JP6042153B2 - Olanzapine production method - Google Patents

Description

  The present invention relates to a method for producing olanzapine useful as an antipsychotic drug. Specifically, the present invention relates to a method for producing olanzapine by reacting 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and N-methylpiperazine.

  Olanzapine is a compound useful for treating psychiatric patients and mild anxiety states, and is practically used as an antipsychotic drug (a drug for treating schizophrenia).

  This olanzapine is known to be synthesized according to the following flowchart. That is, 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride (hereinafter also referred to as OZ-04) represented by the following chemical formula (1) and the following chemical formula (2 ) N-methylpiperazine (hereinafter also referred to as OZ-05) represented by the following formula in an organic solvent, and after cooling, water, which is a poor solvent for olanzapine, is added to precipitate the product. This is a method for producing olanzapine represented by the following chemical formula (3) by performing recrystallization using acetonitrile after filtration (see Patent Document 1).

  In this method, in order to carry out the reaction between OZ-04 and OZ-05 at a high temperature of 120 ° C., a mixed solvent (toluene / dimethyl sulfoxide) having a boiling point of 120 ° C. or higher is used as a reaction solvent. ing. However, a high boiling point solvent, particularly dimethyl sulfoxide, does not completely evaporate by the drying operation and may remain in olanzapine after recrystallization and purification.

  Therefore, as a method for solving the residual high boiling point solvent, synthesis of olanzapine without using dimethyl sulfoxide as a reaction solvent, using a low boiling point solvent such as acetone or acetonitrile when reacting OZ-04 and OZ-05. A method has been proposed (see Patent Document 2).

  Furthermore, by utilizing the fact that OZ-05 has a high boiling point of about 138 degrees, a high reaction temperature can be achieved in a solvent-free system that does not use a reaction solvent such as dimethyl sulfoxide, acetone, and acetonitrile, and olanzapine can be produced. It is known (see Patent Document 2).

Japanese Patent Laid-Open No. 7-089965 Special table 2007-515428

  In the method of using the low boiling point solvent disclosed in Patent Document 2 as the reaction solvent, the reaction temperature of OZ-04 and OZ-05 is slow because the reaction temperature cannot be higher than the boiling point of the reaction solvent. It was found that it took about 24 hours. The long reaction of 24 hours is disadvantageous for industrial production, and there is a concern that impurities may be produced as a by-product due to the long reaction.

  Further, in the method of carrying out the reaction in a solvent-free system disclosed in Patent Document 2, OZ-4 has a melting point of 300 ° C. or higher and is solid at room temperature, and OZ-05 has a high boiling point of 138 ° C. Due to the liquid (room temperature), it is possible to achieve the reaction at a high reaction temperature of 80 to 120 ° C., and to increase the reaction rate. However, since there is no organic solvent that dissolves impurities generated by the reaction in a solventless system, it is easy to obtain olanzapine incorporating a large amount of impurities, and it is difficult to obtain olanzapine with high purity.

  The present inventors diligently studied the method for carrying out the reaction in the above solvent-free system. As a result, in order to prevent impurities after the reaction from being taken into olanzapine, the reaction mixture reacted at a reaction temperature of 80 to 120 ° C. can be cooled to 60 to 80 ° C. and compatible with the reaction mixture and water. After mixing the organic solvent, it was found that by adding water in a state maintained at 60 to 80 ° C. to precipitate olanzapine, the precipitation rate of olanzapine can be controlled and high-purity olanzapine can be obtained. It came to be completed.

  That is, the present invention

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と下記式（２）

4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride represented by the following formula (2)

N-methyl piperazine represented by the formula (3) is reacted in the absence of solvent at 80 to 120 ° C.

In the method for producing olanzapine, the reaction mixture obtained by the above reaction was cooled to 60 to 80 ° C., and the reaction mixture and an organic solvent compatible with water were mixed, and then maintained at 60 to 80 ° C. In this state, water is added to precipitate olanzapine.

  According to the method of the present invention, since a reaction solvent is not used in the step of synthesizing olanzapine from OZ-04 and OZ-05, a reaction temperature of 80 to 120 ° C. near the boiling point of OZ-05 can be employed. . Therefore, the reaction can be completed in 4 to 6 hours, which is industrially advantageous.

  In addition, after mixing the reaction mixture and an organic solvent compatible with water, water is added in a state where the temperature of the reaction solution is maintained at 60 to 80 ° C. to precipitate olanzapine, thereby controlling the degree of supersaturation of olanzapine. Since olanzapine can be gradually precipitated, as a result, it is possible to obtain olanzapine with a low impurity content. Therefore, the present invention is suitably employed as a method for producing olanzapine.

  The present invention will be described in detail below.

  In the present invention, OZ-04 and OZ-05 are reacted in the absence of a solvent to obtain a reaction mixture containing olanzapine. For the reaction between OZ-04 and OZ-05, the method described in Patent Document 2 can be employed without any limitation. For example, the reaction temperature can be employed in the range of 80 to 120 ° C.

The reaction time may be appropriately determined by confirming the production status of olanzapine in the reaction solution by high performance liquid chromatography. According to the above reaction conditions, the reaction time is usually about 4 to 6 hours. Then, the conversion rate to the product can achieve 90% or more. In the present invention, OZ-05 may be present in an excess amount of 6 to 10 times the mole of OZ-04. preferable.

  The reaction mixture is then cooled to 60-80 ° C. After cooling the reaction mixture to 60 to 80 ° C., the reaction mixture and an organic solvent compatible with water are mixed. When an organic solvent is not mixed with the reaction mixture, when olanzapine is precipitated by adding water described later, the total amount of the liquid is small with respect to olanzapine, and the olanzapine precipitate becomes agglomerated and difficult to recover. There is a risk that. Therefore, the weight of the reaction mixture used for mixing and the organic solvent compatible with water is preferably 1 to 3 times by weight, preferably 1 to 2 times the weight of the charged OZ-04. More preferably.

  Moreover, when the temperature which cools the said reaction mixture is less than 60 degreeC, when water is added, the precipitation of olanzapine will produce | generate rapidly, an impurity will be taken in into olanzapine, and the purity of olanzapine will fall. In addition, when the cooling temperature exceeds 80 ° C., an organic solvent having a boiling point of 85 ° C. or higher must be used in order to prevent the evaporation of the organic solvent, and when such an organic solvent remains in olanzapine. Removal becomes difficult and the purity of olanzapine is reduced.

  As the organic solvent compatible with the reaction mixture and water, the precipitation temperature of olanzapine, which will be described later, is 60 to 80 ° C., and therefore it is preferable that evaporation can be suppressed within that temperature range. Is preferably an organic solvent of 85 ° C. or lower. From the viewpoint of ease of handling, the boiling point is preferably an organic solvent having a temperature equal to or higher than the precipitation temperature of olanzapine. With such an organic solvent, the organic solvent does not volatilize when olanzapine is precipitated, and olanzapine can be precipitated stably.

  Here, acetonitrile can be mentioned as a specific example of the organic solvent described above. In particular, since acetonitrile has a relatively low boiling point (82 ° C.), it is most preferable because the residual solvent can be easily removed by a drying step described later.

  The greatest feature of the present invention is that olanzapine is precipitated by adding water in a state where the temperature of the reaction solution after mixing the organic solvent is maintained at 60 to 80 ° C.

  When the temperature during precipitation is less than 60 ° C., the supersaturated state of olanzapine is suddenly destroyed by adding water, and the precipitation rate of olanzapine cannot be controlled and the amount of impurities in the precipitated olanzapine is It is not preferable because it increases. On the other hand, when the temperature exceeds 80 ° C., the mixed organic solvent evaporates and the precipitated olanzapine becomes a lump and makes recovery difficult.

  In order to precipitate olanzapine, the temperature at the time of adding water may be maintained at 60 to 80 ° C. However, in order to reduce the amount of impurities in olanzapine and stably obtain high-purity olanzapine, 65 It is more preferable to maintain at -75 degreeC.

  In the present invention, the amount of impurities in olanzapine can be reduced by keeping the olanzapine precipitation rate within a certain range. The deposition rate of such olanzapine can be controlled by the amount of water added for precipitation and the time from the start of addition to the end of addition. The amount of water added is preferably 1 to 10 times by weight, more preferably 2 to 7 times the weight of the charged OZ-04, taking into account the yield of the target product. preferable. Further, the time from the start of addition of water to the end of addition is preferably 20 to 1000 minutes, and more preferably 30 to 200 minutes.

Specific examples of the operation of adding water and precipitating olanzapine described above include a method of continuously adding water and a method of intermittently adding water.
Examples of the method for continuously adding water include a method in which water is continuously dropped until precipitation of olanzapine is completed, that is, the time from the start of addition of water to the end of addition.

  Moreover, the following method can be used suitably as a method of adding water intermittently. This is an addition method in which the interval of adding water is set to 10 to 60 minutes from the start of addition of water to the end of addition of water, and the number of times of adding water is 3 to 10 times. In addition, about the quantity of the water added at once, all the water can also be added at once, and can also be dripped continuously over time. In this case, the time required for one addition is usually preferably in the range of 1 to 15 minutes.

  Next, as a method for maintaining the temperature at the time of precipitation of olanzapine while adding water, water having a temperature of 60 to 80 ° C. may be added. Also, add water while maintaining the temperature of 60-80 ° C using a jacket set at 60-80 ° C so that the temperature at the time of precipitation of olanzapine does not change before and after adding water I can do it.

  Furthermore, olanzapine can be recovered as follows. Before separating the precipitated olanzapine, aging may be performed at room temperature for 3 to 16 hours. Olanzapine 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.

  The olanzapine thus obtained is a high-purity olanzapine with a low impurity content.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited at all by these Examples.

(Evaluation of olanzapine purity)
In the following Examples and Comparative Examples, the purity of olanzapine is a peak area determined under the following high performance liquid chromatography analysis conditions.

(Analysis conditions for high performance liquid chromatography)
Device system: Model 2695-2489 manufactured by WATERS
Column: ZORBAX RX-C8 (manufactured by Agilent Technologies)
Particle size: 5 μm
Inner diameter: 4.6 mm x length 250 mm
Detection wavelength: 220 nm
Column temperature: 35 ° C
Sample temperature: 25 ° C
Mobile phase A: buffer / acetonitrile = 52/48 (V / V)
Mobile phase B: buffer / acetonitrile = 30/70 (V / V)
(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)
Flow rate: 1.5 mL / min
(Olanzapine is observed at about 14 minutes when measured under these conditions.)

(Calculation method for yield of crude olanzapine)
The following calculation formula was used.
(Yield) = (olanzapine crude product yield) / (olanzapine crude product yield)
= (Oranzapine crude product yield) / (OZ-04 charge x 1.175)

Example 1
In a reaction vessel (four-neck flask), 2-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride 20.0 g (0.075 mol) and N-methylpiperazine 60 .3 g (66.8 mL, 0.602 mol, 8 times mol with respect to OZ-04) was added, and the four-necked flask was immersed in an oil bath set at 120 ° C., and the reaction temperature was maintained at 120 ° C. Stirring was carried out with a stirring blade inserted into the necked flask. The reaction was carried out with a reaction time of 4 hours. After completion of the reaction, the four-necked flask was immersed in an oil bath set at 70 ° C., and the temperature of the reaction mixture was cooled to 70 ° C.

  Thereafter, 23.6 g of acetonitrile (1.18 times by weight with respect to OZ-04) was mixed with the reaction mixture, and 60.0 g of distilled water heated to 70 ° C. was maintained while maintaining the temperature of the reaction mixture at 70 ° C. 3 times the weight of OZ-04) is divided into 4 times every 10 minutes, and 1 time is added over 3 minutes, so that the time from the start of addition of water to the end of addition is 42 minutes. Olanzapine was precipitated. After the entire amount of olanzapine was precipitated, the mixture was cooled to room temperature over 4 hours and stirred for 15 hours.

  The precipitate was collected by filtration, washed twice with 20 mL of distilled water, and then dried under reduced pressure at 40 ° C. for 6 hours to obtain 19.8 g of a crude olanzapine. Moreover, the yield of the olanzapine crude body was 84%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.85%.

Example 2
While maintaining the temperature of the reaction mixture at 73 ° C., 60.0 g of distilled water (3 times by weight with respect to OZ-04) was added in 30 portions every 4 times, and added from the start of the addition of water. Olanzapine was precipitated in the same manner as in Example 1 except that olanzapine was precipitated so that the time until completion was 102 minutes, to obtain 20.1 g of olanzapine crude product. The yield of crude olanzapine was 85%. The area percentage purity of olanzapine by HPLC was 99.84%.

Example 3
While maintaining the temperature of the reaction mixture at 67 ° C., 60.0 g of distilled water (3 times by weight with respect to OZ-04) was added in 11 divided portions every 10 minutes. Except that olanzapine was precipitated so that the time until completion was 133 minutes, olanzapine was precipitated in the same manner as in Example 1 to obtain 18.8 g of olanzapine crude product. The yield of the olanzapine crude product was 80%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.88%.

Example 4
Add 120.0 g of distilled water (6 times by weight with respect to OZ-04) divided into 4 portions every 10 minutes, so that the time from the start of addition of water to the end of addition is 42 minutes. The olanzapine was precipitated in the same manner as in Example 1 except that 21.1 g of olanzapine crude product was obtained.

The yield of the olanzapine crude product was 90%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.75%.

Example 5
Olanzapine 60.0 g of distilled water (3 times by weight with respect to OZ-04) was added in 4 divided portions every 60 minutes so that the time from the start of addition of water to the end of addition was 192 minutes. The olanzapine was precipitated by the same operation as in Example 1, except that 18.4 g of olanzapine crude product was obtained.

The yield of the olanzapine crude product was 78%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.87%.

Reference example 1
In a reaction vessel, 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride 3.0 g (0.034 mol) and N-methylpiperazine 27.2 g (30.1 mL) 0.271 mol, 8 times mol), and the temperature of the reaction mixture was 120 ° C. with stirring, and the reaction was performed at the same temperature for 4 hours. After completion of the reaction, the temperature of the reaction mixture was cooled to 70 ° C., and 3.54 g of acetonitrile (1.18 times by weight with respect to OZ-04) was mixed. Next, 9.0 g of distilled water (3 times by weight with respect to OZ-04) was continuously added while maintaining the liquid temperature of the reaction mixture at 70 ° C., and the time from the start of addition of water to the end of addition The olanzapine was allowed to settle so as to be 10 minutes. Further, the solution was cooled to room temperature over 3.5 hours, and the solution was stirred for 3 hours. The precipitate was collected by filtration, washed twice with 3.0 mL of distilled water, and then dried under reduced pressure at 40 ° C. for 6 hours to obtain 2.67 g of an olanzapine crude product.

Further, the yield of the olanzapine crude product was 76%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.25%.

Reference example 2
While maintaining the temperature of the reaction mixture at 63 ° C., 9.0 g of distilled water (3 times by weight with respect to OZ-04) was divided into 4 portions every 3 minutes, and 1 portion was added over 3 minutes. The olanzapine was precipitated by the same operation as in Example 6 except that olanzapine was precipitated so that the time from the start of addition of water to the end of addition was 21 minutes, to obtain 2.40 g of a crude olanzapine. . The yield of crude olanzapine was 68%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.14%.

Reference example 3
While maintaining the temperature of the reaction mixture at 77 ° C., 9.0 g of distilled water (3 times by weight with respect to OZ-04) was divided into 3 portions every 5 minutes, and 1 portion was added over 3 minutes. The olanzapine was precipitated in the same manner as in Example 6 except that olanzapine was precipitated so that the time from the start of addition of water to the end of addition was 19 minutes, to obtain 2.67 g of a crude olanzapine. . The yield of crude olanzapine was 73%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 99.06%.

Comparative Example 1
The olanzapine was precipitated in the same manner as in Example 1 except that olanzapine was precipitated while the temperature of the obtained reaction mixture was cooled to 90 ° C. and maintained at 90 ° C., but was mixed into the reaction mixture. Acetonitrile boiled and the olanzapine precipitate was agglomerated and could not be recovered.

Comparative Example 2
The olanzapine was precipitated in the same manner as in Example 1 except that olanzapine was precipitated while the temperature of the obtained reaction mixture was cooled to 50 ° C and maintained at 50 ° C. Obtained. The yield of the olanzapine crude product was 65%. As a result of evaluating the area percentage purity of olanzapine by high performance liquid chromatography, the area percentage purity was 98.0%.

  The results of Examples 1 to 8 and Comparative Examples 1 and 2 are shown in Table 1.

Claims (1)

Following formula (1)

4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride represented by the following formula (2)

And N-methylpiperazine represented by the following formula (3)

In the method for producing olanzapine, the reaction mixture obtained by the above reaction is cooled to 60 to 80 ° C., the reaction mixture and an organic solvent compatible with water are mixed, and then the temperature of the reaction solution is changed to 60 to 60 ° C. In a state maintained at 80 ° C.
From the start of addition of water to the end of addition of water, the interval of adding water is set to an interval of 10 to 60 minutes, and the number of times of adding water is 3 to 10 times,
A method for producing olanzapine by adding water.