KR101127814B1 - Novel intermediate and process for preparing sildenafil or its salt using the same - Google Patents

Abstract

PURPOSE: A novel imine intermediates and a method for preparing sildenafil are provided to obtain a large amount of sildenafil under a mild condition. CONSTITUTION: A method for preparing a compound of chemical formula 1 comprises: a step of preparing a compound of chemical formula 3 from a compound of chemical formula 2; a step of reacting the compound of chemical formula 3 with chlorosulfonic acid or chlorosulfonic acid and thionyl chloride to obtain a compound of chemical formula 4; and a step of reacting the compound of chemical formula 4 with methyl piperazine under the presence of base.

Description

Novel intermediate and process for preparing sildenafil or its salt using the same}

The present invention relates to novel intermediates useful for the production of sildenafil, methods for their preparation, and methods for producing sildenafil using the same.

Sildenafil is a drug used to treat erectile dysfunction in men, and its chemical name is 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3- n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7one and has the structure of Formula 1. Sildenafil may be in the form of a pharmaceutically acceptable salt, such as citrate, and is used in the form of citrate in the clinic.

<Formula 1>

Sildenafil and its preparation were first described in EP 0463756 as a useful drug for treating hypertension. The method for preparing sildenafil disclosed in EP 0463756 is shown in Scheme 1 below.

<Scheme 1>

However, the production process according to EP 0463756 has a low reaction yield (about 23%) and has a disadvantage in that it is not suitable for mass production on an industrial scale since the purification process by chromatography must be performed during the reaction.

As a manufacturing method for improving such a problem, Korean Patent Registration No. 10-0207352 discloses a manufacturing method as in Scheme 2 below.

<Scheme 2>

The preparation method according to Scheme 2 removes the chromatographic purification process, but the process of step 3 has to carry out the long-term process for three days, and the yield is about 44%, which is still limited in industrial scale mass production. .

In addition, WO2001 / 22918 discloses a method for preparing sildenafil via an imine intermediate, as shown in Scheme 3 below.

<Scheme 3>

In the preparation method according to Scheme 3, in order to introduce chlorosulfone groups into ethoxybenzaldehyde, an aldehyde is prepared as an intermediate in the form of diethylacetal (first step), and then chlorosulfone groups are introduced (second step), After reacting with methyl piperazine (third step), an imine intermediate is formed (fourth step), and then cyclization reaction (fifth step) to produce sildenafil. The manufacturing method was removed the chromatographic purification process, the lack of the reaction process takes a long time to improve the manufacturing process, but the reaction yield is only about 53%, there is still a limitation in mass production on an industrial scale.

The present invention provides a method for preparing sildenafil or a pharmaceutically acceptable salt thereof via a novel intermediate, which can avoid the chromatographic purification step and the long-term reaction step in the whole process, and can perform the reaction under mild conditions, Provided are methods for preparing sildenafil or a pharmaceutically acceptable salt thereof suitable for industrial scale mass production. In particular, the present invention provides a process by which sildenafil or a pharmaceutically acceptable salt thereof can be produced in high yield and purity by way of a novel intermediate.

It is therefore an object of the present invention to provide a process for preparing sildenafil or a pharmaceutically acceptable salt thereof via a novel intermediate.

It is also an object of the present invention to provide the novel intermediates and methods for their preparation.

According to one aspect of the present invention, there is provided a process for preparing a compound of formula 3, comprising reacting a compound of formula 2 with sodium hydrogen sulfite:

<Formula 2>

<Formula 3>

According to another aspect of the invention, (a) preparing a compound of formula (3) from a compound of formula (2), (b) a compound of formula (3) chlorosulfonic acid; Or reacting with chlorosulfonic acid and thionyl chloride to prepare a compound of formula 4, (c) reacting the compound of formula 4 with methylpiperazine in the presence of a base to produce a compound of formula 1 (sildenafil), And optionally (d) converting the compound of formula 1 (sildenafil) to a pharmaceutically acceptable salt thereof, a method for preparing sildenafil or a pharmaceutically acceptable salt thereof:

<Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

According to another aspect of the invention, there is provided a compound of formula 2 useful as an intermediate in the manufacture of sildenafil:

<Formula 2>

According to another aspect of the present invention, there is provided a process for preparing a compound of formula 2, comprising reacting a compound of formula 5 with a compound of formula 6

<Formula 2>

<Formula 5>

<Formula 6>

According to the present invention, when preparing sildenafil or a pharmaceutically acceptable salt thereof via a novel intermediate (ie, a compound of formula 2), sildenafil from the starting material (2-ethoxybenzaldehyde, a compound of formula 5) It can be prepared pure (with HPLC purity of at least 99.9%) with a high yield of about 78%. In addition, the production method according to the present invention can avoid the chromatographic purification step and the long-term reaction step in the whole process, and can be performed in a mild condition, it is very suitable for mass production on an industrial scale.

The present inventors analyzed various reaction processes in order to identify the cause of the low reaction yield of the production method according to WO2001 / 22918 (see Scheme 3 above). In the preparation method according to Scheme 3, in order to introduce chlorosulfone groups into ethoxybenzaldehyde, an aldehyde is prepared as an intermediate in the form of diethylacetal (first step), and then chlorosulfone group is introduced (second step), and then methyl After reacting with piperazine (third step), an imine intermediate is formed (fourth step), and then cyclization reaction (fifth step) to produce sildenafil. The respective yields in the first to fifth steps were 84% (first step), 78% (second step), 95% (third step), 95% (fourth step), and 90% (second) 5 step), the yield was greatly reduced in the first step and the second step. As a result of various analyzes on the cause of the yield decrease, a loss occurs in the distillation under reduced pressure carried out to obtain the acetal intermediate produced in the first step, the acetal intermediate is unstable and there is a storage problem. In addition, in the process of reacting chlorosulfonic acid in the second process and adding water to form a precipitate, it was found that the aldehyde group also produced a decomposition product in an acidic aqueous solution, which greatly reduced the yield.

Based on the results of this analysis, the inventors have designed a new manufacturing method that can avoid the reaction with chlorosulfonic acid in the synthesis of acetal intermediates and in the presence of aldehyde groups. In other words, the inventors of the present invention, when synthesized directly from the ethoxybenzaldehyde to the new intermediate, the imine intermediate, cyclization reaction, chlorosulfonic acid, and then reacted with methyl piperazine, surprisingly all the processes over 90% It was found that it can be carried out in the reaction yield. Thus, the preparation method according to the invention can produce sildenafil or a pharmaceutically acceptable salt thereof from a starting material (2-ethoxybenzaldehyde) in a high yield of about 78%. In addition, the production method of the present invention can avoid the chromatographic purification process and the reaction process for a long time in the whole process, each process can be carried out under mild conditions, it is very suitable for mass production on an industrial scale.

Reaction scheme of the method for preparing sildenafil or a pharmaceutically acceptable salt thereof according to the preparation method of the present invention is shown in Scheme 4 below.

<Scheme 4>

The present invention provides a method for preparing a compound of Formula 3, comprising reacting a novel intermediate compound of Formula 2 with sodium hydrogen sulfite, wherein the compound of Formula 2 is a compound of Formula 5 and a It can obtain by making the compound of 6 react. The present invention also provides a method for preparing sildenafil or a pharmaceutically acceptable salt thereof (preferably citrate) thereof from the compound of Formula 3 prepared by the above method.

Hereinafter, each manufacturing process is explained in full detail.

Novel compounds of formula (2) can be prepared by reacting a compound of formula (5) with a compound of formula (6). Thus, according to one aspect of the invention the compound of formula (2); And it provides a method for producing a compound of Formula 2 comprising reacting the compound of Formula 5 with the compound of Formula 6.

The compound of Formula 5 (ie, 2-ethoxybenzaldehyde) may be purchased commercially as a known material, and the compound of Formula 6 may also be prepared according to a known production method (for example, EP 0463756) as a known compound. have.

The reaction of the compound of formula 5 with the compound of formula 6 is carried out by using at least one organic solvent such as toluene, xylene, chlorobenzene, diphenyl ether, methylene chloride, chloroform, carbon tetrachloride, and dichloroethane. It may be carried out in a selected organic solvent, preferably in toluene. The reaction can be carried out under the conditions of the warming used (eg about 40-80 ° C.) or at the reflux temperature of the solvent used. It may also be carried out under pressure as necessary. The reaction time is not particularly limited, and may be performed, for example, for 1.5 hours to 5 hours.

The reaction product of the compound of Formula 5 and the compound of Formula 6 may be separated in high purity and high yield without performing a separate purification process. That is, by simply performing cooling, filtration, washing, and drying processes of the reaction mixture, the compound of formula 2 can be prepared in high purity (at least 99.8% HPLC purity) and high yield (at least 95%). Cooling of the reaction mixture can be carried out, for example, in the range of 0 ~ 10 ℃. The washing process may be performed using, for example, an organic solvent such as hexane. In addition, the drying process may be performed using a conventional vacuum drying process.

The present invention also provides a method for preparing a compound of Formula 3, comprising reacting a compound of Formula 2 with sodium hydrogen sulfite.

The reaction of the compound of Formula 2 with sodium hydrogen sulfite is one or more solvents selected from dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, and dimethylacetamide, preferably dimethylacetamide. To 160 ° C, 90 to 110 ° C. The reaction is preferably to use an excess of sodium hydrogen sulfite with respect to the compound of formula (2), specifically, by adding sodium hydrogen sulfite in a ratio of 1.5 to 4 equivalents to 1 equivalent of compound of formula (2) It is preferable.

In particular, the reaction of the compound of Formula 2 with sodium hydrogen sulfite can be added to the compound of Formula 2 in a stepwise manner to reduce side reactions as well as to obtain a high yield of the product. It turns out that there is. That is, the reaction between the compound of Formula 2 and sodium hydrogen sulfite is 0.5 to 1 equivalents (for example, 0.5 equivalents) of sodium hydrogen sulfite at 1-2 hour intervals (for example, 1.5 hour intervals). Particularly preferably, stepwise addition to the compound of formula (2).

The reaction product of the compound of formula 2 and sodium hydrogen sulfite can be separated by cooling the reaction mixture to about 30-50 ° C., filtering off excess sodium hydrogen sulfite, and then concentrating the filtrate under reduced pressure. have. If desired, it is preferable to add some methylene chloride to dissolve some of the precipitated solids before performing the process of removing the sodium hydrogen sulfite (ie, by filtration). In addition, if necessary, the filtrate from which the sodium hydrogen sulfite is removed may be washed one or more times with water. The separated reaction product, ie the compound of formula 3, can also be purified using a mixed solvent of methylene chloride and acetone.

From the reaction of the compound of formula 2 with sodium hydrogen sulfite, the compound of formula 3 can be prepared in high purity (at least 99.8% HPLC purity) and high yield (at least 94%).

The present invention also provides a process for preparing sildenafil or a pharmaceutically acceptable salt thereof from the novel intermediates described above. That is, the present invention (a) preparing a compound of formula 3 from the compound of formula (2), (b) the compound of formula (3) chlorosulfonic acid; Or reacting with chlorosulfonic acid and thionyl chloride to prepare a compound of formula 4, (c) reacting the compound of formula 4 with methylpiperazine in the presence of a base to produce a compound of formula 1 (sildenafil), And optionally (d) converting the compound of formula 1 (sildenafil) into a pharmaceutically acceptable salt thereof.

Step (a) is a reaction of the compound of formula 2 with sodium hydrogen sulfite, which may be carried out as described above.

Step (b) adds a compound of formula 3 to chlorosulfonic acid to perform the reaction; Alternatively, the compound of formula 3 may be added to chlorosulfonic acid, and thionyl chloride may be added to carry out the reaction. The reaction of the compound of Formula 3 with chlorosulfonic acid is slowly added dropwise to the compound of Formula 3 at a temperature of -5 to 5 ℃ to chlorosulfonic acid, stirred for about 2 hours, and then 3 hours at 15 to 20 ℃ Preferably by stirring for 24 hours. Alternatively, the compound of Formula 3 may be slurried in methylene chloride, followed by dropwise addition of 5 to 10 equivalents of chlorosulfonic acid at about −5 ° C., and then refluxed at room temperature for 6 hours. In addition, after completion of the dropwise addition, an equivalent of thionyl chloride may be further added to carry out the reaction. After completion of the reaction, methylene chloride was added at -5 ° C, quenched by adding ice (ie, after the reactivity of chlorosulfonic acid was extinguished), and the organic layer was separated and concentrated to obtain a compound of formula (4). If necessary, the obtained compound of formula 4 may be purified using a mixed solvent of methylene chloride and ethyl acetate or a mixed solvent of methylene chloride and acetone. From the reaction of step (b), the compound of formula 4 can be prepared in high yield (at least 92%).

Step (c) may be carried out by reacting the compound of formula 4 with methylpiperazine in the presence of a base. The reaction may be carried out in an organic solvent such as methylene chloride, and the base may use a conventional organic base such as triethylamine. The reaction can be carried out at room temperature or at 10-25 ° C. The obtained product, ie, sildenafil (compound of Formula 1), can be separated by adding water, separating the organic layer, and concentrating it under reduced pressure. If necessary, the obtained compound of formula 1 may be recrystallized using a mixed solvent of methylene chloride and ethyl acetate. From the reaction of step (c), the compound of formula 1 (ie sildenafil) can be prepared in high purity (at least 99.8% HPLC purity) and in high yield (at least 94%).

The sildenafil obtained as above (i.e. compound of formula 1) may be converted to its pharmaceutically acceptable salt, preferably citrate according to conventional methods (i.e. step (d)). Citric acid (about 1) was dissolved in a solvent such as methanol, ethanol, acetone, acetonitrile, preferably methanol, and then dissolved in a suitable solvent (e.g., methanol, acetone, water and the like, preferably methanol). 0.995 equivalents) can be added and then converted to citrate by reaction under heating (for example, about 40-80 ° C., more preferably 55-65 ° C.) for 1 to 3 hours. When the reaction is carried out in a mixed solvent of a solvent and water, for example, a mixed solvent of ethanol and water, or a mixed solvent of acetonitrile and water, the reaction may be performed in a completely dissolved state. The mixed solvent of and the mixed solvent of acetonitrile and water are preferably a mixed solvent having a volume ratio of 1: 0.1 to 0.2.The obtained citrate is cooled to room temperature, slurried at 5 to 10 ° C. if necessary, and then filtered. And drying.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are intended to illustrate the invention and not to limit the invention.

In the following examples, melting points were measured using MPA100 / SRS (SRS; Stanford Research Systems) equipment, and HPLC purity analysis was performed using Waters HPLC. All ¹ H-NMR spectra were measured using a Varian FT-NMR (Varian, 400 MHz) instrument.

Example 1. Preparation of 5-propyl-4-{[2-ethoxy-benzylidene] amino} -2-methyl-2H-pyrazole-3-carboxamide (compound of formula 2)

5-propyl-4-amino-2-methyl-2H-pyrazole-3-carboxamide (100.0 g) was slurried in toluene (400 mL). While stirring at room temperature, a solution of 2-ethoxybenzaldehyde (90.6 g, 1.1 equiv) dissolved in toluene (100 mL) was added. The temperature of the reaction mixture was gradually raised to 60 ° C. and stirred for 4 hours while maintaining the same temperature. The reaction mixture was slowly cooled to rt, again to 5 ° C. and stirred for 2 h. The reaction mixture was filtered under reduced pressure to separate the solid. The obtained solid was washed with hexane (100 ml) and dried under reduced pressure at 70 ° C. for 12 hours to give 163.9 g (95.0%) of the title compound.

Melting Point: 147.9 ~ 148.9 ℃

HPLC purity: 99.80%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm); 0.92 (t. 3 H); 1.43 (t. 3 H); 1.72 (h. 2 H); 2.70 (t. 2 H); 4.08-4.13 (q. 2 H); 4.17 (s. 3 H); 6.91-6.93 (d. 1 H); 7.01 (t. 1 H); 7.42 (t. 1 H); 7.92 (d. 1 H); 8.76 (broad peak); 9.02 (s. 1 H)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm); 0.95 (t. 3 H); 1.36 (t. 3 H); 1.72 (h. 2 H); 2.62 (t. 2 H); 4.01 (s. 3 H); 4.13 (q. 2 H); 7.05 (t. 1 H); 7.14 (d. 1 H); 7.47 (m. 1 H); 7.76 (br s. 1 H); 7.88 (dd. 1 H); 8.15 (br s. 1 H); 8.92 (s. 1 H)

Example 2. 5- (2-Ethoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo- [4,3-d] pyrimidin-7-one ( Preparation of the compound of formula 3

5-propyl-4-{[2-ethoxy-benzylidene] amino} -2-methyl-2H-pyrazole-3-carboxamide (compound of formula 2) (60.0 g) obtained in Example 1 was dimethyl. Slurry in acetamide (180 mL), slowly warm to complete dissolution. When the mixture was further heated to reach an internal temperature of 90 ° C., sodium hydrogen sulfite (15.3 g, 0.5 equivalents) was added thereto, followed by further warming and reaction at an internal temperature of about 105 ° C. for 1.5 hours. While maintaining the temperature of the reaction mixture at about 105 ℃, 0.5 equivalents of sodium hydrogen sulfite were added at intervals of 1.5 hours, a total of 3 equivalents was added, followed by stirring for 12 hours. The reaction mixture was cooled to about 50 ° C., methylene chloride (360 mL) was added, stirred at 30 ° C. for 0.5 h and then filtered under reduced pressure. The solid and the reaction vessel were washed with methylene chloride (180 mL) to remove excess sodium hydrogen sulfite, and then the filtrate was washed with purified water (180 mL, 4 times). The obtained organic layer was concentrated under reduced pressure to obtain a solid. This solid was added to a mixed solvent of methylene chloride (60 mL) and acetone (300 mL), heated to 35 ° C., stirred for 1 hour, and then stirred at 5 ° C. for 2 hours. The reaction mixture was filtered under reduced pressure and the solid obtained was dried under reduced pressure at 50 ° C. for 12 hours to obtain 56.1 g (94.1%) of the title compound.

Melting Point: 144 ～ 146 ℃

HPLC purity: 99.82%

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm); 1.01 (t. 3 H); 1.57 (t. 3 H); 1.78-1.89 (m. 2H); 2.90 (t. 2 H); 4.22-4.27 (m. 5 H); 6.98-7.00 (d. 1 H); 7.08-7. 12 (m. 1 H); 7.38-7.43 (m. 1 H); 8.43 (d. 1 H); 11.10 (broad peak).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm); 0.91 (t. 3 H); 1.31 (t. 3 H); 1.72 (h. 2 H); 2.75 (t. 2 H); 4.10 (q. 5 H); 4.13 (s. 3 H); 7.04 (t. 1 H); 7.12 (d. 1 H); 7.44-7.47 (m. 1 H); 7.63 (dd. 1 H); 11.95 (br s. 1 H).

Example 3. 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine Preparation of -7-one (Compound of Formula 4)

5- (2-Ethoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo- [4,3-d] pyrimidin-7-one obtained in Example 2 (50.0 g) was added dropwise to chlorosulfonic acid (100 mL) cooled to about -5 ° C. After completion of the dropwise addition, the same temperature was maintained for 2 hours, and then stirred at about 20 ° C for 8 hours. Methylene chloride (200 mL) was added to the reaction mixture, which was then cooled to -10 ° C., followed by a small amount of crushed ice (50 g), followed by addition of ice water (200 mL) and methylene chloride (100 mL). The organic layer was separated, washed with purified water (200 mL, 4 times), and then concentrated under reduced pressure. A mixed solvent of methylene chloride (35 mL) and ethyl acetate (500 mL) was added to the obtained solid, and the mixture was warmed to 60 ° C., and then cooled slowly to room temperature to precipitate a precipitate. The reaction mixture was slurried at 5 ° C. for 2 hours and then filtered under reduced pressure. The resulting solid was dried under reduced pressure at 50 ° C. for 12 hours to give 60.7 g (92.3%) of the title compound.

Melting Point: 180 ~ 181 ℃

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm); 0.92 (t. 3 H); 1.30 (t. 3 H); 1.71 (h. 2 H); 2.77 (t. 2 H); 4.11 (q. 2 H); 4.14 (s. 3 H); 7.07 (d. 1 H); 7.67 (dd. 1 H); 7.83 (d. 1 H).

Example 4. 5- [2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo Preparation of [4,3-d] pyrimidin-7one (Compound 1, Sildenafil)

5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrid obtained in Example 3 Midin-7-one (compound of formula 4) (30.0 g) was slurried in methylene chloride (300 mL). Methylpiperazine (7.3 g) and triethylamine (7.4 g) were dissolved in methylene chloride (150 mL), and then slowly added to the slurry while stirring at 5 ° C., followed by further stirring at temperature for 4 hours. The reaction mixture was washed with purified water (200 mL, twice), and then the organic layer was separated and concentrated under reduced pressure. A mixed solvent of methylene chloride (20 mL) and ethyl acetate (150 mL) was added to the obtained solid, and the mixture was warmed to 60 ° C., and then slowly cooled to room temperature to form a precipitate. The reaction mixture was slurried at 5 ° C. for 2 hours and then filtered under reduced pressure. The resulting solid was dried under reduced pressure at 50 ° C. for 12 hours to give 32.6 g (94.1%) of the title compound.

HPLC purity: 99.80%

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm); 0.91 (t. 3 H); 1.30 (t. 3 H); 1.71 (h. 2 H); 2.12 (s. 3 H); 2.34 (br s. 4H); 2.75 (t. 2 H); 2.87 (br s. 4 H); 4.14 (s. 3 H); 4.18 (q. 2 H); 7.35 (d. 1 H); 7.79-7.81 (m. 2H); 12.22 (br s. 1 H).

Example 5 Preparation of Sildenafil Citrate

<Method 1>

Sildenafil (compound of Formula 1) (10.0 g) obtained in Example 4 was slurried in ethanol (150 mL), and then gradually warmed to completely dissolve it. A solution of citric acid (4.03 g, 0.995 equiv) in ethanol (50 mL) / purified water (10 mL) mixed solvent was slowly added to the solution. The reaction mixture was stirred at 60 ° C. for 2 hours and then slowly cooled to room temperature. The reaction mixture was slurried at 5 ° C. for 3 hours and then filtered under reduced pressure. The resulting solid was dried under reduced pressure at 50 ° C. for 12 hours to obtain 12.6 g (90.0%) of sildenafil citrate. (HPLC purity: 99.85%)

<Method 2>

Sildenafil (compound of Formula 1) (10.0 g) obtained in Example 4 was slurried in acetonitrile (150 mL), and then gradually warmed to completely dissolve it. A solution of citric acid (4.03 g, 0.995 equiv) in acetonitrile (50 mL) / purified water (30 mL) was slowly added to the solution. The reaction mixture was stirred at 65 ° C. for 2 hours and then slowly cooled to room temperature. The reaction mixture was slurried at 5 ° C. for 3 hours and then filtered under reduced pressure. The resulting solid was dried under reduced pressure at 50 ° C. for 12 hours to obtain 13.1 g (93.2%) of sildenafil citrate. (HPLC purity: 99.91%)

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm); 0.91 (t. 3 H); 1.30 (t. 3 H); 1.72 (h. 2 H); 2.12 (s. 3 H); 2.24 (br s. 4H); 2.51 (br s. 4H); 2.60 (d. 2 H); 2.69 (d. 2 H); 2.75 (t. 2 H); 2.93 (br s. 4H); 4.14 (s. 3 H); 4.19 (q. 2 H); 7.36 (d. 1 H); 7.80-7.83 (m. 2H); 12.23 (br s. 1 H).

XRD analysis results of the sildenafil citrate obtained are shown in Table 1 below. The XRD analysis was performed under the conditions of Scan range 3-80 ^o 2TH, Step Size 0.02 ^o 2TH, Scan Step Time 1.0s.

2θ Relative Strength (I / I ₀ )% 7.4381 44.65 8.1405 100.00 10.3621 84.58 14.0198 37.38 14.4824 56.71 14.8487 36.98 17.7868 40.70 19.9565 81.80 20.9468 31.31 22.7519 31.65 23.1376 47.45 28.5959 22.86

<Method 3>

Sildenafil (compound of Formula 1) (10.0 g) obtained in Example 4 was slurried in methanol (100 mL), and then gradually warmed to completely dissolve it. A solution of citric acid (4.03 g, 0.995 equiv) in methanol (50 mL) was slowly added to the solution. The reaction mixture was stirred at 55 ° C. for 2 hours and then slowly cooled to room temperature. The reaction mixture was slurried at 5 ° C. for 3 hours and then filtered under reduced pressure. The resulting solid was dried under reduced pressure at 50 ° C. for 12 hours to obtain 12.2 g (87.0%) of sildenafil citrate. (HPLC purity: 99.85%)

Claims (10)

A method for preparing a compound of Formula 3, comprising reacting a compound of Formula 2 with sodium hydrogen sulfite:
<Formula 2>

<Formula 3>

The method according to claim 1, wherein the reaction between the compound of Formula 2 and sodium hydrogen sulfite is performed by adding sodium hydrogen sulfite at a ratio of 1.5 to 4 equivalents to 1 equivalent of compound of Formula 2 Way. The method of claim 2, wherein the reaction between the compound of Formula 2 and sodium hydrogen sulfite is carried out by stepwise addition of sodium hydrogen sulfite to the compound of Formula 2 in 0.5 to 1 equivalents at 1-2 hour intervals. Manufacturing method. The method of claim 1, wherein the compound of Formula 2 is prepared by reacting a compound of Formula 5 with a compound of Formula 6.
&Lt; Formula 5 >

<Formula 6>

(a) preparing a compound of formula 3 from a compound of formula 2 according to any one of claims 1 to 4,
(b) chlorosulfonic acid; Or reacting with chlorosulfonic acid and thionyl chloride to prepare a compound of formula 4, and
(c) preparing a compound of formula 1 by reacting the compound of formula 4 with methylpiperazine in the presence of a base;
Method for preparing a compound of Formula 1, comprising:
<Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

(a) preparing a compound of formula 3 from a compound of formula 2 according to any one of claims 1 to 4,
(b) chlorosulfonic acid; Or reacting with chlorosulfonic acid and thionyl chloride to prepare a compound of formula 4,
(c) reacting the compound of Formula 4 with methylpiperazine in the presence of a base to prepare a compound of Formula 1, and
(d) converting the compound of Formula 1 into a pharmaceutically acceptable salt thereof
A method of preparing a pharmaceutically acceptable salt of a compound of Formula 1, comprising:
<Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

The method according to claim 6, wherein the pharmaceutically acceptable salt of the compound of Formula 1 is citrate, and step (d) reacts the compound of Formula 1 with citric acid in a mixed solvent of ethanol and water or a mixed solvent of acetonitrile and water. Method for producing characterized in that it is carried out. 8. A process according to claim 7, wherein step (d) is carried out in a mixed solvent of ethanol and water in a volume ratio of 1: 0.1 to 0.2 or a mixed solvent of acetonitrile and water in a volume ratio of 1: 0.1 to 0.2. delete delete