JP2002234890A - Method for producing amorphous paroxetine hydrochloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a method for producing amorphous paroxetine hydrochloride useful as a medicine by an industrially advantageous method. SOLUTION: Paroxetine hydrochloride containing isopropyl alcohol is reacted with a base to afford paroxetine, which is then reacted with acetic acid to provide paroxetine acetate and the resultant paroxetine acetate is reacted with hydrogen chloride in ethanol to afford an ethanol solution of paroxetine hydrochloride not substantially containing isopropyl alcohol and the ethanol solution is subjected to spray drying to provide the objective amorphous paroxetine hydrochloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing amorphous paroxetine hydrochloride which has an inhibitory action on 5-hydroxytryptamine (5-HT) and is effective as a therapeutic agent for various diseases such as depression and Parkinson's disease. .

[0002]

BACKGROUND OF THE INVENTION Paroxetine (ie (3S, 4R)
The hydrochloride salt of -3- [5- (1,3-dioxaindanyl) oxymethyl] -4- (p-fluorophenyl) piperidine) and paroxetine are known compounds. Paroxetine hydrochloride as a pharmaceutical is provided as crystals. It is said that there are many types of crystal forms of paroxetine hydrochloride, and for example, crystals of paroxetine hydrochloride hemihydrate are known (US Pat. No. 4,007,196, Japanese Patent Publication No. 6-47587). However, when it is used as a drug, it has been pointed out that a crystal is slow in absorption into the body.

[0003]

SUMMARY OF THE INVENTION The present invention provides a method for industrially advantageously producing amorphous paroxetine hydrochloride having good absorbability in the body.

[0004]

SUMMARY OF THE INVENTION The present inventors have found that from paroxetine hydrochloride containing isopropyl alcohol, using an industrially advantageous method, it is stable as amorphous and substantially free of isopropyl alcohol. It has been found that amorphous paroxetine hydrochloride can be easily produced.

That is, in the present invention, paroxetine hydrochloride containing isopropyl alcohol is reacted with a base to form paroxetine, and then the paroxene is reacted with acetic acid to form paroxetine acetate, and then the paroxetine acetate is chlorided in ethanol. Reacting with hydrogen to obtain an ethanol solution of paroxetine hydrochloride substantially free of isopropyl alcohol, and spray-drying the ethanol solution to obtain amorphous paroxetine hydrochloride. The present invention provides a method for producing amorphous paroxetine hydrochloride free from.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, paroxetine hydrochloride containing isopropyl alcohol is preferably obtained as a solid, because the quality is stable and the handling is easy, and it is particularly preferable to obtain it as crystals. preferable. Paroxetine hydrochloride containing isopropyl alcohol is disclosed in U.S. Pat.
It can be produced by a method described in JP-A-47587, JP-A-9-316072, or the like. Among them, in the present invention, a method for producing hemihydrate crystals is described.
It is preferable to use a compound which is produced according to the method described in Example 8 of JP-129280 and can be obtained as an intermediate of hemihydrate crystals.

The amount of isopropyl alcohol contained in paroxetine hydrochloride containing isopropyl alcohol is preferably 2% by mass to 10% by mass, and more preferably 2% to 5% by mass.

The paroxetine hydrochloride containing isopropyl alcohol may contain a solvent other than isopropyl alcohol, for example, may contain water. When water is contained, the content is preferably more than 0% by mass to 2% by mass with respect to paroxetine hydrochloride, and particularly preferably 0.2 to 2% by mass.
It is preferably from 0.5 mass%. Paroxetine hydrochloride containing isopropyl alcohol is disclosed in
In accordance with the method described in Example 8 of JP-A-129280, the compound may be dried to give anhydrous paroxetine hydrochloride.

In the present invention, paroxetine is obtained by reacting a base with paroxetine hydrochloride containing isopropyl alcohol.

The base is preferably an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, etc., and particularly preferably potassium hydroxide or sodium hydroxide. Potassium hydroxide is preferred. The base is
It is preferable to use 1 to 10 moles, particularly preferably 1 to 6 moles per mol of paroxetine hydrochloride. When the base is solid under the reaction conditions, it is preferably used as a solution, and more preferably as an aqueous solution. When an aqueous solution is used, the base concentration in the aqueous solution is 1
It is preferably from 0 to 50% by mass, particularly preferably from 15 to 30% by mass. In addition, the reaction with a base is usually preferably performed at 0 to 60 ° C, particularly preferably at 15 to 40 ° C.
The reaction with a base can be carried out under increased pressure, reduced pressure, or normal pressure, and is usually preferably performed at a pressure near atmospheric pressure. The reaction time is preferably 5 minutes to 10 hours,
Particularly, 10 minutes to 2 hours are preferable. Further, the reaction with the base is preferably performed under a nitrogen stream.

The reaction with a base is preferably carried out in the presence of a solvent. As the solvent, toluene and water are preferred. Toluene is 1 to 1 with respect to paroxetine hydrochloride.
It is preferable to use 0 times the mass, and particularly preferably 2 to 5 times the mass. Water is preferably used in an amount of 1 to 10 times, more preferably 3 to 8 times the mass of paroxetine hydrochloride. When toluene and water are used as the solvent, a mixture of toluene and water may be prepared and then introduced into the reaction system, or toluene and water may be separately introduced into the reaction system. As the water, tap water, ion-exchanged water, purified water, distilled water, or the like is preferably used.

The reaction of paroxetine hydrochloride containing isopropyl alcohol with a base produces paroxetine. After completion of the reaction, it is preferable to carry out ordinary post-treatment on the reaction product containing paroxetine. When the reaction product contains water and toluene, it is preferable to perform a post-treatment by a method of adding a sodium chloride aqueous solution to the reaction product, stirring the mixture, and separating a toluene layer containing paroxetine. Further, if necessary, the solvent or the low-boiling compound may be distilled off by distillation (this distillation may be performed under reduced pressure). Furthermore, the resulting paroxetine can be isolated and purified, but in the present invention, without performing purification, can be used in the next acid chloride process.
The concentration of the aqueous sodium chloride solution used here is preferably from 5% by mass to a saturated concentration, particularly preferably from 10% by mass to a saturated concentration. The temperature at the time of adding the aqueous sodium chloride solution is preferably from 5 to 40C, particularly preferably from 10 to 30C.

Next, in the present invention, paroxetine is reacted with acetic acid to convert it into paroxetine acetate. The acetic acid is preferably used in a molar amount of 1 to 3 times, more preferably 1 to 1.5 times the molar amount of paroxetine.

The reaction with acetic acid is preferably carried out in the presence of a reaction solvent. Organic solvents are preferred as the reaction solvent,
Particularly, aprotic organic solvents such as toluene and chlorobenzene are preferable, and toluene is particularly preferable. The amount of toluene is preferably 1 to 10 times, more preferably 2 to 5 times the mass of paroxetine. The reaction temperature is 0
100 ° C is preferable, and particularly preferably 50 to 80 ° C. The reaction time is preferably 0.5 to 10 hours, particularly 1 to 5 hours are preferred. The reaction with acetic acid can be carried out under reduced pressure or normal pressure, and is usually preferably carried out at a pressure near atmospheric pressure. The reaction with acetic acid is preferably performed under a nitrogen stream.

The paroxetine acetate formed by the reaction with acetic acid is preferably obtained as crystals. Further, paroxetine acetate obtained as crystals is preferably collected by filtration and then washed with an organic solvent. As the organic solvent, low-boiling organic solvents such as pentane, hexane, heptane, and cyclohexane are preferable, and hexane is particularly preferable. The amount of the case of using an organic solvent is 1 to 10 with respect to paroxetine
Double mass is preferable, and 1 to 3 times mass is particularly preferable. The crystals of paroxetine acetate obtained by washing with an organic solvent may be used as they are in the next step, or those obtained by further drying under reduced pressure to remove the organic solvent may be used in the next step.

Next, in the present invention, paroxetine acetate is reacted with hydrogen chloride in ethanol to give an ethanol solution of paroxetine hydrochloride substantially free of isopropyl alcohol (hereinafter abbreviated as an ethanol solution of paroxetine hydrochloride). .) The amount of ethanol is preferably 1 to 10 times the mass of paroxetine acetate,
Particularly, the mass is preferably 1 to 5 times. The amount of hydrogen chloride is preferably 1 to 10 moles, more preferably 1 to 3 moles per mole of paroxetine acetate. The reaction temperature is preferably from 0 to 80 ° C, particularly preferably from 20 to 60 ° C. The reaction pressure is
The pressure may be a reduced pressure or a normal pressure. Usually, a pressure near the atmospheric pressure is preferable. The reaction time is preferably from 5 minutes to 10 hours, particularly preferably from 10 minutes to 3 hours. The reaction is preferably performed under a nitrogen stream.

As ethanol, dehydrated ethanol is preferred. As the dehydrated ethanol, it is preferable to use one having a content of 90% by mass or more.
It is preferable to use one having a content of 5% by mass or more. Also,
The water content of the dehydrated ethanol is preferably 0.2% by mass or less, and particularly preferably 0.005% by mass or less.

As a method for introducing hydrogen chloride into the reaction system, for example, a method of blowing into a solution of paroxetine acetate in ethanol is used. An ethanol solution of hydrogen chloride is prepared in advance, and the solution is mixed with an ethanol solution of paroxetine acetate. And the like. When preparing an ethanol solution of hydrogen chloride, the concentration of hydrogen chloride in the solution is 5 to 5.
It is preferably 40% by mass, particularly preferably 10 to 30% by mass.

The amount of isopropyl alcohol in paroxetine hydrochloride substantially free of isopropyl alcohol is 0% by mass (ie, not present at all),
Even if present, it is less than 1% by mass (preferably less than 0.1% by mass).

The ethanol solution of paroxetine hydrochloride is
It is preferable to use it as it is in the next step, or to repeat addition of ethanol and further distillation of the ethanol under reduced pressure. The operation of adding ethanol and distilling under reduced pressure is preferably carried out once or more, particularly 1 to 20 times.
It is preferably performed twice, particularly preferably two to ten times. When ethanol is added, the amount of ethanol is preferably 0.5 to 10 times the mass of paroxetine hydrochloride, and particularly preferably 1 to 5 times the mass of paroxetine hydrochloride. In these operations, paroxetine hydrochloride is preferably kept in a solution state in terms of ease of operation and the like. An ethanol solution of paroxetine after these operations, by using a spray drying process can be residual solvent to obtain a substantially free amorphous paroxetine hydrochloride.

Next, in the present invention, an ethanol solution of paroxetine hydrochloride is spray-dried to obtain amorphous paroxetine hydrochloride.

It is desirable to use a solvent recovery type spray drying apparatus as the spray drying apparatus. Paroxetine hydrochloride in an ethanol solution of paroxetine hydrochloride used for spray drying is preferably diluted to a concentration lower than the saturation concentration, and the dilution concentration is appropriately adjusted according to the fluidity of the solution. preferable.

The amorphous paroxetine hydrochloride obtained by spray drying is usually obtained in the form of a powder. The particle size of the powder can be adjusted by the concentration of the ethanol solution of paroxetine hydrochloride used for spray drying, the liquid sending speed, the spray pressure, the size of the spray nozzle, and the like. The liquid sending speed is changed depending on the production capacity of the device. Further, it is preferable to adjust the liquid sending speed according to the particle size of the powder or the degree of drying. Further, the chamber inlet temperature of the spray dryer is preferably set according to the degree of the boiling point or dry ethanol, preferably 30 to 200 ° C., from 40 to 13
0 ℃ is particularly preferred. When the powder obtained by spray drying may be charged with static electricity, it is desirable to ground the powder collecting container to remove the static electricity.

The amorphous paroxetine hydrochloride obtained by spray drying can be formulated as it is and used as a drug. However, in the present invention, it is preferable to further perform a drying operation. Drying is preferably carried out by vacuum drying using the conventional vacuum pump. The temperature at the time of drying under reduced pressure is preferably from 10 to 80 ° C, particularly from 20 to 50 ° C.
C is preferred. The degree of reduced pressure during drying under reduced pressure is preferably 1 kPa (absolute pressure), and the degree of reduced pressure is preferably adjusted according to the degree of drying. The drying time is also adjusted according to the degree of drying, and is usually preferably 1 to 72 hours, particularly preferably 2 to 48 hours.

When synthesizing amorphous paroxetine hydrochloride according to the production method of the present invention, when a large amount of synthesis is desired, or when the production capacity of each step is different, the specific step is performed twice or more. For example, operations such as merging the products obtained, dividing the product of a specific step, and leading to the next step may be performed. For example, the spray drying process
Or more times to obtain the desired amorphous paroxetine hydrochloride of the present invention. In the case where the spray drying step is performed twice or more, the ethanol solution of paroxetine hydrochloride used in the spraying step may be a product obtained by dividing the product obtained in the previous step to obtain the solution, or
It may be a product obtained by performing the measurement more than once. The product of amorphous paroxetine hydrochloride in two or more parts obtained by performing the spray drying step two or more times can be obtained by further dividing the product or combining two or more products. Good.

When two or more divided products of amorphous paroxetine hydrochloride are to be combined, mixing may be performed using a stir bar or the like, or a blender such as a V-shaped mixer or a drum-type mixer may be used. And it is preferable to mix using a blender. By using a blender, amorphous paroxetine hydrochloride having more uniform quality can be obtained. The mixing can be carried out under reduced pressure or normal pressure, and it is usually preferable to carry out the mixing at a pressure near the atmospheric pressure. The temperature is 10 to 3
5 ° C is preferred, and 10-25 ° C is particularly preferred. Also,
It is preferable to carry out under a nitrogen stream.

In the hydrochloride production process and the spray drying process subsequent to the hydrochloride production process, the non-hydrated anhydrous hydrochloride can be produced by producing the hydrochloride under conditions substantially free of water. The amorphous paroxetine hydrochloride of the present invention is preferably an anhydride obtained under substantially anhydrous production conditions.

According to the production method of the present invention, stable amorphous paroxetine hydrochloride containing no crystals can be produced by an industrially advantageous method. The amorphous form of the present invention produced in the process of the present invention is powdery, it is easy to handle advantages.

[0029]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

(Example 1) Production example of paroxetine In a nitrogen stream, paroxetine hydrochloride (1005.9 g, the content of isopropyl alcohol is 2.9% by mass based on paroxetine hydrochloride) and toluene (4.67 L). And water (6.67 L). 2 in this mixture
A 3% by mass aqueous solution of potassium hydroxide (potassium hydroxide / water = 909.0 g / 2.97 L) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the stirring, the aqueous layer was distilled off, and a 14% by mass aqueous solution of sodium chloride (sodium chloride / water = 493.5 g / 2.97 L) was added to the toluene layer, followed by stirring at room temperature for 30 minutes. After completion of the stirring, the aqueous layer was distilled off, and the toluene layer was subjected to suction filtration. The filtrate was concentrated under reduced pressure to obtain a toluene solution of paroxetine.

[0031] (Example 2) paroxetine toluene solution under production example nitrogen stream of paroxetine acetate (1.68L)
(Production of Example 1 was performed twice to combine the products.)
Was dissolved in toluene (9.32 L). Water tank temperature 40
Acetic acid (328.7 g) was added at 0 ° C, and the mixture was stirred for 30 minutes. After confirming the crystallization of paroxetine acetate, the temperature of the tank was reduced to 7
The temperature was raised to 0 ° C., and the mixture was stirred for 2 hours after the internal temperature became constant. The water bath temperature was set to 20 ° C., and the mixture was left to cool and stir for 18 hours. The resulting acetate was washed with hexane (1.80 L) and further washed with hexane (4.86 L) with stirring for 70 minutes. The filtered acetate was dried under reduced pressure using a vacuum pump for 18 hours to give paroxetine acetate (1992.
4 g) were obtained.

(Example 3) Production example of paroxetine hydrochloride In a nitrogen stream, dehydrated ethanol (9.3 L) was added to paroxetine acetate (1980.2 g) and dissolved at 40 ° C. This ethanol solution, 16 mass% hydrochloric acid ethanol solution (hydrochloric acid / ethanol = 375 g / 2.5L)
Was added and stirred for 30 minutes. Ethanol (3.3 L) was added to the reaction solution, and the added amount of ethanol was concentrated under reduced pressure. This operation was performed five times to obtain an ethanol solution of paroxetine hydrochloride (1213.2 g, the content of isopropyl alcohol was 0.1% by mass or less based on paroxetine hydrochloride).

Example 4 Production Example of Amorphous Paroxetine Hydrochloride An ethanol solution of paroxetine hydrochloride (6066.1 g) was prepared using a spray dryer for organic solvent (GS-310, manufactured by Yamato Scientific Co., Ltd.) (the production method of Example 3). Half amount of the ethanol solution obtained in the above) was spray-dried. Spray drying conditions are as follows: under nitrogen atmosphere, nozzle size 0.5 mmφ, inlet temperature 90 ° C, nozzle spray pressure 0.075 MPa, liquid sending speed 1
It was set to 0 ml / min. The obtained hydrochloride was dried under reduced pressure using a vacuum pump for 18 hours to obtain amorphous paroxetine hydrochloride (882.6 g).

¹ H-NMR (400 MHz, CDC
_{l 3) δ; 9.9 (br} , 2H); 7.20-7.23
(M, 2H); 6.98-7.02 (m, 2H);
62 (d, J = 8.4 Hz, 1H); 6.34 (d, J
= 2.2 Hz, 1H); 6.12 (dd, J = 2.2,
8.4 Hz, 1H); 5.89 (s, 2H); 3.73
(Br, 1H); 3.67 (br, 1H); 3.60
(M, 1H); 3.48 (m, 1H); 3.17 (b
3.05 (br, 1H); 2.92 (b
r, 1H); 2.66 (br, 1H); 2.40 (b
r, 1H); 2.04 (br, 1H).

¹⁹ F-NMR (376 MHz, CDCl
_3, reference CFCl ₃₎ δ; -115.4.

[0036] The powder X-ray diffraction pattern of the amorphous paroxetine hydrochloride is shown in Figure 1. According to X-ray diffraction diagram, halo effect is clearly visible, and the intensity is very small, the product was confirmed to be amorphous form.

X-ray analysis was performed under the following conditions. Apparatus: “Rotaflex RU-20” manufactured by Rigaku Corporation
0 "Measurement conditions: tube; Cu, tube voltage; 50 kV, tube current; 2
00 mA, sampling width; 0.010 °, scanning speed;
0.500 ° / min, scan axis; 2θ / θ, divergence slit;
1 °, scattering slit; 1 °, receiving slit; 0.30 m
m.

(Example 5) Mixing Example of Amorphous Paroxetine Hydrochloride 739.3 g of amorphous paroxetine hydrochloride (first time), 75
0.7 g (second time) was obtained. These amorphous paroxetine hydrochlorides were mixed with a V-shaped mixer (P-K BLEND M
ASTER, Patternson-Kelley)
At 25 ° C. and a container rotation speed of 21 r. p. m. The mixing time was 5 minutes under atmospheric pressure. The obtained amorphous paroxetine was a homogeneous amorphous body.

[0039]

According to the production method of the present invention, stable amorphous paroxetine hydrochloride containing no crystals can be produced by an industrially advantageous method. Further, the amorphous body of the present invention produced by the method of the present invention is in a powder form, and has an advantage that it is easy to handle.

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction diagram of the amorphous paroxetine hydrochloride obtained in Example 4 (vertical axis: peak intensity (unit: cps), horizontal axis: 2θ / θ (degree))

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Naoya Shimokawa 10 Goi Kaigan, Ichihara-shi, Chiba Prefecture Asahi Glass Co., Ltd. Yoshitomi Morisawa 10 Goi Kaigan, Ichihara City, Chiba Prefecture Asahi Glass Co., Ltd. F-term (reference) 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA04 BC21 MA04 ZA02 ZA12 ZC20

Claims (4)

[Claims] 1. A method in which paroxetine hydrochloride containing isopropyl alcohol is reacted with a base to form paroxetine, and then paroxene is reacted with acetic acid to form paroxetine acetate, and then the paroxetine hydrochloride is reacted with hydrogen chloride in ethanol. To obtain an ethanol solution of paroxetine hydrochloride substantially free of isopropyl alcohol,
A method for producing amorphous paroxetine hydrochloride substantially free of isopropyl alcohol, comprising spray-drying the ethanol solution to obtain amorphous paroxetine hydrochloride. 2. The method according to claim 1, wherein the paroxetine hydrochloride containing isopropyl alcohol contains 2 to 5% by mass of isopropyl alcohol. 3. The method according to claim 1, wherein the base is potassium hydroxide. 4. The method according to claim 1, wherein the step of spray-drying is carried out twice or more to obtain an amorphous paroxetine hydrochloride, and the amorphous paroxetine hydrochloride formed in the two or more steps is divided into two or more parts. A method for producing mixed amorphous paroxetine hydrochloride, comprising mixing paroxetine hydrochloride at 10 to 35 ° C. for 3 to 60 minutes.