KR20100057294A - The preparation method of sumatriptan - Google Patents

Abstract

PURPOSE: A method for manufacturing sumatriptan is provided to simplify process by reducing the amount of reagent and to massively produce sumatriptan at high purity and yield. CONSTITUTION: A sumatriptan compound of chemical formula 1 is prepared by reacting dimethyl amine of chemical formula 2((CH3_)_2NH) with hydroxyl indole compound of chemical formula 3. The preparation is performed under the presence of hydrogen at 1-5 pressure using a catalyst. The catalyst is copper oxide, chromium oxide, or silica.

Description

The preparation method of sumatriptan

The present invention relates to a method for producing 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide (hereinafter referred to as sumatriptan) which is used as a migraine treatment.

Methods for preparing sumatriptan, a compound of Formula 1, which is used as a migraine treatment, have been reported in various forms.

[Formula 1]

First, in British Patent No. 2124210 (Japanese Patent Laid-Open No. Hei 1-878337, US Patent No. 4,816,470), 4-hydrazinobenzene methanesulfonamide hydrochloride and 3-cyanopropanal dimethyl acetal are used as starting materials as shown in Scheme 1 below. It is known to make cyanide indole intermediate, reduce it and dimethylate to make sumatriptan.

Scheme 1

Alternatively, British Patent No. 2162522 (Japanese Patent Laid-Open No. 1-894608, US Patent No. 5,037,845) uses 4-hydrazinobenzene methanesulfonamide hydrochloride and thiophenylacetaldehyde as starting materials, as shown in Scheme 2 below. After making a thiophenyl indole intermediate, a method for producing sumatriptan is known in three steps.

Scheme 2

As another method, a method for preparing sumatriptan according to Schemes 3 and 4 is known as a method using British Patent No. 2124210 and British Patent No. 2162522. In the method of Scheme 3 below, 4-hydrazinobenzene methanesulfonamide hydrochloride and 4-chlorobutanal dimethyl acetal are used as starting materials to prepare chloroethyl indole intermediate, which is substituted with dimethylamine to prepare sumatriptan.

Scheme 3

In addition, in the method of Scheme 4, an amino indole intermediate was prepared using 4-hydrazinobenzene methanesulfonamide hydrochloride and 4-chlorobutanal dimethyl acetal as starting materials, and then dimethylated to prepare sumatriptan.

Scheme 4

In addition, as a method of applying the British Patent No. 2162522, the amino amino hydrazone intermediate using 4-hydrazinobenzene methanesulfonamide hydrochloride and 4-dimethylaminobutanal dimethyl acetal as starting materials It is known how to make sumatriptan.

Scheme 5

However, the methods according to Schemes 1 to 5 have not only a relatively low yield of the reaction as a whole, but also a very high purity of the product, which is very difficult to purify. In addition, in the case of using a polyphosphate ester (PPE), polyphosphate is not a commercially available reagent, so there is a problem that it is difficult to apply industrially.

In addition, when using the method of U.S. Patent No. 5,300,506, hydroxy hydrazone and hydroxy indole intermediate were prepared using 4-hydrazinobenzene methanesulfonamide hydrochloride and 2,3-dihydrofuran as starting materials as shown in Scheme 6 below. After making, the sumatriptan can be produced via indole mesylate.

Scheme 6

However, the method also consumes a lot of reagents through a four step process, and there is a problem in that the purification is complicated.

In addition, many other methods for making sumatriptan are known, but most of them have a problem in that the production process is complicated, the yield is very low, the purification process is very difficult, and the polyphosphate ester which is difficult to apply industrially is used.

Thus, the present inventors focused on the supplement of the above problems of the prior art and proceeded with the research to make hydroxy indole using dihydrofuran, and then confirmed that it is possible to produce sumatriptan directly through a simple reaction, the present invention Was completed.

Accordingly, it is an object of the present invention to provide a production method useful for the preparation of sumatriptan of the formula (1).

In order to achieve the above object, the present invention reacts the hydroxy indole compound represented by the following formula (3) and the dimethylamine represented by the following formula (2), and the compound represented by the formula (1) It provides a method for producing sumatriptan comprising the step of preparing.

[Formula 1]

[Formula 2]

(CH ₃ ) ₂ NH

(3)

The method may further include preparing a hydroxy indole compound of Formula 3 through reflux by adding an aqueous phosphoric acid solution to an ethyl acetate solution of Hydrazone of Formula 4 below.

[Formula 4]

In addition, the method of the present invention may further comprise the step of reacting 4-hydrazinobenzene methanesulfonamide hydrochloride and 2,3-dihydrofuran in an aqueous alcohol solution to prepare a hydrazone of the formula (4).

In addition, the method of the present invention is a first step of preparing a hydrazone of the formula (4) by reacting 4-hydrazinobenzene methanesulfonamide hydrochloride and 2,3-dihydrofuran in an aqueous alcohol solution of the hydrazone of the formula (4) The second step of preparing a hydroxy indole compound of the formula (3) by adding an aqueous solution of phosphoric acid to the ethyl acetate solution, and by reacting the hydroxy indole compound of the formula (3) and dimethylamine of the formula (2), the compound of the formula It is preferable to include a third step of preparing a.

Hereinafter, the present invention will be described in detail.

The present invention is characterized in that it provides a method for preparing sumatriptan, which is easily synthesized using a commercially available reagent compared to the conventional methods, and is suitable for mass production with high purity.

The present invention can be prepared in the sumatriptan of the formula (1) using 4-hydrazinobenzene methanesulfonamide hydrochloride (V) as a starting material according to Scheme 7.

Scheme 7

In the reaction scheme, the first step reaction is used to produce a hydrazone compound (IV) using 2,3-dihydrofuran (VI) in an aqueous solution of alcohol using 4-hydrazinobenzene methanesulfonamide hydrochloride (V) as a starting material. It's a step. The resulting hydrazone compound can be used directly in the next step without purification.

The reaction temperature of the first step is 0 to 50 ℃, preferably 10 to 30 ℃, the reaction time is 1 to 10 hours, preferably 2 to 5 hours. Dihydrofuran is used in the amount of 1 to 4 equivalents based on the starting material, and preferably 1 to 2 equivalents.

In addition, in the second step reaction, an aqueous phosphate solution is added to the ethyl acetate solution of hydrazone (IV) to reflux to produce the hydroxyindole compound (III).

The reaction temperature of the second step is 50 to 100 ℃, preferably 60 to 80 ℃, the reaction time is 1 to 8 hours, preferably 2 to 5 hours. In addition, the volume ratio of ethyl acetate and the aqueous solution of phosphoric acid is 1: 1 to 20: 1, preferably mixed at a ratio of 2: 1 to 5: 1.

In the present invention, the third step of the reaction is characterized in that the reaction proceeds by adding a dimethylamine (II) and a catalyst to hydroxy indole (III) in the presence of hydrogen gas, high purity and high yield of the desired sumatriptan through this step Can be obtained.

The reaction temperature of the third step is 60 to 250 ° C, preferably 120 to 160 ° C. The pressure of the hydrogen gas is 1 to 5 atmospheres, preferably 1 to 2 atmospheres.

The dimethylamine is used in the amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, based on 1 equivalent of the hydroxy indole compound.

The catalyst may be used by appropriately mixing one or more kinds of cuprous oxide, chromium oxide, alumina, silica and the like. For example, the catalyst may use only cuprous oxide, or may be used by mixing cuprous oxide and another catalyst together. More preferably, the catalyst is 25 to 60 parts by weight of cuprous oxide, 0 to 1 parts by weight of chromium oxide, 0 to 40 parts by weight of alumina, and 0 to 70 parts by weight of silica in a weight ratio to hydroxy indole (III). Preference is given to using%.

The present invention provides a method capable of producing a large amount of sumatriptan, which is used as a migraine treatment agent in high purity and high yield in a simpler and more economical manner by reducing the steps of the reaction and the amount of reagents, thereby simplifying the process.

Hereinafter, preferred embodiments of the present invention will be described. However, the following examples are only preferred embodiments of the present invention, and the present invention is not limited to the following examples.

Example 1

To a solution of 0.3 g of methanol and 0.25 L of water was added to 30 g of 4-hydrazinobenzene methanesulfonamide hydrochloride (I), and 10 g of 2,3-dihydrofuran (II) 0.06 L of 10 g of 2,3-dihydrofuran (II) was prepared. The aqueous solution was added dropwise for 5 minutes. After the reaction solution was stirred at 15 ° C. for 3 hours, the pH was adjusted to 10 using an aqueous 33% sodium hydroxide solution. The solvent was removed under reduced pressure, hydrazone (III) was extracted with 0.5 L of ethyl acetate and washed several times with water. The ethyl acetate solution of the extracted hydrazone was used as it is in the next step without further purification.

Example 2

A solution of phosphoric acid (50 g) and water (20 mL) was added while slowly heating the ethyl acetate solution of hydrazone (III), the product of Example 1 above. After refluxing this reaction liquid over 4 hours, it cooled to normal temperature. The phosphoric acid layer of the reaction solution was removed and washed with water. After extraction with ethyl acetate, 12 g of hydroxy indole (IV) was obtained through reduced pressure distillation of the solvent. This compound was used as is in the next step without further purification.

¹ H NMR (DMSO-d ₆ ) δ 10.85 (s, 1H), 7.55 (s, 1H), 7.31 (d, 1H), 7.16 (s, 1H), 7.07 (d, 1H), 6.78 (s, 1H ), 4.34 (s, 2H), 3.65 (m, 2H), 2.86 (t, 2H), 2.54 (s, 3H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 128.0, 124.3, 124.0, 121.4, 120.0, 112.2, 111.6, 62.3, 57.1, 29.5, 29.4.

Example 3

A catalyst made by mixing 1.05 g of cuprous oxide, 0.042 g of chromium oxide, and 2.94 g of silica was added to 10 ml of dimethylamine (50% aqueous solution) in an aqueous solution of 4.2 g of hydroxy indole (IV) which is the product of Example 2, Hydrogen was replaced to 1 atm and heated to 120 ° C. for 8 hours. The reaction solution was cooled, filtered and washed with methanol. The solvent of this liquid was distilled under reduced pressure, and it extracted with ethyl acetate. Activated carbon was added to this organic layer, and the mixture was stirred at room temperature for 1 hour, and then the celite was filtered and concentrated under reduced pressure to obtain a white solid. This was recrystallized with acetone to obtain 1.5 g of pure sumatriptan (VI) crystals (purity 98.4%).

¹ H NMR (DMSO-d ₆ ) δ 10.83 (s, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.24, 1H), 7.16 (d, J = 2.20, 1H), 7.07 (dd, J = 8.34, 1.54, 1H), 6.79 (s, J = 4.76, 1H), 4.34 (s, 2H), 2.80 (dd, 2H), 2.52 (m, 2H + 3H), 2.55 (s, 3H), 2.21 (s, 6 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 127.8, 124.3, 123.7, 121.3, 120.2, 113.2, 111.7, 60.6, 57.1, 45.7, 29.5, 23.6.

Example 4

To 250 g of 4-hydrazinobenzene methanesulfonamide hydrochloride (I), 2.5 L of ethanol and 2 L of water were prepared, and 82.5 g of 2,3-dihydrofuran (II) 0.5 L of ethanol at 15 ° C was prepared. An aqueous solution of was added dropwise for 20 minutes. After the reaction solution was stirred at 25 ° C. for 1 hour, the pH was adjusted to 10 using an aqueous 33% sodium hydroxide solution. The solvent was removed under reduced pressure, hydrazone (III) was extracted with 4 L of ethyl acetate and washed several times with water. The ethyl acetate solution of the extracted hydrazone was used as it is in the next step without further purification.

≪ Example 5 >

A solution of phosphoric acid (400 g) and water (150 mL) was added while slowly heating the ethyl acetate solution of hydrazone (III), the product of Example 4. The reaction solution was refluxed for 3 hours and then cooled to room temperature. The phosphoric acid layer of the reaction solution was removed and washed with water. After extraction with ethyl acetate, 115 g of hydroxy indole (IV) was obtained through reduced pressure distillation of the solvent. This compound was used as is in the next step without further purification.

¹ H NMR (DMSO-d ₆ ) δ 10.85 (s, 1H), 7.55 (s, 1H), 7.31 (d, 1H), 7.16 (s, 1H), 7.07 (d, 1H), 6.78 (s, 1H ), 4.34 (s, 2H), 3.65 (m, 2H), 2.86 (t, 2H), 2.54 (s, 3H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 128.0, 124.3, 124.0, 121.4, 120.0, 112.2, 111.6, 62.3, 57.1, 29.5, 29.4.

Example 6

A catalyst made by mixing 12 g of cuprous oxide and 8 g of alumina was added to 70 ml of dimethylamine (2 M THF solution) in an aqueous solution of 20 g of hydroxy indole (IV), which is the product of Example 5, and then replaced with hydrogen to 1 atm. And heated to 150 ° C. for 4 h. The reaction solution was cooled, filtered and washed with methanol. The solvent of this liquid was distilled under reduced pressure, and it extracted with ethyl acetate. Activated carbon was added to the organic layer, and the mixture was stirred at room temperature for 1 hour, filtered through celite, and concentrated under reduced pressure to obtain an off-white solid. This was recrystallized with acetone to obtain 11 g of pure sumatriptan (VI) crystals. (99.6% purity)

¹ H NMR (DMSO-d ₆ ) δ 10.83 (s, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.24, 1H), 7.16 (d, J = 2.20, 1H), 7.07 (dd, J = 8.34, 1.54, 1H), 6.79 (s, J = 4.76, 1H), 4.34 (s, 2H), 2.80 (dd, 2H), 2.52 (m, 2H + 3H), 2.55 (s, 3H), 2.21 (s, 6 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 127.8, 124.3, 123.7, 121.3, 120.2, 113.2, 111.7, 60.6, 57.1, 45.7, 29.5, 23.6.

Example 7

A catalyst in which 12 g of cuprous oxide was added to 50 ml of dimethylamine (50% aqueous solution) was added to an aqueous solution of 20 g of hydroxy indole (IV) which is the product of Example 5, and then hydrogen was replaced with 2 atm. Heated for 8 hours. The reaction solution was cooled, filtered and washed with methanol. The solvent of this liquid was distilled under reduced pressure, and it extracted with ethyl acetate. Activated carbon was added to the organic layer, and the mixture was stirred at room temperature for 1 hour, filtered through celite, and concentrated under reduced pressure to obtain a white solid. This was recrystallized with acetone to obtain 12.2 g of pure sumatriptan (VI) crystals. (97.2% purity)

¹ H NMR (DMSO-d ₆ ) δ 10.83 (s, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.24, 1H), 7.16 (d, J = 2.20, 1H), 7.07 (dd, J = 8.34, 1.54, 1H), 6.79 (s, J = 4.76, 1H), 4.34 (s, 2H), 2.80 (dd, 2H), 2.52 (m, 2H + 3H), 2.55 (s, 3H), 2.21 (s, 6 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 127.8, 124.3, 123.7, 121.3, 120.2, 113.2, 111.7, 60.6, 57.1, 45.7, 29.5, 23.6

Example 8

A catalyst made by mixing 5 g of cuprous oxide, 0.2 g of chromium oxide, and 2 g of silica was added to 50 ml of dimethylamine (50% aqueous solution) in an aqueous solution of 20 g of hydroxy indole (IV) which is the product of Example 5, and then hydrogen was substituted. To 1 atm and heated to 160 ° C. for 5 hours. The reaction solution was cooled, filtered and washed with methanol. The solvent of this liquid was distilled under reduced pressure, and it extracted with ethyl acetate. Activated carbon was added to the organic layer, and the mixture was stirred at room temperature for 1 hour, filtered through celite, and concentrated under reduced pressure to obtain an off-white solid. This was recrystallized with acetone to obtain 10.5 g of pure sumatriptan (VI) crystals. (Pure 98.1%)

¹ H NMR (DMSO-d ₆ ) δ 10.83 (s, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.24, 1H), 7.16 (d, J = 2.20, 1H), 7.07 (dd, J = 8.34, 1.54, 1H), 6.79 (s, J = 4.76, 1H), 4.34 (s, 2H), 2.80 (dd, 2H), 2.52 (m, 2H + 3H), 2.55 (s, 3H), 2.21 (s, 6 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 127.8, 124.3, 123.7, 121.3, 120.2, 113.2, 111.7, 60.6, 57.1, 45.7, 29.5, 23.6

Example 9

A catalyst made by mixing 6 g of cuprous oxide, 0.2 g of chromium oxide, 2 g of alumina, and 4 g of silica was added to 70 mL of dimethylamine (2M THF solution) in an aqueous solution of 20 g of hydroxy indole (IV) which is the product of Example 5, Hydrogen was replaced to 1 atm and heated to 150 ° C. for 4 hours. The reaction solution was cooled, filtered and washed with methanol. The solvent of this liquid was distilled under reduced pressure, and it extracted with ethyl acetate. Activated carbon was added to the organic layer, and the mixture was stirred at room temperature for 1 hour, filtered through celite, and concentrated under reduced pressure to obtain an off-white solid. This was recrystallized with acetone to obtain 12.9 g of pure sumatriptan (VI) crystals. (98.4% purity)

¹ H NMR (DMSO-d ₆ ) δ 10.83 (s, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.24, 1H), 7.16 (d, J = 2.20, 1H), 7.07 (dd, J = 8.34, 1.54, 1H), 6.79 (s, J = 4.76, 1H), 4.34 (s, 2H), 2.80 (dd, 2H), 2.52 (m, 2H + 3H), 2.55 (s, 3H), 2.21 (s, 6 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 127.8, 124.3, 123.7, 121.3, 120.2, 113.2, 111.7, 60.6, 57.1, 45.7, 29.5, 23.6

Comparative Example 1

3 g of triethylamine was added to a THF (100 mL) solution of 4 g of hydroxy indole (IV), which is the product of Example 5, and then 2.4 g of methanesulfonyl chloride was added dropwise at 0 ° C. After stirring at 0 ° C. for 1 hour, an aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and washed with water. After concentration of the solvent under reduced pressure, 4.2 g of indole mesylate (VII) was obtained.

¹ H NMR (DMSO-d ₆ ) δ 11.1 (s, 1H), 7.5 (s, 1H), 7.35 (d, 1H), 7.28 (s, 1H), 7.12 (d, 1H), 6.81 (s, 1H ), 4.35 (s, 2 H), 3.8-2.3 (m, 10 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.3, 127.5, 124.7, 124.5, 121.1, 120.6, 111.8, 109.6, 70.6, 56.9, 46.2, 37.2, 29.5, 25.4.

Comparative Example 2

To 4.2 g of indole mesylate (VII) which is the product of Comparative Example 1, 50 mL of acetonitrile, 2.4 g of sodium iodide, 2.1 g of diisopropylamine and 18 mL of dimethylamine (2M THF solution) were added and heated to 70 ° C. After the reaction was completed, the mixture was concentrated under reduced pressure, ethyl acetate and 10% aqueous potassium carbonate solution were added, and the mixture was washed with water. Activated carbon was added to the extracted organic layer, stirred at room temperature for 1 hour, and then filtered through celite, concentrated under reduced pressure, concentrated under reduced pressure, and then recrystallized with acetone to obtain 1.4 g of desired sumatriptan (VI) crystals. (96.6% purity)

¹ H NMR (DMSO-d ₆ ) δ 10.83 (s, 1H), 7.50 (s, 1H), 7.31 (d, J = 8.24, 1H), 7.16 (d, J = 2.20, 1H), 7.07 (dd, J = 8.34, 1.54, 1H), 6.79 (s, J = 4.76, 1H), 4.34 (s, 2H), 2.80 (dd, 2H), 2.52 (m, 2H + 3H), 2.55 (s, 3H), 2.21 (s, 6 H).

¹³ C NMR (DMSO-d ₆ ) δ 136.4, 127.8, 124.3, 123.7, 121.3, 120.2, 113.2, 111.7, 60.6, 57.1, 45.7, 29.5, 23.6

According to the method of the present invention, it is possible to economically mass-produce sumatriptan used as a migraine treatment.

Claims (8)

A method for preparing sumatriptan comprising the step of reacting a hydroxy indole compound represented by the following Chemical Formula 3 with a dimethylamine represented by the following Chemical Formula 2 to prepare a compound represented by the following Chemical Formula 1. [Formula 1]

[Formula 2] (CH ₃ ) ₂ NH (3)

The method of claim 1, wherein the reaction proceeds by adding a catalyst in the presence of a hydrogen gas. The method of claim 2, wherein the pressure of the hydrogen gas is 1 to 5 atmospheres. The method of claim 2, wherein the catalyst is at least one selected from cuprous oxide, chromium oxide, alumina, and silica. According to claim 2, wherein the catalyst is 25 to 60 parts by weight of cuprous oxide, 0 to 1 parts by weight of chromium oxide, 0 to 40 parts by weight of alumina and silica 0 by weight to the hydroxy indole compound represented by the formula (3) To 70 parts by weight, including the sumatriptan. The method of claim 1, wherein the dimethylamine is used in an amount of 1 to 5 equivalents based on 1 equivalent of the hydroxy indole compound. According to claim 1, The method further comprises the step of preparing a hydroxy indole compound of the formula (3) by reflux by adding an aqueous solution of phosphoric acid to the ethyl acetate solution of the hydrazone of the formula (4), the sumatriptan. [Formula 4]

The method of claim 7, wherein the method further comprises the step of reacting 4-hydrazinobenzene methanesulfonamide hydrochloride with 2,3-dihydrofuran in an aqueous alcohol solution to prepare a hydrazone of Formula 4, sumatriptan Manufacturing method.