WO2014098410A1

WO2014098410A1 - Method for preparing bosentan monohydrate, novel intermediate used therefor, and method for preparing same

Info

Publication number: WO2014098410A1
Application number: PCT/KR2013/011488
Authority: WO
Inventors: 전종수; 이성룡; 김백중; 강석원
Original assignee: 제일약품주식회사
Priority date: 2012-12-20
Filing date: 2013-12-11
Publication date: 2014-06-26
Also published as: KR102004422B1; KR20140080103A

Abstract

The present invention provides a method for preparing bosentan monohydrate, a novel intermediate used therefor, and a method for preparing same. The novel intermediate composition of the present invention is produced at a high yield and high purity, and by using said intermediate composition, high-purity bosentan monohydrate can be economically mass produced at a high yield.

Description

Method for preparing bosentan monohydrate, novel intermediates used therein and method for producing same

The present invention relates to a process for preparing bosentan monohydrate, novel intermediates used therein and a process for producing the same.

Bosentane represented by the following [Formula 1] is a sulfonamide compound useful for the treatment of cardiovascular diseases such as hypertension, ischemia, vasospasm and angina by having endothelin inhibitory activity.

[Formula 1]

In particular, bosentane monohydrate having a moisture content of about 3 to 5% is sold under the trade name Tracleer ^® by Actelion Pharmaceuticals.

The bosentan was first disclosed in US Pat. No. 5,292,740. US Patent No. 5,292,740 discloses a monochloro compound of Compound 4 by reacting the sulfonamide potassium salt of Compound 3 with 4,6-dichlorobipyrimidine compound of Compound 2 as shown in Scheme 1 below. And 2) a method of preparing bosentan of compound 6 by reacting monochloro compound of compound 4 with ethylene glycol and sodium.

Scheme 1

However, in the reaction of [Scheme 1], an undesired impurity such as dimeric impurities of [Formula 2] is generated by coupling the monochloro compound of Compound 4 with 1 molecule of ethylene glycol. As a result, a problem arises in that the purity of the final obtained bosentane is lowered. In order to lower the amount of these impurities, a multi-stage crystallization and purification method is required, and there is a problem that the yield is lowered during purification.

[Formula 2]

In addition, the reaction of [Scheme 1] is characterized in that using sodium. However, sodium has a risk of explosion upon contact with moisture, making it difficult to use industrially.

Meanwhile, US Patent No. 6,136,971 discloses a method for synthesizing high purity bosentan monohydrate 1 using Compound 9 in which one hydroxyl group is protected, as shown in Scheme 2, in order to prevent impurities.

Scheme 2

In the method of [Scheme 2], a substituted pyrimidine monohalide derivative is reacted with ethylene glycol mono t-butyl ether in toluene in the presence of sodium hydroxide to obtain a t-butyl ether derivative, which is deprotected in toluene using formic acid. To obtain a 2- (formyloxy) ethoxy derivative. Finally, bosentane monohydrate is obtained by removing the formyl group using aqueous sodium hydroxide.

However, the manufacturing method has to go through the protection step and the deprotection step of ethylene glycol, thereby causing a problem of generating additional labor, time, cost. Therefore, the manufacturing method is not suitable on an industrial scale.

Looking at international publication WO 2009/083739, another document for preparing bosentan monohydrate, as shown in [Scheme 3], to prepare a bosentane barium salt using ethylene glycol and barium hydroxide in the monochloro compound 8, A method of acid treatment with dilute hydrochloric acid to remove the bosentane barium salt and to produce bosentane monohydrate is disclosed. The patent document states that the use of the weak base barium hydroxide instead of the strong base sodium hydroxide can reduce the generation of unwanted impurities, thereby improving the purity of the final bosentane.

Scheme 3

However, the manufacturing method of [Scheme 3] uses expensive barium hydroxide, which requires high cost, which is not suitable for industrial scale, and it is difficult to obtain bosentane with high purity only in the form of barium salt.

Therefore, there is a need for an improved manufacturing method capable of economically producing high purity bosentan in high yield without complicated processes.

An object of the present invention is to provide a production method capable of mass production of high purity bosentan monohydrate in high yield and economical.

Another object of the present invention is to provide a benzenesulfonamide sodium salt dihydrate intermediate compound useful for preparing bosentan monohydrate in high yield and high purity, and a method for preparing the same.

보센탄 일수화물의 제조방법Method for preparing bosentan monohydrate

The present invention provides a method for producing bosentan monohydrate.

Method for preparing bosentan monohydrate according to the present invention is 1) by the following [Scheme I], 4,6-dichloro-5- (2-methoxyphenoxy) -2,2 in the presence of the first base in an organic solvent. '-Bipyrimidine reacts with 4- (tert-butyl) benzenesulfonamide to give 4- (tert-butyl) -N- [6-chloro-5- (2-methoxyphenoxy)-(2,2' -Bipyrimidin) -4-yl] benzenesulfonamide alkali metal salt;

Scheme I

{M is lithium, sodium, potassium}

2) 4- (tert-butyl) -N- [6-chloro-5- (2-methoxyphenoxy)-prepared in the first step in the presence of a second base in an organic solvent by the following [Scheme II]. (2,2'-bipyrimidin) -4-yl] benzenesulfonamide Alkali metal salt is reacted with ethylene glycol to produce crude-bosentan, followed by addition of acid to prepare bosentan acid addition salt step; And

Scheme II

3) a third step of converting the bosentane acid addition salt prepared in the second step into a bosentane monohydrate by the following [Scheme III];

Scheme III

It may include.

The organic solvent used in the process for preparing bosentan monohydrate according to the present invention is dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, 1,4-dioxane and these It may be selected from the group consisting of a mixed solvent of, preferably dimethyl sulfoxide may be used.

The first base used in the first step of the method for producing bosentan monohydrate according to the present invention may be selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate. Sodium carbonate can be used.

In addition, the reaction of the first step may be performed for 2 to 10 hours at 60 to 120 ℃. Preferably it may be carried out at 60 to 100 ℃ for 4 to 10 hours, more preferably at 70 to 80 ℃ may be performed for 5 to 10 hours.

The alkali metal salt prepared in the first step according to the present invention may be a dihydrate, preferably a sodium salt dihydrate having the structure [I].

[Formula I]

The alkali metal salt dihydrate according to the present invention may be obtained by adding purified water after the reaction of the first step.

The second base used in the second step of the method for producing bosentan monohydrate according to the present invention may be selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide. Therefore, in the present invention, since sodium is not used as the second base, the explosion risk can be eliminated.

In addition, the crude (crude) in the second step is preferably carried out for 2 to 8 hours at 40 to 80 ℃. More preferably, it is performed for 3 to 6 hours at 40 to 60 ℃, most preferably at 4 to 5 hours at 40 to 50 ℃. Since the reaction does not proceed at a high temperature, it is possible to reduce the generation of impurities by side reactions.

The bosentane acid addition salt prepared in the second step according to the present invention is separated into a stable solid phase (crystalline or amorphous), which is useful for purification, and the acid used in the second step is a bosentane acid moiety when pKa is less than 3 Salting can be prepared in high yield and high purity.

Thus, the acid used in the second step is hydrochloric acid, hydrobromic acid, methane sulfonic acid, benzenesulfonic acid, sulfuric acid, p -toluenesulfate. It may be selected from the group consisting of p- toluenesulfonic acid, oxalic acid and maleic acid.

Further, the beam ambrisentan acid addition salts according to the invention are p-toluene sulfonate is most preferred that the-toluenesulfonic acid (p -toluenesulfonic acid) and the mixture to the prepared [formula II] of the structural beam ambrisentan p.

[Formula II]

The water-soluble solvent used in the third step may be water, acetone, alcohol or a mixture thereof, the alcohol is preferably C1 ~ C4 alcohol.

Since the bosentan monohydrate prepared according to the production method of the present invention is manufactured in high yield and high purity through a simple manufacturing process, the production method of the present invention is very suitable for the production of bosentan monohydrate.

보센탄 일수화물 제조에 유용한 신규 중간체 화합물New Intermediate Compounds Useful for the Preparation of Bosentan Monohydrate

The present invention provides a benzenesulfonamide sodium salt dihydrate having the following structure [Formula I] usefully used in the production of bonded carbon monohydrate.

[Formula I]

The benzenesulfonamide sodium salt dihydrate compound is a novel compound, it can be produced in high yield and high purity through a simple manufacturing process. In addition, by using the benzenesulfonamide sodium salt dihydrate intermediate prepared in high purity as a reaction material of the next step, bosentane acid addition salts and bosentan monohydrate can be prepared in high purity and high yield through a simple manufacturing process.

신규 중간체의 제조방법Method of Preparation of New Intermediates

The present invention provides a method for preparing benzenesulfonamide sodium salt dihydrate which is usefully used for the preparation of bosentan monohydrate.

The benzenesulfonamide sodium salt dihydrate is 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine in the presence of a base in an organic solvent by the following [Scheme I-1]. It can be prepared by reacting with 4- (tert-butyl) benzenesulfonamide and adding purified water.

Scheme I-1

The organic solvent used in Scheme [I-1] is made of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, 1,4-dioxane, and a mixed solvent thereof. It may be selected from the group, the base may be used sodium hydroxide or sodium carbonate.

In addition, the reaction of [Scheme I-1] is preferably carried out at 60 to 120 ℃ for 2 to 10 hours. More preferably, it may be performed at 60 to 100 ° C. for 4 to 10 hours, and most preferably at 70 to 80 ° C. for 5 to 10 hours.

Benzenesulfonamide sodium salt dihydrate prepared through the reaction can be prepared in high yield and high purity.

The production method of the present invention exhibits the effect of economically mass-producing high purity bosentan monohydrate in high yield.

In addition, the benzenesulfonamide sodium salt dihydrate intermediate of the present invention is easily prepared in high yield and high purity, and has the effect of producing bosentan monohydrate in high yield and high purity.

1 is a DSC graph of benzenesulfonamide sodium salt dihydrate obtained in Example 1. FIG.

2 is an MS graph of benzenesulfonamide sodium salt dihydrate obtained in Example 1. FIG.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

실시예 1 내지 5 : 벤젠설폰아미드 알칼리 금속염의 제조Examples 1 to 5: Preparation of Benzenesulfonamide Alkali Metal Salts

실시예 1: 벤젠설폰아미드 나트륨염 이수화물의 제조Example 1 Preparation of Benzenesulfonamide Sodium Salt Dihydrate

43.2 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 204 mL of dimethylsulfoxide seed, 30.8 g of 4- (tert-butyl) benzenesulfonamide, 24.4 g of sodium carbonate Was added to the reactor. Stir at 70-80 ° C. for 10 hours. After cooling to room temperature, 344 mL of purified water was added dropwise. Stir for 30 minutes and filter. 172 mL of purified water and 172 mL of ethyl acetate were washed successively. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 68.8 g (95.0%) of sulfonamide sodium salt dihydrate was obtained.

¹ H NMR (400 MHz, DMSO-d6): δ 1.22 (s, 9H), 3.79 (s, 3H), 6.41-6.63 (d, 1H), 6.75-6.68 (t, 1H), 6.95-6.99 (t , 1H), 7.05 ~ 7.07 (d, 1H), 7.27 ~ 7.30 (d, 2H), 7.60 ~ 7.63 (t, 1H), 7.68 ~ 7.70 (d, 2H), 8.95 ~ 8.96 (d, 2H)

MS (EI) m / z 548 [M + Na] ⁺

Purity (HPLC): 99.90%

Moisture (Karl Fischer method): 7.1%

In addition, as a result of DSC measurement of the compound, as shown in FIG. 1, the water desorption temperature was 116.56 ° C., and the melting point was measured at 233.41 ° C. FIG.

실시예 2: 벤젠설폰아미드 나트륨염 이수화물의 제조Example 2: Preparation of Benzenesulfonamide Sodium Salt Dihydrate

20.0 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 65 mL of dimethylformamide, 15.4 g of 4- (tert-butyl) benzenesulfonamide, sodium hydroxide 7.0 g was added to the reactor. Stir at 90-100 ° C. for 6 hours. After cooling to room temperature, 200 mL of purified water was added dropwise. Stir for 30 minutes and filter. 43 mL of purified water and 43 mL of ethyl acetate were washed successively. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 23.7 g (70.8%) of sulfonamide sodium salt dihydrate was obtained.

Purity (HPLC): 99.87%

Moisture (Karl Fischer): 6.9%

¹ H NMR, MS, DSC measurement results are the same as in Example 1.

실시예 3: 벤젠설폰아미드 나트륨염 이수화물의 제조Example 3: Preparation of Benzenesulfonamide Sodium Salt Dihydrate

5.0 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 10 mL of dimethylformamide, 3.7 g of 4- (tert-butyl) benzenesulfonamide, 2.0 g of sodium carbonate Was added to the reactor. Stir at 90-100 ° C. for 5 hours. After cooling to room temperature, 45 mL of purified water was added dropwise. Stir for 30 minutes and filter. 43 mL of purified water and 43 mL of ethyl acetate were washed successively. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 6.7 g (80.1%) of sulfonamide sodium salt dihydrate was obtained.

Purity (HPLC): 99.72%

Moisture (Karl Fischer method): 7.1%

¹ H NMR, MS, DSC measurement results are the same as in Example 1.

실시예 4: 벤젠설폰아미드 나트륨염 이수화물의 제조Example 4 Preparation of Benzenesulfonamide Sodium Salt Dihydrate

20.0 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 195 mL of xylene, 15.4 g of 4- (tert-butyl) benzenesulfonamide, 7.0 g of sodium hydroxide Was added to the reactor. Stir at 90-100 ° C. for 6 hours. Cooled to room temperature, stirred for 30 minutes, and filtered. 43 mL of ethyl acetate and 43 mL of purified water were washed successively. The filtered solid was stirred in 150 mL of purified water for 1 hour, filtered and washed successively with purified water and ethyl acetate. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 26.0 g (77.7%) of sulfonamide sodium salt dihydrate was obtained.

Purity (HPLC): 99.57%

Moisture (Karl Fischer method): 6.7%

¹ H NMR, MS, DSC measurement results are the same as in Example 1.

실시예 5: 벤젠설폰아미드 칼륨염의 제조Example 5: Preparation of Benzenesulfonamide Potassium Salt

12.5 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 180 mL of toluene, 9.0 g of 4- (tert-butyl) benzenesulfonamide, 11.0 g of potassium carbonate, 2.6 g tetrabutylammonium bromide was charged into the reactor. The reaction solution was stirred at reflux for 10 hours. Cooled to room temperature and filtered. Washed with 73 mL of toluene. The filtered solid was stirred in 200 mL of purified water for 1 hour, filtered and washed successively with purified water and acetonitrile. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 17.7 g (87.7%) of sulfonamide potassium salt were obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.21 (s, 9H), 3.83 (s, 3H), 6.43-6.45 (d, 1H), 6.77-6.81 (t, 1H), 6.95-6.99 ( t, 1H), 7.07-7.09 (d, 1H), 7.26-7.29 (d, 2H), 7.59-7.81 (t, 1H), 7.80-7.83 (d, 2H), 8.98-8.99 (d, 2H)

Purity (HPLC): 98.57%

실시예 6 내지 10 : 보센탄 산부가염의 제조Examples 6 to 10 Preparation of Bosentane Acid Addition Salts

실시예 6 : 보센탄 Example 6 Bosentan pp -톨루엔설폰산염의 제조Preparation of Toluene Sulfonate

5.1 g of sodium hydroxide and 80 mL of ethylene glycol are added to the reactor and stirred at 45 to 50 ° C. for 30 minutes. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 15.0 g of salt dihydrate and 34 mL of dimethyl sulfoxide were added and stirred at 40-50 ° C. for 4 hours. Cooled to 20-25 ° C and 86 mL of dimethyl chloride, 86 mL of dilute hydrochloric acid (9 mL of 35% hydrochloric acid + 77 mL of purified water) were added. 7 mL of 35% hydrochloric acid was added to adjust pH to 4-5. The layers were separated and the organic layer was taken, and the water layer was extracted again with dimethyl chloride. The organic layer obtained was washed successively with 86 mL of purified water and 86 mL of 20% sodium chloride. After dehydration with anhydrous magnesium sulfate, it was filtered and washed with 17 mL of dimethylchloride. The filtrate was concentrated under reduced pressure. 258 mL of acetonitrile and 58 mL of methanol were added to the residue, followed by addition of 5.4 g of p -toluenesulfonic acid hydrate. After stirring for 1 hour, the precipitated crystals were filtered and washed with 52 mL of acetonitrile. Vacuum drying at 50-60 ° C. yielded 13.0 g (70.0%) of bosentan p -toluenesulfonate.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.26 (s, 9H), 2.29 (s, 3H), 3.48 to 3.50 (t, 2H), 3.79 (s, 3H), 4.34 to 4.37 (t , 2H), 6.70 ~ 6.72 (d, 1H), 6.78 ~ 6.82 (t, 1H), 7.01 ~ 7.05 (t, 1H), 7.07 ~ 7.09 (d, 1H), 7.12 ~ 7.14 (d, 2H), 7.48 ~ 7.51 (d, 2H), 7.53-7.56 (d, 2H), 7.68-7.71 (t, 1H), 8.21-8.23 (d, 2H), 9.10-9.11 (d, 2H)

Purity (HPLC): 99.90%

실시예 7: 보센탄 Example 7: Bosentan pp -톨루엔설폰산염의 제조Preparation of Toluene Sulfonate

3.7 g of sodium hydroxide and 50 mL of ethylene glycol were added to the reactor and heated to 50 to 60 ° C. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 10.0 g of salt dihydrate and 20 mL of 1,4-dioxane were added and stirred at 50 to 60 ° C. for 6 hours. Cooled to 20-25 ℃ and 50 mL of dimethyl chloride, 50 mL of diluted hydrochloric acid (5 mL of 35% hydrochloric acid + 45 mL of purified water) was added. 35% hydrochloric acid was added to adjust pH to 4-5. The layers were separated and the organic layer was taken, and the water layer was extracted again with dimethyl chloride. The obtained organic layer was washed successively with 76 mL of purified water and 76 mL of 20% sodium chloride. After dehydration with anhydrous magnesium sulfate, the mixture was filtered and washed with dimethylchloride. The filtrate was concentrated under reduced pressure. The residue was dissolved in 100 mL of acetonitrile and 3.8 g of p -toluenesulfonic acid hydrate was added thereto. After stirring for 1 hour, the precipitated crystals were filtered and washed with 52 mL of acetonitrile. Vacuum drying at 50-60 ° C. yielded 8.5 g (69.0%) of bosentan p -toluenesulfonate.

Purity (HPLC): 99.87%

¹ H NMR data is the same as in Example 6.

실시예 8: 보센탄 Example 8: Bosentan pp -톨루엔설폰산염의 제조Preparation of Toluene Sulfonate

1.7 g of sodium hydroxide and 30 mL of ethylene glycol are added to the reactor and stirred for 30 minutes at 45 to 50 ° C. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 5.0 g of salt dihydrate and 11 mL of dimethylacetamide were added thereto, followed by stirring at 40 to 50 ° C. for 5 hours. Cooled to 20-25 ° C and 29 mL of dimethylchloride, 29 mL of dilute hydrochloric acid (3 mL of 35% hydrochloric acid + 27 mL of purified water) were added. 2.3 mL of 35% hydrochloric acid was added to adjust the pH to 4-5. The layers were separated and the organic layer was taken, and the water layer was extracted again with dimethyl chloride. The obtained organic layer was washed successively with 29 mL of purified water and 29 mL of 20% sodium chloride. After dehydration with anhydrous magnesium sulfate, it was filtered and washed with 5 mL of dimethylchloride. The filtrate was concentrated under reduced pressure. 85 mL of acetonitrile and 18 mL of methanol were added to the residue, and 1.8 g of p -toluenesulfonic acid hydrate was added thereto. After stirring for 1 hour, the precipitated crystals were filtered and washed with 52 mL of acetonitrile. Vacuum drying at 50-60 ° C. yielded 4.4 g (71.0%) of bosentan p -toluenesulfonate.

Purity (HPLC): 99.88%

¹ H NMR data is the same as in Example 6.

실시예 9: 보센탄 염산염의 제조Example 9 Preparation of Bosentan Hydrochloride

1.7 g of sodium hydroxide and 30 mL of ethylene glycol are added to the reactor and stirred for 30 minutes at 45 to 50 ° C. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 5.0 g of salt dihydrate and 11 mL of dimethyl sulfoxide were added thereto, followed by stirring at 40-50 ° C. for 4 hours. Cooled to 20-25 ° C and 29 mL of dimethylchloride, 29 mL of dilute hydrochloric acid (3 mL of 35% hydrochloric acid + 27 mL of purified water) were added. 2.3 mL of 35% hydrochloric acid was added to adjust the pH to 4-5. The layers were separated and the organic layer was taken, and the water layer was extracted again with dimethyl chloride. The obtained organic layer was washed successively with 29 mL of purified water and 29 mL of 20% sodium chloride. After dehydration with anhydrous magnesium sulfate, it was filtered and washed with 5 mL of dimethylchloride. The filtrate was concentrated under reduced pressure. 55 mL of 2-propanol was added to the residue and heated to 50-60 ° C. 1.88 mL of 2-propanolic 5M hydrochloric acid was slowly added dropwise, cooled to 20-30 ° C. and stirred for 4 hours. The mixture was cooled to 0˜10 ° C., further stirred for 1 hour, and the precipitated crystals were filtered and washed with 10 mL of cold 2-propanol. Vacuum drying at 50-60 ° C. gave 3.27 g (65.0%) of bosentane hydrochloride.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.26 (s, 9H), 3.48 to 3.50 (t, 2H), 3.79 (s, 3H), 4.34 to 4.37 (t, 2H), 6.70 to 6.72 (d, 1H), 6.77 ~ 6.82 (t, 1H), 7.01 ~ 7.09 (m, 2H), 7.53 ~ 7.55 (d, 2H), 7.68 ~ 7.70 (t, 1H), 8.22 (br s, 2H), 9.09 ~ 9.11 (d, 2H)

Purity (HPLC): 99.82%

실시예 10: 보센탄 황산염의 제조Example 10 Preparation of Bosentan Sulfate

1.7 g of sodium hydroxide and 30 mL of ethylene glycol are added to the reactor and stirred for 30 minutes at 45 to 50 ° C. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 5.0 g of salt dihydrate and 11 mL of dimethyl sulfoxide were added thereto, followed by stirring at 40-50 ° C. for 4 hours. Cooled to 20-25 ° C and 29 mL of dimethylchloride, 29 mL of dilute hydrochloric acid (3 mL of 35% hydrochloric acid + 27 mL of purified water) were added. 2.3 mL of 35% hydrochloric acid was added to adjust the pH to 4-5. The layers were separated and the organic layer was taken, and the water layer was extracted again with dimethyl chloride. The obtained organic layer was washed successively with 29 mL of purified water and 29 mL of 20% sodium chloride. After dehydration with anhydrous magnesium sulfate, it was filtered and washed with 5 mL of dimethylchloride. The filtrate was concentrated under reduced pressure. 60 mL of acetonitrile were added to the residue, and 0.53 mL of 98% sulfuric acid was added dropwise. Stirred for 3 hours, cooled to 0 ~ 10 ℃ again stirred for 1 hour. The precipitated crystals were filtered off and washed with 10 mL of cold acetonitrile. Vacuum drying at 50-60 ° C. afforded 3.78 g (68.0%) of bosentan sulfate.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.26 (s, 9H), 3.47 to 3.50 (t, 2H), 3.79 (s, 3H), 4.34 to 4.37 (t, 2H), 6.69 to 6.72 (d, 1H), 6.77-6.81 (t, 1H), 7.01-7.09 (m, 2H), 7.53-7.55 (d, 2H), 7.68-7.71 (t, 1H), 8.21-8.22 (d, 2H) , 9.10-9.11 (d, 2H)

Purity (HPLC): 99.85%

실시예 11 및 12 : 보세탄 일수화물의 제조Examples 11 and 12 Preparation of Bonded Monohydrate

실시예 11: 보센탄 일수화물의 제조Example 11: Preparation of Bosentan Monohydrate

11.5 g of bosentan p -toluenesulfonate obtained in Example 6, 44 mL of anhydrous ethanol, and 62 mL of purified water were added to a reactor, and then 1.5 g of sodium hydrogencarbonate was added dropwise. After stirring for 1 hour at 20 ~ 25 ℃ and filtered, and washed with 14 mL of anhydrous ethanol and 20 mL of purified water. The filtered crude bosen carbohydrate was added to the reactor, and 49 mL of anhydrous ethanol and 24 mL of acetone were added thereto. Warmed to 40 ~ 45 ℃ to dissolve and filtered to remove impurities. The mixture was washed with 10 mL of anhydrous ethanol and 5 mL of acetone. 122 mL of purified water was added dropwise to the filtrate, and the mixture was stirred at 20 to 25 ° C for 1 hour. The precipitated crystals were filtered and washed with anhydrous ethanol and purified water mixture. Vacuum drying at 50-60 ° C. yielded 8.4 g (93.0%) of bosentane monohydrate.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.24 (s, 9H), 3.46 (s, 2H), 3.78 (s, 3H), 4.32 (s, 2H), 6.68 ~ 6.79 (m, 2H ), 7.02 to 7.08 (m, 2H), 7.52 to 7.54 (d, 2H), 7.65 (s, 1H), 8.28 to 8.30 (d, 2H), 11.31 (s, 1H)

MS (EI) m / z 552 [M−H ₂ O + H] ⁺

Purity (HPLC): 99.97%

Moisture (Karl Fischer method): 3.0%

실시예 12: 보센탄 일수화물의 제조Example 12 Preparation of Bosentan Monohydrate

5.0 g of bosentan p -toluenesulfonate obtained in Example 7, 16 mL of anhydrous ethanol, and 25 mL of purified water were added to a reactor, and then 0.7 g of sodium hydrogencarbonate was added dropwise. After stirring for 1 hour at 20 ~ 25 ℃ and filtered, and washed with 5 mL of anhydrous ethanol and 11 mL of purified water. The filtered crude bosen carbohydrate was added to the reactor, and 21 mL of anhydrous ethanol and 11 mL of acetone were added thereto. Warmed to 40 ~ 45 ℃ to dissolve and filtered to remove impurities. The mixture was washed with 5 mL of anhydrous ethanol and 3 mL of acetone. 61 mL of purified water was added dropwise to the filtrate, and the mixture was stirred at 20 to 25 ° C for 1 hour. The precipitated crystals were filtered and washed with anhydrous ethanol and purified water mixture. Vacuum drying at 50-60 ° C. yielded 3.6 g (92.8%) of bosentan monohydrate.

Purity (HPLC): 99.95%

Moisture (Karl Fischer method): 3.1%

¹ H-NMR and MS measurement results are the same as in Example 11.

측정방법 How to measure

1) ¹ H-NMR (Nuclear Magnetic Resonance Spectrum)

Manufacturer: Varian

Device Name: Mercury Plus 400 MHz NMR

2) MS (mass spectrum)

Manufacturer: AB SCIEX

-Device Name: API-2000

3) HPLC (High Performance Liquid Chromatography)

Manufacturer: Agilent Technologies

-Device Name: SYS-LC-1200 series

-Column: Zorbax RX-C8 (4.6 × 250mm, 5 ㎛, 80Å) or equivalent

Mobile phase A: Dissolve 1.36 g of potassium dihydrogen phosphate in 750 mL of purified water, bring the pH to 2.5 with phosphoric acid, and mix with 250 mL of acetonitrile.

Mobile phase B: Dissolve 1.36 g of potassium dihydrogen phosphate in 300 mL of purified water, bring the pH to 2.5 with phosphoric acid, and mix with 700 mL of acetonitrile.

Flow rate: 1.5 ml / min

Detector wavelength: 220 nm

Mobile phase gradient:

4) DSC (시차주사열량계)4) Differential Scanning Calorimeter (DSC)

Manufacturer: TA instrument Inc., U.S.A.

Model Name: DSC 1000 (Differential Scanning Calorimeter)

-Temperature increase rate: Increases to 300 ℃ at 10 ℃ / min

5) Karl-Fisher 수분 측정5) Karl-Fisher Moisture Measurement

Manufacturer: Metrohm

Model Name: 787 KF Titrino

Solvent Used: Methanol

The benzenesulfonamide sodium salt dihydrate intermediate of the present invention is easily prepared in high yield and high purity and can be economically mass-produced in high yield using high purity bosentane monohydrate.

Claims

1) 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine and 4- (tert-butyl in the presence of the first base in an organic solvent ) reacting a benzenesulfonamide, 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene A first step of preparing a sulfonamide alkali metal salt;

Scheme I

{M is lithium, sodium, potassium}

2) by the [Reaction Scheme II], prepared in the first step under the second presence of a base in an organic solvent 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyrimidin) -4-yl] benzenesulfonamide Alkali metal salt is reacted with ethylene glycol to produce crude-bosentan, followed by addition of acid to prepare bosentan acid addition salt step; And

Scheme II

Scheme III

Method for producing bosentan monohydrate comprising a.

The method of claim 1, wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, 1,4-dioxane and mixed solvents thereof. Method for producing bosentan monohydrate.

The method of claim 2, wherein the organic solvent is dimethyl sulfoxide.

The method of claim 1, wherein the first base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate.

The method of claim 4, wherein the first base is sodium carbonate.

The method of claim 1, wherein the reaction of the first step is performed at 60 to 120 ° C. for 2 to 10 hours.

The method of claim 1, wherein the alkali metal salt is a dihydrate.

The method of claim 7, wherein the alkali metal salt dihydrate is obtained by adding purified water after the reaction of the first step.

The method of claim 7, wherein the alkali metal salt dihydrate is a sodium salt dihydrate having the structure [Formula I].

[Formula I]

The method of claim 1, wherein the second base is selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide.

The method of claim 1, wherein the second base is sodium hydroxide.

According to claim 1, wherein the crude (crude) -bosentan production reaction of the second step is carried out for 2 to 8 hours at 40 to 80 ℃ manufacturing method of bosentan monohydrate.

The method of claim 1, wherein the acid has a pKa of less than 3.

The method of claim 11, wherein the acid is hydrochloric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonic acid, sulfuric acid, sulfuric acid, p -toluenesulfonic acid ( p). -toluenesulfonic acid), oxalic acid (oxalic acid) and maleic acid (maleic acid) is a method for producing bosentan monohydrate selected from the group consisting of.

The method of claim 1, wherein the bosentan acid addition salt is bosentan p -toluenesulfonate having the structure of [Formula II].

[Formula II]

The method of claim 1, wherein the water-soluble solvent is water, acetone, alcohol or a mixture thereof.

The method of claim 16, wherein the alcohol is C1 to C4 alcohol.

Benzenesulfonamide sodium salt dihydrate having the structure [Formula I].

[Formula I]

According to Scheme I-1, 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine and 4- (tert-butyl) benzene in the presence of a base in an organic solvent A method for producing benzenesulfonamide sodium salt dihydrate prepared by reacting sulfonamide and adding purified water.

Scheme I-1

The method of claim 19, wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, 1,4-dioxane and mixed solvents thereof. Method for producing a benzenesulfonamide sodium salt dihydrate.

20. The method of claim 19, wherein the base is sodium hydroxide or sodium carbonate.

The method of claim 19, wherein the reaction is performed at 60 to 120 ° C. for 2 to 10 hours.