properties of this type I crystal OZ-04, the purity was 99.44%, the content of OZP-RCB was 0.23%, and the yield was 90.3%.

When XRD is measured using this type I crystal OZ-04 as a sample, the X-ray diffraction chart shown in FIG. 2 is obtained. This crystal has 2θ = 11.4 °, 13.7 °, 15.5 °, 24. It was found to be a compound having a crystal structure that gives characteristic peaks at 2 °, 25.0 °, and 26.7 °. Therefore, it was confirmed that this crystal was not the structure of the type II crystal OZ-04 obtained in Example 1. The melting point was 316 ° C.
(Solubility evaluation)
The solubility of the obtained type I crystal OZ-04 in ethanol was confirmed by the above method and found to be 5.0 mg / ml.
(Water content evaluation)
When the mass loss was evaluated by TG, the mass loss of the obtained I-type crystal OZ-04 was 0.2%. Moreover, the moisture content measurement result by the Karl Fischer moisture measuring device was 0.6%.

Comparative Example 2
After the reaction, the operation of Example 1 was carried out except that the crystal was precipitated with the tip speed maintained at 0.5 m / s to obtain an I-type crystal OZ-04. Regarding the physical properties of the obtained type I crystal OZ-04, the purity was 99.82%, the content of OZP-RCB was 0.07%, and the yield was 84.5%. Moreover, when XRD measurement was performed with respect to the obtained I-type crystal OZ-04, the X-ray diffraction chart shown in Comparative Example 1 was obtained, and it was confirmed that it was not the structure of the II-type crystal OZ-04.

Comparative Example 3
After the reaction, the reaction solution was rapidly cooled to 70 ° C., held at 70 ° C. for 30 minutes, and the operation of Example 1 was carried out except that crystals were precipitated. Got. Regarding the physical properties of the obtained type I crystal OZ-04, the purity was 99.87%, the content of OZP-RCB was 0.10%, and the yield was 79.3%. When XRD measurement was performed on the obtained I-type crystal OZ-04, the X-ray diffraction chart shown in Comparative Example 1 was obtained, and it was confirmed that it was not the structure of the II-type crystal OZ-04.

Claims (2)

  4-amino-2 having a crystal structure giving characteristic peaks at least in the vicinity of 2θ = 7.4 °, 8.4 °, 16.5 °, 17.3 ° by X-ray diffraction using Cu—Kα ray -Methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate.   The temperature of the reaction solution in which crystals of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride is dissolved is set to 60 ° C. to 67 ° C., and the tip speed is set to 0.7 m. 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate is precipitated while stirring at a rate of not less than / s and not greater than 2.0 m / s. A process for producing 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride hydrate according to claim 1.

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