KR20060087891A - A method for producing azapirone or salt thereof using 8-(2-pyrimidinyl)-8-aza-5-azoniaspriro[4.5]decane sulfonate salt and an intermediate compound useful for the same - Google Patents

Abstract

The present invention provides a compound represented by the following Chemical Formula 2 by reacting 1- (2-pyrimidinyl) piperazine of Chemical Formula 3 and 1,4-butanediol disulfonate of Chemical Formula 8 in an organic solvent in the presence of a base. Preparing a-(2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt; And ii) reacting the 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt of formula 2 with the cyclic imide of formula 7 in an organic solvent in the presence of a base Provided are a method for preparing azapyrone or a salt thereof represented by the formula (1), and an intermediate used therein.

Azapyrone, 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt

Description

A method for producing azapyrone or its salt using 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt and intermediates used in the method azapirone or salt especially using 8- (2-pyrimidinyl) -8-aza-5-azoniaspriro [4.5] decane sulfonate salt and an intermediate compound useful for the same}

The present invention relates to a process for preparing azapyrone or a salt thereof using 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt and to an intermediate used in the method. will be.

Azapyron or its salts are currently used to treat anxiety and depression. In the past, benzodiazepine-based alprazolam, broromazepam, diazepam, and potassium clorazepate have been used, but side effects of central nervous system have been reported. Azapyronic drugs are used.

The present invention relates to a method for preparing an azapyron-based depression treatment represented by Formula 1, more specifically, known as buspirone, gepirone, ballistic spiron, WY-47,846 and the like. A method for preparing azapyrone or a salt thereof and an intermediate used in the method represented by the formula (2).

(화학식 1)

(Formula 1)

(화학식 2)

(Formula 2)

Representative azapyron-based depression treatment is as follows. Busspirone, Z, described in US Pat. No. 3,717,634:

In addition, gepirone, Z: described in US Pat. No. 4,423,049:

And Tandospirone, Z, described in US Pat. No. 4,507,303:

WY-47,846, Z, described in US Pat. No. 4,892,943:

Etc.

All four drugs have N- (2-pyrimidinyl) piperazinylbutyl groups as the same side chains, and thus, various studies on the efficient introduction of N- (2-pyrimidinyl) piperazinylbutyl groups have been conducted. come.

Looking at the conventional manufacturing method related to the manufacturing method according to the invention as follows.

U.S. Patent No. 3,398,151 and U.S. Patent No. 3,717,634 disclose spiro-glutaric anhydride, imide metal salts or N-substituted glutarimide 4- (N-aminobutyl) -1- Reaction with (2-pyrimidinyl) piperazine, N-substituted-4- (N-halobutyl) -1- (2-pyrimidinyl) piperazine or 4- (2-pyrimidinyl) piperazine To prepare azapyrone. However, there are disadvantages in that it is difficult to manufacture a high purity drug due to the complex process and the generation of impurities during the intermediate synthesis process. US Pat. No. 4,507,303 also provides a method for producing N- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,3-norbornadicarboximide in the same manner as the above patents. This is described but with similar drawbacks.

In addition to the above patents, we will look at the related art more related to the present invention. First, U.S. Patent No. 4,351,939 discloses 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane halogen salt method as shown in Formula 4 and a method for preparing buspyron of Formula 5a using the same. It is described.

Wherein X is chloride, bromide and iodine. The patent requires a long time high temperature reaction for the preparation of the 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane halogen salt represented by the formula (4), and without the precipitation of the formula (4) The disadvantage is that filtration at high temperatures is required to remove the salt. In addition, the compound of formula 4 has a strong hygroscopicity in the air has a difficult industrial use.

U.S. Patent No. 5,521,313 discloses an inorganic salt in the US Patent No. 4,351,939, which is difficult to filter because inorganic salts are generated. Thus, the halogen salt is formulated in an yield of 83% using an ion exchange resin as in Scheme 2 below. 3,3-dimethylglutarimide of formula 7b or bicyclo [2.2.1] heptan-2,3-di-exo-carboximide [bicycleo [2.2. 1] heptane-2,3-di-exo-carboximide] and a salt represented by Chemical Formula 6 are prepared. This is a high temperature reaction to prepare a gepirone (gepirone) of the formula (5b) or a ballandospirone (tandospirone) of the formula (5c). The disadvantage of this technique is that the formula 4 has to be converted into a hydroxide salt using an ion exchange resin, which makes the manufacturing process difficult and uneconomical in terms of equipment and cost. In addition, the prepared formula 6a or 6b is hygroscopic and sticky strong vacuum drying and difficult to store and handle. There is a difficulty in industrial use for the same reason as described above.

The present invention provides an economical method for producing a high purity azapyrone-based drug represented by the formula (1) and an intermediate for producing the same. That is, the present invention provides a method for the efficient preparation of high purity azapyron-based drugs using the novel spiro-quaternary ammonium sulfonate salt.

Accordingly, it is an object of the present invention to provide a novel method for preparing azapyrone-based drugs.

Another object of the present invention is to provide novel intermediates which can be usefully used in the method of the present invention.

The present invention is a method for producing azapyrone or a salt thereof represented by the formula (1),

(화학식 1)

(Formula 1)

,

,

또는

이다)Where Z is

,

,

or

to be)

Iii) 1- (2-pyrimidinyl) piperazine of the following formula (3) and 1,4-butanediol disulfonate of the formula (8) are reacted in an organic solvent in the presence of a base to give 8- ( Preparing a 2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt; And

(화학식 3),

(Formula 3),

(화학식 8),

(Formula 8),

(화학식 2),

(Formula 2),

(In Formulas 8 and 2, R is a C ₁ to C ₄ alkyl, substituted or unsubstituted aromatic compound group.)

Ii) reacting the 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt of Chemical Formula 2 with the cyclicimide of Chemical Formula 7 in an organic solvent in the presence of a base; It provides a method for producing an azapyrone represented by the formula (1) or a salt thereof, comprising the step of preparing azapyrone or a salt thereof represented by the formula (1).

(화학식 7)

(Formula 7)

In Formula 7, Z is as described above.

The process of the present invention comprises the steps of: i) reacting 1- (2-pyrimidinyl) piperazine of formula 3 and 1,4-butanediol disulfonate of formula 8 in an organic solvent in the presence of a base to Preparing the indicated 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt. In step i) R in formulas 2 and 8 are C ₁ to C ₄ alkyl, substituted or unsubstituted aromatic compound groups. Preferably, R is a methyl, benzyl or p-toluenyl group, particularly preferably a methyl group. In addition, the base may be, for example, alkali hydroxide, amide, alcoholate or carbonate, but is not limited thereto. Preferably, the base is sodium carbonate. In addition, the organic solvent may be one or more selected from C ₁ to C ₄ alcohol, benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, dibutyl ether, and mixtures thereof, but these examples It is not limited to. Preferably, the organic solvent is isopropanol.

The compound of formula 3 used as starting material in step i) of the present invention may be prepared by any method known in the art or may be commercially available. For example, it can be prepared from piperazine and 2-cloropyrimidine as described in US Pat. No. 4,507,078. 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt of formula (2) is characterized in that the compound of formula (3) and (8) Under the base, unlike the conventional long-term reaction, it can be almost quantitatively prepared by only warming for 2 to 5 hours. The compound of Formula 3 and the compound of Formula 8 are preferably included in a ratio of 1: 1 to 1.5 equivalents. In addition, in the conventional method, if the high temperature filtration is not carried out to remove the inorganic material after the completion of the reaction, the halogen salt represented by the formula (4) is precipitated and the yield is reduced, so that industrial production is difficult. Except for the salt, the precipitate is not precipitated. When the filtrate is cooled to 5 to 10 ° C, the sulfonate salt represented by the formula (2) is precipitated to facilitate separation. In addition, while conventional halogen salts have hygroscopicity, sulfonate salts have no hygroscopicity and are easy to manufacture and handle, thus enabling industrial use. The reaction is carried out at the boiling point of the selected solvent, about 80 ° C. to 140 ° C. Suitable reaction time may vary from 2 hours to 5 hours depending on the reaction temperature and the solvent selected.

Step ii) of the present invention comprises the 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt of formula 2 prepared as i) and the cyclic imide of formula 7 Reacting in an organic solvent in the presence of a base to prepare an azapyrone represented by the formula (1) or a salt thereof. Bases that can be used in step ii) include, but are not limited to, alkali hydroxides, amides, alcoholates or carbonates. Preferably, the base is potassium carbonate. In addition, the organic solvent that can be used may be one or more selected from alcohols of C ₁ to C ₄ , benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, dibutyl ether and mixtures thereof. It is not limited to this. Preferably, the organic solvent is isopropyl alcohol.

The reaction of step ii) of the present invention is preferably carried out under warming conditions. The reaction temperature is preferably a boiling point of the selected solvent, about 80 ℃ to 160 ℃, but is not limited to this range and may vary depending on the solvent selected. Suitable reaction time is 2-7 hours, depending on the reaction temperature and the solvent selected.

The present invention may further comprise the step of separating the reaction mixture comprising the compound of formula 1 obtained from step ii) into an organic solvent layer and a water layer and concentrating the organic solvent layer. In this case, the organic solvent may be one or more selected from ethyl acetate, dichloromethane, chloroform, benzene, toluene, and mixtures thereof, but is not limited thereto. Preferably, the extraction solvent is ethyl acetate. As a result, the azapyrone derivative represented by the formula (1) present in the concentrate may be prepared in a yield of 90% or more.

In addition, the method of the present invention may further comprise the step of preparing a salt of the compound of the formula (1) by reacting the concentrate obtained as described above with an acid in a C ₁ ~ C ₄ alcohol solvent and purifying the obtained salt. The C ₁ to C ₄ alcohol solvent includes, for example, methanol, ethanol and isopropanol, but is not limited to these examples. In addition, the acid is preferably hydrochloric acid, phosphoric acid, sulfuric acid, hydrochloric acid, bromic acid, methanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, acetic acid, lactic acid, malic acid, gluconic acid, tartaric acid, citric acid, maleic acid and At least one acid selected from the group consisting of fumaric acid.

An example of azapyrone or a salt preparation method of the present invention as described above is shown in the following scheme. R and Z in Scheme 3 are as described above.

The present invention also provides a compound of formula (2) which can be used in the process for the preparation of the azapyrone or salts thereof of the present invention.

(화학식 2)

(Formula 2)

In formula (2), R is a C ₁ to C ₄ alkyl, substituted or unsubstituted aromatic compound group. Preferably, R is a methyl, benzyl or p-toluenyl group, particularly preferably a methyl group.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Example 1: Preparation of 1,4-butanediol dimethanesulfonate

1,4-butanediol (36 g, 0.40 mol) was dissolved in pyridine (100 mL) and cooled to 5 ° C. according to the known US Pat. No. 2,917,432. Methanesulfonyl chloride (96 g, 0.84 mol) was added dropwise thereto at 20 ° C or lower. After stirring for 30 minutes at room temperature it was warmed up to 60 ℃. After cooling to 5 ° C. or lower, ice water (300 mL) was added to form white crystals. The white crystals obtained were washed with ice water, filtered and dried to give 78 g (yield: 79%) of pure 1,4-butanediol dimethanesulfonate. This was recrystallized in acetone and ether mixed solvent to obtain a high purity 1,4-butanediol dimethanesulfonate.

mp 114-117 ° C .; 1 H-NMR (DMSO- d ₆ , 300 MHz) δ 1.76 (m, 4H), 3.19 (s, 6H), 4.22 (m, 4H)

Example 2: Preparation of 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane methanesulfonate salt

1- (2-pyrimidinyl) piperazine (101.7 g, 0.43 mol) and 1,4-butanediol dimethanesulfonate (105.9 g, 0.43 mol) together with isopropanol (145.5 g, 1.37 mol) 1017 ml) was warmed to 80 ° C for 2 hours. After completion of the reaction, the mixture was filtered at room temperature to remove the inorganic salts, and then the filtrate was cooled to 5 to 10 ° C. and filtered to obtain 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane methanesulfonate salt. 121.9 g (yield: 95%) were obtained.

mp 200-202 ° C; R _f 0.3 (chloroform / methanol / acetic acid = 2/2/1); 1 H-NMR (CDCl ₃ , 300 MHz) δ 2.33 (m, 4H), 2.65 (s, 3H), 3.67 (t, J = 5.1 Hz, 4H), 3.89 (t, J = 6.6 Hz, 4H), 4.15 (t, J = 4.8 Hz, 4H), 6.61 (t, J = 4.8 Hz, 1H), 8.31 (d, J = 4.8 Hz, 2H)

Example 3: N- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,3-norbornanedicarboximide [N- [4- [4- (2-Pyrimidinyl ) -1-piperazinyl] butyl] -2,3-norbonanedicarboximide] (ballistic pyrone)

Bicyclo [2.2.1] heptane-2,3-di-exo-carboximide [bicycleo [2.2.1] heptane-2,3-di-exo-carboximide] (63.8 g, 0.39 mol) and 8- (2 -Pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane methanesulfonate salt (115.5 g, 0.39 mol) was dissolved in dimethylformamide (319 mL) and potassium carbonate (107.8 g, 0.78 mol) Was added and warmed at 100 ° C. for 2 hours. After completion of the reaction, the reaction solution was separated into layers by toluene (319 mL) and water (319 mL), and the residue obtained by concentrating the organic layer was recrystallized with toluene and n-hexane to obtain N- [4- [4- (2-pyri). 204.7 g (yield: 92.1%) of midinyl) -1-piperazinyl] butyl] -2,3-norbornanedicarboximide were obtained.

mp 111-113 ° C .; 1 H-NMR (DMSO- d ₆ , 300 MHz) δ 0.97 (d, J = 10.8 Hz, 1H), 1.15 (d, J = 10.8 Hz, 1H), 1.31 (d, J = 7.2 Hz, 2H), 1.48 -1.57 (m, 6H), 2.48 (t, 2H), 2.60-2.64 (m, 4H), 2.69-2.74 (m, 4H), 2.35 (t, 2H), 3.8 (t, 4H), 6.65 (t , J = 4.8 Hz, 1H), 8.36 (d, J = 4.8 Hz, 2H)

N- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,3-norbornanecarboxyamide (204.7 g, 0.53 mol) prepared above was added to 95% ethanol (1023.5). In ml). Citric acid monohydrate (133.6 g, 0.64 mol) was added to the solution at room temperature and stirred for 2 hours, and the resulting solid was filtered to give a purity (HPLC) of at least 99.9% N- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -2,3-norbornanedicarboxymid citric acid salt 276.5 g (yield: 90.0%) were prepared.

mp 169.5 ° C

Example 4: 8- [4- [4- (2-pyrimidinyl) -1-pyrerazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione [8- [4- [ Preparation of 4- (2-Pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione] (Buspyron)

3,3-tetramethyleneglutarimid (110 g, 0.66 mol) and 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane methanesulfonate salt (218.1 g, 0.66 mol ) Was dissolved in dimethyl sulfoxide (550 ml), and sodium carbonate (139.9 g, 1.32 mol) was added thereto, followed by warming at 120 ° C. for 3 hours. After completion of the reaction, the reaction solution was separated by ethyl acetate (550 mL) and water (550 mL), and the organic layer was concentrated and recrystallized with toluene and n-hexane to give 8- [4- [4- (2- 239.2 g of pyrimidinyl) -1-pyrazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione (yield: 94.0%) was obtained.

mp 100 ° C .; 1 H-NMR (CDCl ₃ , 300 MHz) δ 1.42-1.58 (m, 8H), 1.63-1.72 (m, 4H), 2.37-2.31 (m, 2H), 2.45 (t, 4H), 2.58 (s, 4H ), 3.70-3.81 (m, 6H)), 6.42 (t, 1H), 8.22 (d, 2H)

8- [4- [4- (2-pyrimidinyl) -1-pyrerazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione (239.2 g, 0.62 mol) prepared above. Isopropanol (478.4 ml) and concentrated hydrochloric acid (77.5 g, 0.74 mol) were put together in a container and stirred, and 8- [4- [4- (2-pyrimidinyl) -1-pi having a purity of 99.9% or more (HPLC). 237.5 g (yield: 90.7%) of ferrazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione hydrochloride were obtained.

mp 201 ~ 202 ℃

According to the method of the present invention, azapyrone or a salt thereof can be easily produced in high purity and high yield using a low-cost reaction reagent.

According to the compound of formula 2 of the present invention, it can be used as an intermediate to prepare azapyrone or a salt thereof.

Claims (10)

As a method for producing azapyrone or a salt thereof represented by the formula (1),

(Formula 1) Where Z is

,

,

or

to be.) Iii) 1- (2-pyrimidinyl) piperazine of the following formula (3) and 1,4-butanediol disulfonate of the formula (8) are reacted in an organic solvent in the presence of a base to give 8- ( Preparing a 2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt; And

(Formula 3),

(Formula 8),

(Formula 2) (In Formulas 8 and 2, R is a C ₁ to C ₄ alkyl, substituted or unsubstituted aromatic compound group.) Ii) reacting the 8- (2-pyrimidinyl) -8-aza-5-azoniaspiro [4.5] decane sulfonate salt of Chemical Formula 2 with the cyclicimide of Chemical Formula 7 in an organic solvent in the presence of a base; To prepare azapyrone or a salt thereof represented by the formula (1),

(Formula 7) (Z in formula 7 is as described above) A method for preparing azapyrone or salts thereof. The method of claim 1, wherein in step i) R is methyl, benzyl or p-toluenyl. The process of claim 1 wherein the base in step i) or ii) is an alkali hydroxide, amide, alcoholate or carbonate. The method of claim 1, wherein in step i) the organic solvent is selected from C ₁ to C ₄ alcohols, benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, dibutyl ether and mixtures thereof. Which is one or more. The method of claim 1, wherein the organic solvent in ii) is selected from C ₁ to C ₄ alcohols, benzene, toluene, xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, dibutyl ether and mixtures thereof. One or more. The method of claim 1, further comprising adding an organic solvent and water to the reaction mixture obtained from step ii), separating the organic solvent layer and the water layer, and concentrating the organic solvent layer. The method of claim 6, wherein the organic solvent is at least one selected from ethyl acetate, dichloromethane, chloroform, benzene, toluene, and mixtures thereof. The process of claim 6 further comprising the step of reacting the resulting concentrate with an acid in a C ₁ to C ₄ alcohol solvent to prepare a salt of the compound of formula 1 and to purify the obtained salt. 9. The method of claim 8, wherein the acid is hydrochloric acid, phosphoric acid, sulfuric acid, hydrochloric acid, bromic acid, methanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, acetic acid, lactic acid, malic acid, gluconic acid, tartaric acid, citric acid, maleic acid and And selected from the group consisting of fumaric acid. Compound of Formula 2:

(Formula 2) (In Formula 2, R is a C ₁ to C ₄ alkyl, substituted or unsubstituted aromatic compound group.)