JP2016030745A - Method for producing bosentan or hydrate thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce: high purity bosentan by suppressing the formation of 4-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide which is a reaction by-product or a hydrate thereof.SOLUTION: There is produced high purity bosentan by suppressing the formation of a reaction by-product by carrying out a reaction between 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide and ethylene glycol by using alkali metal salt of disilazane as a base and a dehydrating agent or a hydrate thereof.SELECTED DRAWING: Figure 4

Description

  The present invention relates to a process for producing industrially practicable high-purity bosentan or a hydrate thereof.

Bosentan represented by the following formula (I) is 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidine -4-yl] benzenesulfonamide (hereinafter referred to as compound (I)) is an international general name.

Bosentan is not usually isolated by an anhydride, but forms monohydrate (hereinafter referred to as compound (II)) represented by the following formula (II) with water used in the post-treatment of the reaction. Be released.

  Bosentan monohydrate is commercially available under the trade name Toraclear (registered trademark), and is known to inhibit the binding of endothelin-1 to the endothelin receptor in vascular endothelial cells and exhibit therapeutic effects on pulmonary hypertension. ing.

In Patent Document 1, sodium ethylene glycol solution and 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidine-2) represented by the following formula (III): Both -yl) pyrimidin-4-yl] benzenesulfonamide (hereinafter referred to as compound (III)) was heated to 110 ° C. to obtain bosentan.

  In Patent Document 2, compound (III) is reacted with ethylene glycol in the presence of potassium such as potassium tert-butoxide, potassium phosphate, potassium carbonate or the like, and the resulting bosentan potassium salt is treated with hydrochloric acid. And converted to monohydrate.

  In Patent Document 3, ethylene glycol, sodium hydroxide and compound (III) are reacted by heating at 92 to 97 ° C. for 5 hours, and then neutralized with an aqueous tartaric acid solution to obtain bosentan monohydrate (II). It has gained.

European Patent No. 0526708 International Publication No. 2010/103362 International Publication No. 2009/093127

The reaction between compound (III) and ethylene glycol proceeds by heating in the presence of a base. As the reaction nears completion, that is, when the amount of compound (III) as a reaction substrate decreases, impurities are gradually generated and increases with time as heating is continued. As a result of isolating and analyzing this impurity, 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) represented by the following formula (IV): It was found to be pyrimidin-4-yl] benzenesulfonamide (hereinafter referred to as compound (IV)).

In Patent Document 1, an ethylene glycol solution of sodium is used, but this must be prepared at the time of use by dissolving metallic sodium in ethylene glycol. Since metallic sodium reacts violently with water and easily ignites, and its surface is easily oxidized, it is usually stored in kerosene. Further, when ethylene glycol is deprotonated using metallic sodium, hydrogen gas is generated as a reaction by-product, and there is a risk of explosion. Thus, metallic sodium is very dangerous in handling and should be avoided in industrial production sites.

  On the other hand, as described in Patent Documents 2 and 3, when the reaction is carried out using a base such as potassium tert-butoxide or sodium hydroxide instead of metallic sodium, the risk decreases because metallic sodium is not used. However, the amount of the by-product of the compound (IV) described above is increased compared to the case where metallic sodium is used. In addition to potassium tert-butoxide and sodium hydroxide, many bases cannot produce bosentan monohydrate having a purity equivalent to or higher than that of metallic sodium.

  Reference is now made to FIGS. The reaction rate and the byproduct of impurities (compound (IV)) were compared between the case of using sodium metal as the base and the case of using potassium tert-butoxide. Briefly, after deprotonation of ethylene glycol with metallic sodium or potassium tert-butoxide, the reaction was carried out by adding compound (III) and heating. The progress of the reaction and the content of compound (IV) were evaluated by HPLC.

  As shown in FIG. 1, the reaction rate differs greatly between the case of using metallic sodium as the base and the case of using potassium tert-butoxide, and the reaction is slow when potassium tert-butoxide is used. When metallic sodium is used, the reaction is completed in 2 hours, but when potassium tert-butoxide is used, the reaction rate is slightly less than 80% even if the reaction is carried out for 8 hours.

  Moreover, as shown in FIG. 2, the by-product of compound (IV) is clearly more when potassium tert-butoxide is used. When sodium metal is used, the content of compound (IV) is about 2.7% at 2 hours when the reaction is almost completed, whereas when potassium tert-butoxide is used, the reaction time is 8 hours. Although the reaction rate is still about 77% at the point of time, the content of compound (IV) is 3% or more.

  On the other hand, when sodium hydroxide is used as the base, the reaction rate is almost the same as when sodium metal is used, but the byproduct of compound (IV) is better when sodium hydroxide is used. The content of compound (IV) is about 3.7% when sodium hydroxide is used at the point of 2 hours when the reaction is almost complete, about 1% than when metallic sodium is used. There were many.

When used as a pharmaceutical, it is important to increase the purity of bosentan, which is a physiologically active substance, or a hydrate thereof (compound (I) or (II)). It is desired to suppress the by-product of compound (IV) as much as possible. In particular, once compound (IV) is by-produced, it is difficult to separate from compound (I) or (II), which is the target product, and therefore it is desired to suppress its generation as much as possible. Accordingly, there is a need for a new process for producing bosentan or a hydrate thereof that suppresses the by-product of compound (IV), which is an impurity, while avoiding the use of difficult and dangerous metallic sodium.
In addition, in the above reaction, ethylene glycol serves not only as a reaction substrate but also as a solvent. Ethylene glycol is a viscous liquid and has poor fluidity as a solvent. In actual production, it is desirable to improve this poor fluidity.

The present invention provides a process for producing high-purity bosentan and a hydrate thereof by reacting compound (III) with ethylene glycol by heating in the presence of a base.
The inventors studied various bases for the purpose of avoiding the use of high-danger metal sodium and obtaining bosentan or a hydrate thereof having a purity equal to or higher than that of metal sodium. As a result, it has been found that when an alkali metal salt of disilazane is used as a base, bosentan or a hydrate thereof having a purity equivalent to that when metal sodium is used is obtained. Further, at that time, it was found that an objective compound with higher purity can be obtained by using an alkali metal salt of disilazane dissolved in an organic solvent such as tetrahydrofuran.

Accordingly, the present invention provides 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl in the presence of an alkali metal salt of disilazane. The present invention provides a process for producing bosentan or a hydrate thereof by reacting benzenesulfonamide with ethylene glycol.
The alkali metal salt of disilazane is an alkali metal salt of alkyldisilazane, preferably an alkali metal salt of hexamethyldisilazane. The alkali metal salt of hexamethyldisilazane is preferably selected from a lithium salt, a sodium salt, and a potassium salt, and particularly preferably a lithium salt.
The alkali metal salt of disilazane may be an organic solvent solution. For example, the alkali metal salt of disilazane used in the method of the present invention is a tetrahydrofuran solution of an alkali metal salt of disilazane.

Reaction rate comparison results when using metallic sodium and potassium tert-butoxide Comparison results of compound (IV) content when using sodium metal and potassium tert-butoxide Reaction rate comparison results when metallic sodium is used, lithium hexamethyldisilazane is used, and sodium hexamethyldisilazane is used Compound (IV) content comparison results when metallic sodium is used, lithium hexamethyldisilazane is used, and sodium hexamethyldisilazane is used

The present invention provides a method for producing bosentan or a hydrate thereof by reacting compound (III) with ethylene glycol by heating in the presence of an alkali metal salt of disilazane.
The alkali metal salt of disilazane has the following structure.

In the formula, M is an alkali metal, and R ^{1 to} R ⁶ are independently hydrogen or a hydrocarbon group. The alkali metal is preferably lithium, sodium or potassium, and particularly preferably lithium. The hydrocarbon group is alkyl having 1 to 6 carbons or aryl having 4 to 8 carbons such as methyl and ethyl, preferably methyl.

Disilazane is, for example, hexaalkyldisilazane. The hexaalkyldisilazane is, for example, hexamethyl or hexaethyldisilazane, preferably hexamethyldisilazane. The disilazane compound is exemplified by J.C. Am. Chem. Soc., 66, 1707, (1944).
The alkali metal salt of disilazane may be any of lithium salt, sodium salt, and potassium salt, preferably lithium salt.

  Accordingly, the alkali metal salt of disilazane is preferably a lithium salt, sodium salt or potassium salt of hexamethyldisilazane, more preferably a lithium salt or sodium salt of hexamethyldisilazane. The lithium salt and sodium salt of hexamethyldisilazane are sold by, for example, Tokyo Chemical Industry Co., Ltd.

In the presence of an alkali metal salt of disilazane, ethylene glycol (HO—CH 2 —CH 2 —OH) is converted to an alkali metal ethylene glycolate (HO—CH 2 —CH 2 —OM, where M is an alkali metal). By reacting metal ethylene glycolate with compound (III), bosentan (compound (I)) or a hydrate thereof (compound (II)) is produced.
The reaction rate and impurities (compound (IV)) by-product when lithium hexamethyldisilazane and sodium hexamethyldisilazane were used as the base were compared with those using metal sodium. These tests were performed in the same manner as in FIGS.

  As shown in FIG. 3, when lithium hexamethyldisilazane is used, the reaction is completed in 2 hours, which is almost the same as when metallic sodium is used. When sodium hexamethyldisilazane is used, the reaction is slightly delayed.

  As to the production rate of the compound (IV) as an impurity, as shown in FIG. 4, when hexamethyldisilazane was used, a better result was obtained than when metal sodium was used. Both lithium hexamethyldisilazane and sodium hexamethyldisilazane had a compound (IV) content of about 2% at the end of the reaction, which was more desirable than 2.7% when using metallic sodium.

The alkali metal salt of disilazane may be used as a solid or as an organic solvent solution, but if used as an organic solvent solution, the fluidity of the reaction solution will be improved and applied to actual production. Desirable above. Any organic solvent may be used as long as it does not inactivate the alkali metal salt of hexamethyldisilazane and is miscible with ethylene glycol. For example, tetrahydrofuran, 1,4-dioxane, acetonitrile and the like are preferable, and tetrahydrofuran is preferable.
The alkali metal salt of disilazane is usually added in an amount of 1 to 8 equivalents, preferably 4 equivalents, relative to compound (III) as a reaction substrate. Ethylene glycol is added in an amount of 5 to 12 ml, preferably 6.5 ml with respect to 1 g of compound (III).

Ethylene glycol is sold, for example, by Wako Pure Chemical.
Compound (III), ie 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide, is known. It can be manufactured according to the method. For example, see US Pat. Briefly, compound (III) is obtained by condensing 4,6-dichloro-5- (2-methoxyphenoxy) -2,2′-bipyrimidine and 4-tert-butylbenzenesulfonamide in the presence of a base. can get.

Usually, the reaction is carried out at 60 to 110 ° C. and is completed in 2 to 10 hours. For example, when an alkali metal salt of disilazane is used as a solid and no solvent is used, the reaction is performed at 90 to 110 ° C., and the reaction is completed in 2 to 5 hours. For example, when an alkali metal salt of disilazane is used as an organic solvent solution such as tetrahydrofuran, the reaction is carried out at the reflux temperature of the solvent, so the reaction temperature is 65 to 70 ° C. It takes 6 to 10 hours. However, the slow response is not only a disadvantage. As already described, if this reaction is continued to be heated after completion of the reaction, the compound (IV), which is an impurity, increases with time. As the reaction temperature is lowered and the reaction rate is lowered, the by-product rate of this impurity is also lowered, so that there is an advantage that the quality can be easily controlled.
For example, when the reaction is carried out under reflux with heating using a tetrahydrofuran solution of lithium hexamethyldisilazane, it takes 7 to 9 hours to complete the reaction, but the content of compound (IV) at the end of the reaction is about 0.5. % (See Example 3). This is about 1/4 of the case where lithium hexamethyldisilazane is used as a solid, which dramatically improves the purity of bosentan monohydrate (II).

Bosentan or a hydrate thereof obtained by the method of the present invention is then processed by a known method. For example, after completion of the reaction, the reaction solution is cooled and then slowly dropped into acidic water. In this case, the better fluidity of the reaction liquid not only has good operability, but also has the merit that the loss of the reaction liquid is small and that dangerous metal components remain in the reaction vessel. In addition, if an alkali metal salt of disilazane is used as the organic solvent solution, ethylene glycol has no role as a solvent, so the amount used can be reduced to the minimum necessary, improving volumetric efficiency during extraction and reducing manufacturing costs. Is also connected. Therefore, it can be said that the reaction is preferably performed using an alkali metal salt of disilazane as an organic solvent solution such as tetrahydrofuran.
Bosentan monohydrate (II) is obtained by extracting the reaction product with a suitable organic solvent such as ethyl acetate and then concentrating under reduced pressure. Preferably, the bosentan monohydrate (II) is purified by an operation such as recrystallization.

  The following examples illustrate the invention, but the invention is not limited thereby. The scope of the invention is defined by the claims.

The reaction and purity were evaluated by HPLC.
HPLC conditions:
HPLC: Shimadzu LC-2010HT
Column: Inertsil ODS-3 particle size 5 μm 4.6 × 250 mm
Oven: 35 ° C
Detection wavelength: 220 nm
Flow rate: 1 ml / min Mobile phase: Methanol-0.03 mol / l phosphate buffer (pH 7.5) = 60-40
Sample solution: mobile phase

The reaction rate was calculated as follows.
Reaction rate (%) = bosentan peak area / (compound (III) peak area + bosentan peak area) × 100
The evaluation of the content of compound (IV) was performed by calculation as follows.
Compound (IV) content (%) = Compound (IV) peak area / (Bosentan peak area + Compound (IV) peak area) × 100

Example 1
Under a nitrogen stream, 15 ml of ethylene glycol was added to the reaction vessel, and 1.46 g of lithium hexamethyldisilazane was slowly added. After heating to 60 ° C. and dissolution, the mixture was allowed to cool and returned to room temperature. Add 25.0 g of 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide at 100 ° C. The reaction was performed for 2 hours.
Reaction rate: 99.9%
Compound IV content: 1.87%

(Example 2)
Under a nitrogen stream, 15 ml of ethylene glycol was added to the reaction vessel, and 1.60 g of sodium hexamethyldisilazane was slowly added. After heating to 60 ° C. and dissolution, the mixture was allowed to cool and returned to room temperature. Add 25.0 g of 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide at 100 ° C. The reaction was performed for 5 hours.
Reaction rate: 99.9%
Compound IV content: 2.03%

(Example 3)
Under a nitrogen stream, 254 ml of ethylene glycol was added to the reaction vessel and cooled with ice, and 221 ml of 28% lithium hexamethyldisilazane tetrahydrofuran solution was slowly added dropwise. After stirring at room temperature for 20 minutes, 25.0 g of 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide Was added and heated to reflux for 7 hours.
Reaction rate: 99.9%
Compound IV content: 0.48%

In another container, 400 ml of water and then 22.8 g of DL-tartaric acid were added and dissolved, and then ice-cooled. The reaction solution was added dropwise to the aqueous solution little by little to quench the reaction solution. The reaction vessel was washed with 40 ml of tetrahydrofuran, extracted with 400 ml of toluene, washed with brine, and the organic layer was concentrated under reduced pressure. To the residue, 200 ml of methanol and 40 ml of tetrahydrofuran were added and suspended by boiling for 30 minutes, followed by cooling. The crystals were collected by filtration and dried to obtain 37.3 g of bosentan monohydrate.
Yield: 86.0%
HPLC purity: 99.5%
Compound IV content: 0.27%

(Comparative example)
In the following comparative examples, bosentan monohydrate was prepared using a base other than the alkali metal salt of hexamethyldisilazane.
(Comparative Example 1)
Under a nitrogen stream, 32 ml of ethylene glycol was added to the reaction vessel, and then finely cut metallic sodium was slowly added. After confirming dissolution of sodium, 5.0 g of 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide Was added and warmed. After reacting at 100 ° C. for 2 hours, 20 ml of ethylene glycol was added for dilution, and the mixture was further allowed to cool.
Reaction rate: 99.9%
Compound IV content: 2.73%

In a separate container, 50 ml of water and then 2.14 g of DL-tartaric acid were added and dissolved, and further 25 ml of tetrahydrofuran was added and cooled on ice. The reaction solution was added dropwise to this solution little by little to quench the reaction solution. The mixture was extracted with 50 ml of ethyl acetate, washed with brine, and the organic layer was concentrated under reduced pressure. To the residue, 25 ml of methanol was added and suspended by boiling for 30 minutes, followed by cooling. The crystals were collected by filtration and dried to obtain 5.98 g of bosentan monohydrate.
Yield: 73.3%
HPLC purity: 98.0%
Compound IV content: 1.79%

(Comparative Example 2)
Under a nitrogen stream, 15 ml of ethylene glycol was added to the reaction vessel, and then 1.0 g of potassium tert-butoxide was slowly added. After confirming dissolution by heating to 60 ° C., 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzene 1.0 g of sulfonamide was added and the reaction was carried out at 100 ° C. for 8 hours.
Reaction rate: 76.7%
Compound IV content: 3.06%

(Comparative Example 3)
16 ml of ethylene glycol was added to the reaction vessel, followed by 0.76 g of sodium hydroxide. After confirming dissolution by heating to 60 ° C., the mixture was allowed to cool to room temperature and 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidine- 2.5 g of 4-yl] benzenesulfonamide was added and warmed. After reacting at 100 ° C. for 2 hours, 10 ml of ethylene glycol was added for dilution, and the mixture was further allowed to cool.
Reaction rate: 99.9%
Compound IV content: 3.71%

In a separate container, 25 ml of water and then 1.07 g of DL-tartaric acid were added and dissolved, and further 12.5 ml of tetrahydrofuran was added and ice-cooled. The reaction solution was added dropwise to this solution little by little to quench the reaction solution. The mixture was extracted with 25 ml of ethyl acetate, washed with brine, and the organic layer was concentrated under reduced pressure. 12.5 ml of methanol was added to the residue and the mixture was boiled and suspended for 30 minutes, then cooled, and the crystals were collected by filtration and dried to obtain 2.3 g of bosentan monohydrate.
Yield: 88.3%
HPLC purity: 96.3%
Compound IV content: 3.45%

Claims (7)

  4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4-yl] benzenesulfonamide in the presence of an alkali metal salt of disilazane A process for producing bosentan or a hydrate thereof by reacting ethylene glycol.   The method according to claim 1, wherein the alkali metal salt of disilazane is an alkali metal salt of alkyldisilazane.   The process according to claim 2, wherein the alkali metal salt of alkyldisilazane is an alkali metal salt of hexamethyldisilazane.   4. The method according to claim 3, wherein the alkali metal salt of hexamethyldisilazane is selected from lithium salt, sodium salt, potassium salt.   The method according to claim 4, wherein the alkali metal salt of hexamethyldisilazane is a lithium salt.   The method according to claim 1, wherein the alkali metal salt of disilazane is a solution of an organic solvent.   The process according to claim 6, wherein the organic solvent is tetrahydrofuran.

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