HK1131778A - Purification process of montelukast and its amine salts - Google Patents

Description

Purification method of montelukast and amine salt thereof

The invention relates to a purification method of montelukast. The invention also relates to novel salts of montelukast that can be used in the purification process.

Background

Montelukast is the International non-patent name (INN) for 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinolinyl) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] sulfanyl ] methyl ] cyclopropaneacetic acid (CAS No. 158966-92-8). Montelukast sodium salt (CAS No 151767-02-1) is currently used to treat asthma, inflammation, angina, cerebral spasm, glomerulonephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.

The structure of montelukast sodium salt corresponds to the following formula (I):

different synthetic strategies for the preparation of montelukast and its salts are known. For example, EP480.717 discloses certain substituted quinolone compounds (including montelukast sodium salt), methods for their preparation, and pharmaceutical compositions using these compounds. Several methods for the preparation of montelukast sodium salt are reported in this document, example 161 relating to the preparation of montelukast sodium salt. According to this example, the preparation of montelukast sodium salt is carried out by its corresponding methyl ester generated in situ, which comprises the coupling of methyl 1- (mercaptomethyl) -cyclopropaneacetate with a protected mesylate (2- (2- (2- (3(S) - (3- (2- (7-chloro-2-quinolyl-) -vinyl) phenyl) -3- (methanesulfonyloxy) propyl) phenyl) -2-propoxy) tetrahydropyran, aided by sodium hydride or cesium carbonate. And the yields of intermediates and final products are low. Other processes for the preparation of montelukast and its salts have been described (see WO04/108.679, US 2005/107612, WO 05/105751, WO 05/105749, WO05/105750, CN 1428335 and CN 1420113).

Generally, montelukast and its pharmaceutically acceptable salts are obtained by complex synthetic processes that result in the formation of several by-products due to competing side reactions. These processes require tedious work-up operations to isolate montelukast and its intermediates and therefore result in a too long time period, which in turn makes these processes more costly and less environmentally friendly. It is known that the purification of montelukast is cumbersome and complex, and it is difficult to obtain montelukast with high purity, because montelukast and its precursors are unstable to oxygen and light which induce rapid degradation. Montelukast is generally obtained in low chemical and optical purity for the reasons mentioned above.

Several methods for purifying montelukast have been described in the art, which are based on the formation of montelukast salts. Thus, EP 737.186 relates to a process for the preparation of montelukast or its salts, which comprises reacting the dilithium dianion of 1- (mercaptomethyl) -cyclopropane-acetic acid with the corresponding mesylate alcohol ((2- (2- (2- (3(S) - (3- (2- (7-chloro-2-quinolyl-) -vinyl) phenyl) -3- (methylsulfonyloxy) -propyl) phenyl) -2-propanol) to obtain montelukast the crude acid is purified by forming its dicyclohexylamine salt, depending on the solvent used, two crystalline salts can be obtained, thus seeding to play a very critical role in the crystallization process, patent application US2005/234241 also discloses a process for the preparation of montelukast, the process proceeds via the formation of a montelukast organic base salt. In particular, example 2 describes the formation of the tert-butylamine salt of montelukast. Patent application WO 06/008751 also describes a process for the preparation of montelukast and a process for the purification of montelukast by means of the formation of several organic montelukast base salts.

According to WO 05/074935, montelukast sodium can be purified as follows: montelukast free acid is obtained in solid form and converted to montelukast sodium.

Therefore, it follows from the common general knowledge in the art that: it would be of interest for the industrial production of these compounds to provide a process for the purification of montelukast and its pharmaceutically acceptable salts in high yield and high optical purity.

Summary of The Invention

The inventors have found that: montelukast can be obtained with high optical purity and high yield by conversion to an amine salt of montelukast selected from the group consisting of tris- (hydroxymethyl) aminomethane salt, L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salt, and L- (+) - α -phenylglycinol salt. These amine salts have in common that: they are chiral amines and the amino moiety is substituted with at least one substituent comprising an ethylene group substituted with a hydroxyl group. The salts of the present invention allow the preparation of montelukast with higher optical purity than other known salts of montelukast, in particular the dicyclohexylamine salt or the tert-butylamine salt of montelukast. The degree of purification is surprisingly high when using crude montelukast with a lower optical purity as starting material. Montelukast can be obtained by a process that is easily industrializable, simple and cost-effective. In addition, montelukast can be prepared with high chemical purity.

Thus, according to a first aspect of the present invention there is provided a process for the purification of montelukast or its pharmaceutically acceptable salts or solvates, including stereoisomers or mixtures thereof, comprising converting montelukast acid or its solvates, including stereoisomers or mixtures thereof, in the presence of a suitable solvent to an amine salt selected from the group consisting of: tris- (hydroxymethyl) aminomethane salts, L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salts and L- (+) - α -phenylglycinol salts.

The present invention also relates to a purification process further comprising a previous purification step comprising a specific set of selective extractions of montelukast or its impurities in a mixture of organic solvents and water at a specific pH and temperature range. Therefore, montelukast can be obtained with high chemical purity.

Another aspect of the invention is the use of an amine salt of montelukast of the present invention for the preparation of montelukast acid or a pharmaceutically acceptable salt thereof.

Finally, another part of the invention is to provide novel salts of montelukast, in particular the following salts of montelukast: tris- (hydroxymethyl) aminomethane salts, L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salts and L- (+) - α -phenylglycinol salts, including solvates of L- (+) - α -phenylglycinol salts with methanol, ethanol or 2-propanol.

Good results in terms of chemical and optical purity have been observed by forming the cyclohexylamine salt of montelukast, and therefore the purification of montelukast by forming the cyclohexylamine salt of montelukast and the cyclohexylamine salt of montelukast itself as a product also form part of the present invention.

Detailed Description

As mentioned above, the purification process of the invention is carried out by forming an amine salt of montelukast selected from the group consisting of: tris- (hydroxy)Methyl) -aminomethane salts, L- (+) -threo-2-amino-1-phenyl-1, 3-propanedio-xide salts and L- (+) -alpha-phenylglycinol salts. The last salt was found to exist in different solvate forms. Solvates of L- (+) - α -phenylglycinol salt of montelukast with methanol, ethanol and 2-propanol therefore also form part of the present invention. The X-ray diffraction patterns of these montelukast salts are shown in fig. 1-5. Recording of X-ray diffraction patterns Using a PANalytical X' Pert PRO diffractometer at Cu-Ka 1 radiationAnd 45kV to 40 mA.

The best results were obtained for the purification of montelukast when L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol or L- (+) - α -phenylglycinol was used for the preparation of the amine salt. Thus, in a preferred embodiment, the amine salt is L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salt, and in another preferred embodiment, the amine salt is L- (+) - α -phenylglycinol salt. In a more preferred embodiment, the salt is an ethanol solvate of L- (+) - α -phenylglycine salt. Although the amines used are chiral amines, their use allows good results to be obtained without costly processes, since these amines are inexpensive as chiral products. Particularly inexpensive is L- (+) - α -phenylglycinol.

The preparation of solvates of L- (+) - α -phenylglycinol salt of montelukast with methanol, ethanol or 2-propanol can be carried out by the general methods described in the examples for preparing amine salts of montelukast according to the present invention, using the corresponding alcohol as crystallization solvent, or by recrystallizing L- (+) - α -phenylglycinol salt of montelukast, previously formed in another solvent, in the corresponding alcohol.

The above amines were prepared using montelukast acid as starting material. Montelukast acid may be provided in solid form or as a solution in a suitable solvent. Preferably, the amine salt of montelukast is prepared in a solvent selected from the group consisting of: (C)₂-C₈) -ethers, (C)₄-C₈) -alkyl esters, (C)₆-C₈) -an aromatic hydrocarbon, (C₆-C₈) -aliphatic hydrocarbons, (C)₂-C₅) -alcohols and mixtures thereof. More preferably, the solvent is selected from: toluene, ethyl acetate, ethanol, 2-propanol and mixtures thereof.

Generally, the amount of amine varies from 0.5 equivalents of amine to 2 equivalents of amine per equivalent of montelukast. Preferably, the amount of amine is from 0.95 equivalents to 1.05 equivalents. The preparation of the amine salt of montelukast is carried out at temperatures from 0 ℃ to reflux temperature, preferably at temperatures from 0 ℃ to room temperature.

Optionally, the amine salt of montelukast obtained may be treated with a suitable solvent at a temperature of from 0 ℃ to reflux temperature. Isolation of the amine salt of montelukast can be carried out by conventional methods such as filtration. Preferably, the suitable solvent is the same as the solvent used in the previous step of preparing the amine salt of montelukast.

The results regarding the optical purity of the amine salts of the present invention are detailed in table 1 (shown below) and in the examples. The enantiomeric excess (e.e.) of the starting montelukast acid used was 98.8%. Unlike what is described in the prior art, these salts are obtained in significantly higher purity and in higher yield.

Table 1:

as mentioned above, the degree of purification is surprisingly high when using crude montelukast with a lower optical purity as starting material. This fact is detailed in a comparative manner in table 2 below.

TABLE 2：

In addition, montelukast can be prepared with high chemical purity. This fact is detailed in table 3 below.

Table 3:

the results show that even when using crude montelukast with a lower chemical purity as starting material by forming the amine salt of the present invention instead of the salts known in the art, a significantly higher chemical purity can be achieved.

As mentioned above, the cyclohexylamine salt of montelukast also shows good results in terms of its chemical and optical purity, which can be used for the purification of montelukast by forming the cyclohexylamine of montelukast. This montelukast salt gave an X-ray diffraction pattern as shown in fig. 6.

In a preferred embodiment, the purification process of the invention also comprises a previous purification step comprising a specific set of selective extraction operations of montelukast or its impurities in a mixture of organic solvents and water at a specific pH and temperature range, so as to obtain montelukast with higher chemical purity, this set of solvent extraction operations comprising: the aqueous phase containing the crude montelukast in salt form is washed at least once with an organic solvent at a pH of 12.0 to 13.5 and a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture. An aqueous solution comprising montelukast in salt form can be obtained, for example, as follows: to a mixture of montelukast acid in an organic solvent is added an aqueous solution of a base. In a more preferred embodiment, the set of solvent extraction operations comprises the steps of: (a) subjecting the aqueous phase comprising crude montelukast in salt form to at least one wash with an organic solvent at a pH of 12.0 to 13.5 and a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture, and then separating the aqueous phase comprising montelukast in salt form; (b) optionally, subjecting the aqueous phase of step (a) to one or more washes with an organic solvent at a pH of 8.5 to 10.0 and a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture, and then separating the aqueous phase comprising montelukast in salt form; (c) extracting purified montelukast from the aqueous phase of step (a) or (b) with an organic solvent at a pH of 4.5 to 8.0 and a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture, and then separating the organic phase comprising montelukast acid; and (d) optionally, isolating montelukast in acid form from the organic phase of step (c). The organic phase in step (c) or the isolated montelukast acid in step (d) may be converted to an amine salt with the amine described above. Thus, montelukast in salt form can be isolated from the organic phase of step (c) as follows: adding an organic base selected from the group consisting of tris- (hydroxymethyl) aminomethane, L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol and L- (+) -alpha-phenylglycinol, and isolating the corresponding montelukast salt from the reaction medium. Likewise, montelukast is isolated from the organic phase of step (c) in the form of a cyclohexylamine salt by adding cyclohexylamine and isolating the salt formed.

The impurities that can be effectively removed using the selective extraction operation of the present invention are as follows:

these impurities, which are normally present in montelukast, can be effectively removed by subjecting the aqueous phase containing montelukast in salt form to a solvent extraction operation at a pH of 12.0 to 13.5.

Other impurities that may be present in montelukast are shown below:

these impurities, if present, can be effectively removed by subjecting the aqueous phase containing montelukast in salt form to a solvent extraction operation at a pH of 8.5 to 10.0.

Preferably, the solvent used for the selective extraction operation is selected from: (C)₂-C₈) -ethers, (C)₆-C₈) -aromatic hydrocarbons，(C₁-C₃) -chlorine-containing solvents and mixtures thereof. More preferably, the solvent is selected from: toluene, t-butyl methyl ether, tetrahydrofuran and mixtures thereof. Preferably, two or three washes at a pH of 12.0 to 13.5 are performed. Preferably, the washing of step (a) is carried out at a pH of from 12.0 to 13.5 and a temperature of from 20 ℃ to 60 ℃. More preferably, at least two washes are performed at a set pH and temperature. Also preferably, the washing of step (b) is carried out at a pH of 9.0 to 9.5 and a temperature of 20 ℃ to 60 ℃. The most suitable temperature conditions vary mainly depending on the solvent used. The temperature can be easily determined by the person skilled in the art based on the teaching of the examples given in the description.

These purification methods are particularly useful for purifying a cyano intermediate of formula (II) from an inorganic base at (C)₁-C₆) Montelukast obtained by reaction in a mixture of alcohol and water.

Certain impurities resulting from these processes can be effectively removed by subjecting the aqueous phase containing montelukast in salt form to a solvent extraction operation at a pH of 12.0 to 13.5. Among these impurities are cyano compounds used as starting materials and the following impurities:

in this case, the purification process further comprises a preceding step in which the compound of formula (II) is reacted with an inorganic base in (C)₁-C₆) -a mixture of alcohol and water to obtain crude montelukast in the form of a salt represented by formula (I). In thatIn this case, at the end of the reaction, the alcohol can be separated, for example, by distillation. Then, an organic solvent and water may be added to the crude reaction product to separate an aqueous phase containing the salt from an organic phase containing montelukast in salt form. Montelukast in salt form can be extracted from the organic phase with water. The resulting aqueous solution comprising montelukast in salt form is subjected to the purification process described above.

The amine salt of montelukast of the present invention is used to prepare montelukast. Thus, they can be converted to montelukast acid by treatment with an organic acid such as formic acid, acetic acid, propionic acid, or butyric acid, or with an inorganic acid such as hydrochloric acid. Preferably, the conversion is carried out in a mixture of an organic solvent and water. More preferably, the organic solvent is toluene or tert-butyl methyl ether. The conversion may be carried out at a temperature of from 0 ℃ to about 10 ℃ below the boiling point of the mixture. More preferably, the conversion is carried out at a temperature of from 40 ℃ to about 10 ℃ below the boiling point of the mixture. Isolation of the product can be carried out by conventional methods such as filtration. When montelukast acid or a pharmaceutically acceptable salt thereof is obtained from the montelukast amine salt of the present invention, the optical purity is not lost.

Montelukast acid can be converted into a pharmaceutically acceptable salt, preferably the sodium salt, by treatment with, for example, a base such as sodium hydroxide, sodium carbonate, sodium methoxide, or sodium tert-butoxide. Likewise, the amine salt of montelukast may also be conveniently converted to a pharmaceutically acceptable salt, preferably the sodium salt, using, for example, sodium methoxide or sodium hydroxide.

The optimum conditions for carrying out the process of the invention vary according to the parameters considered by the person skilled in the art, such as starting materials, molar ratios, temperature and the like. These reaction conditions can be readily determined by one skilled in the art by routine experimentation and the teachings of the examples in this document.

Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components or steps. The abstract of the present application is incorporated herein by reference. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided for illustrative purposes and are not intended to limit the invention.

Drawings

Figure 1 shows the X-ray powder diffraction pattern of the tris- (hydroxymethyl) aminomethane salt of montelukast.

Fig. 2 shows an X-ray powder diffraction pattern of L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salt of montelukast.

Fig. 3 shows an X-ray powder diffraction pattern of L- (+) - α -phenylglycinol salt of montelukast.

Figure 4 shows the X-ray powder diffraction pattern of the ethanol solvate of L- (+) - α -phenylglycine salt of montelukast.

Figure 5 shows the X-ray powder diffraction pattern of the 2-propanol solvate of L- (+) - α -phenylglycine salt of montelukast.

Figure 6 shows the X-ray powder diffraction pattern of the cyclohexylamine salt of montelukast.

Examples

Example 1: purification of montelukast acid using toluene as extraction solvent

45ml of a 0.5M NaOH aqueous solution was added to montelukast acid (impurity i)₂: 0.05 area%; impurity i₃: 1.39 area%; impurity i₅: 0.20 area%; impurity i₆: 0.05 area%) and toluene in 30ml of suspension. A bilayer solution was formed in which montelukast was shown to dissolve as the sodium salt in the aqueous layer. After stirring for 30 minutes at 40 ℃ the organic layer was discarded and two more washes with 30ml of toluene were carried out, each time adjusting the pH between 12.2 and 13.2. The resulting aqueous solution was acidified to pH9.3 using 2M aqueous acetic acid andwashed twice with 30ml of toluene. Both extractions were performed at 60 ℃. Finally, another 30ml portion of toluene was added to the aqueous solution and the mixture was acidified to pH6.0 with aqueous acetic acid (2M) at room temperature. The final organic layer was separated and kept as a solution of purified montelukast acid (purity by HPLC: 96.8 area%; impurity i)₂: 0.02 area%; impurity i₃: 1.23 area%; impurity i₅: not detected; impurity i₆: not detected%). Yield: 83 percent

Example 2: method for producing montelukast acid using tert-butyl methyl ether as extraction solvent Purification of

45ml of a 0.5M aqueous NaOH solution were added to montelukast acid (purity by HPLC: 97.4 area%; impurity i)₂: 0.05 area%; impurity i₃: 1.39 area%; impurity i₅: 0.20 area%; impurity i₆: 0.05 area%) and tert-butyl methyl ether in 30ml of suspension. A bilayer solution was formed in which montelukast was shown to dissolve as the sodium salt in the aqueous layer. After stirring at room temperature for 30 minutes, the organic layer was discarded. Two more washes were carried out at room temperature with 30ml of tert-butyl methyl ether, each time adjusting the pH between 12.5 and 13.5. The resulting aqueous solution was acidified to pH9.2 using 2M aqueous acetic acid and washed twice with 30ml of tert-butyl methyl ether at room temperature. Finally, another 30ml portion of toluene was added to the aqueous solution and the mixture was acidified to pH7.7 with 2M aqueous acetic acid at room temperature. The final organic layer was separated and kept as a solution of purified montelukast acid (chemical purity by HPLC: 97.7 area%; impurity i)₂: not detected; impurity i₃: 1.11 area%; impurity i₅: not detected; impurity i₆: not detected). Yield: 67%.

Example 3: preparation of montelukast acid

143.6g of sodium hydroxide were added to 102g of (R, E) -2- (1- ((1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) -3- (2- (2-hydroxy)Propan-2-yl) phenyl) propylthio) methyl) cyclopropyl) acetonitrile in 407ml ethanol in 96% (v/v) solution. The mixture was stirred at reflux temperature for 30 hours, after which time the solvent was distilled off in vacuo (purity by HPLC: 61.5 area%; impurity i)₂: 1.84 area%; impurity i₅: 3.70 area%; impurity i₆: 1.42 area%). The mixture was partitioned at room temperature using 1000ml of toluene and 1500ml of water. The aqueous phase in which the inorganic salts were dissolved was discarded, the organic phase was mixed with 1500ml of water, and the mixture was heated to 60 ℃ and stirred for 15 minutes. At this point, the product was dissolved in the aqueous layer. The pH of the aqueous layer was 12.5. Some of the impurities resulting from this process are dissolved in the organic layer. Thus, the organic layer was discarded. The toluene washing was repeated at 60 ℃. The resulting aqueous layer was cooled to room temperature and 1000ml of toluene was added, and the pH of the mixture was adjusted to 5.6 using 2M acetic acid solution. The mixture was stirred for 30 minutes and the aqueous layer was discarded. Finally, the organic layer was washed with 1000ml of water and kept as a solution of purified montelukast acid (purity by HPLC: 84.4 area%; impurity i)₂: 0.81 area%; impurity i₅: 0.70 area%; impurity i₆: 0.07 area%). HPLC corrected yield of the title compound obtained from the resulting solution: 86 percent.

Example 4: crystallization of montelukast acid

The toluene solution obtained in the preceding example was stirred at room temperature for 12 hours, after which time a yellow suspension was formed. The resulting solid was filtered off, washed with toluene and dried under vacuum at 30 ℃ for 24 hours, and 53g of montelukast acid (purity by HPLC: 96 area%) was recovered. HPLC corrected yield: 90 percent.

Examples 5 to 8 (comparative examples)

In comparative example 5, the dicyclohexylamine salt of montelukast was prepared under the conditions described in example 13 of EP 737186. Comparative example 6 corresponds to the dicyclohexylamine salt of montelukast prepared under the conditions described in example 2 of WO 04/108679. Comparative examples 7 and 8 are based on the process described in example 2 of US 2005/234241. The enantiomeric excess (e.e.) of the starting montelukast acid used in comparative examples 5-8 was 98.8%, and the HPLC chemical purity was 95.5%. Enantiomeric excess (e.e.) was measured by chiral HPLC. The results are summarized in table 4.

Table 4:

the chemical purity of the tert-butylamine salt of comparative example 8 was 97.3%.

General Process for the preparation of Montelukast amine

1.0 equivalent of amine was added in one portion to a suspension of 0.5g of montelukast acid (e.e.: 98.8%) in 2ml of solvent. If necessary, the suspension is heated until dissolution is achieved. After stirring at room temperature for 18 hours, the resulting suspension was filtered. The solid obtained was dried under vacuum at 30 ℃ for 24 hours. Use ofTABLE 5The general process was repeated with the corresponding amine and solvent shown in (a). Example 9 was carried out using 5.0g of montelukast acid. Example 16 was carried out using 2.4g of montelukast acid. The enantiomeric excess (e.e.) of the starting montelukast acid used in examples 9-18 was 98.8%.

The enantiomer (e.e.) was measured by chiral HPLC. DSC measurements were performed in an open pan from 25.0 ℃ to 250.0 ℃ at a scan rate of 10 ℃/min under a nitrogen purge using DSC mettler toledo DSC822 e.

Table 5:

the L- (+) - α -phenylglycinol salt of montelukast obtained in example 17 gave an X-ray diffraction pattern as shown in fig. 3.

Example 19 (comparative example): preparation of montelukast from montelukast acid with 95.2% e.e Dicyclohexylamine salt of (A)

0.5g of montelukast acid (e.e.: 95.2%) was suspended in 5ml of toluene and 0.11ml of dicyclohexylamine was added in one portion to obtain a clear light brown solution. After stirring for 8 hours, 1ml of heptane was added, the resulting suspension was vacuum filtered, and the obtained solid was vacuum-dried at 30 ℃ for 24 hours to obtain 0.12g of the title compound (yield: 19%, e.e.: 96.5%).

Example 20: preparation of L- (+) -plus of montelukast from montelukast acid with 95.2% e.e. Su-2-amino-1-phenyl-1, 3-propanediol salts

0.5g of montelukast acid (e.e.: 95.2%) was suspended in 5ml of 2-propanol and 0.14g of L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol was added in one portion, the resulting suspension was heated to obtain a clear, light brown solution, then the mixture was cooled to room temperature and after stirring for 4 hours, the resulting suspension was filtered under vacuum. The solid obtained (equal parts of e.e.: 98.6% after vacuum drying at 30 ℃ for 24 hours) was heated in 5ml of 2-propanol for 15 minutes, cooled to room temperature for 2 hours and filtered again. The resulting solid was dried under vacuum at 30 ℃ for 24 hours to obtain 0.35g of the title compound (yield: 55%, e.e.99.8%).

Example 21: preparation of montelukast from montelukast acid having 95.2% e.e L- (+) -alpha-phenylglycinol salt

0.5g of montelukast acid (e.e.: 95.2%) was suspended in 5ml of ethyl acetate and 0.11g of L- (+) - α -phenylglycinol was added in one portion, the resulting suspension was heated to obtain a clear pale brown solution, then the mixture was cooled to room temperature and after stirring for 4 hours, the resulting suspension was filtered under vacuum. The solid obtained (equal parts of e.e.: 98.2% after vacuum drying at 30 ℃ for 24 hours) was heated in 5ml of ethyl acetate for 15 minutes, cooled to room temperature for 2 hours and filtered again. The obtained solid was dried under vacuum at 30 ℃ for 24 hours to obtain 0.42g of the title compound (yield: 82%, e.e.99.5%).

Example 22: preparation of L- (+) -alpha-phenylglycinol of montelukast from montelukast free acid Salt (salt)

189.4g of montelukast acid (purity by HPLC: 93.8 area%, e.e.: 99.4%) were suspended in 1.9L of toluene and 44.3g of L- (+) - α -phenylglycinol were added in one portion. The resulting suspension was heated to obtain a clear light brown solution, then the mixture was cooled to room temperature and after stirring for 2 hours the resulting suspension was filtered under vacuum. The filter cake was washed with 500ml of toluene. The solid obtained (purity by HPLC: 98.4 area%, e.e.: 99.7%) was suspended in 2.9L of toluene, heated at 80 ℃ for 40 minutes, cooled to room temperature and filtered. Purity by HPLC: 98.9 area%, e.e.: 99.9 percent. Yield: 91 percent.

General Process for the preparation of Montelukast acid from amine salts of Montelukast

The amine salt of montelukast acid was suspended in 10 volumes of toluene and 10 volumes of water, and then 2M acetic acid solution was added until the pH was below 6. Then, the mixture was heated between 30 ℃ and 95 ℃ and stirred for 30 minutes, cooled, and the aqueous layer was discarded, and the organic layer was washed with 5 volumes of water and kept as a solution of montelukast acid.

Example 23: preparation of montelukast from the L- (+) -alpha-phenylglycinol salt of montelukast Free acid

169.5g of montelukast L- (+) - α -phenylglycinol salt (e.e.: 99.9%) were suspended in 1695ml of toluene, 1695ml of water was added to the suspension, followed by 170ml of 2M aqueous acetic acid. The mixture was heated to 35 ℃, stirred for 30 minutes, and the aqueous layer was discarded, and the organic layer was washed twice with 850ml of water, and the temperature was maintained at 35 ℃, and the resulting organic solution of montelukast acid was analyzed by chiral HPLC (e.e.: 99.9%). Yield: 97 percent.

Example 24: preparation of montelukast sodium

2.6g of montelukast acid was dissolved in 26ml of toluene and 8.9ml of NaOH in methanol (0.5M) was slowly added at room temperature, the mixture was stirred for 1 hour, and the solvent was removed in vacuo to obtain a residue. To a solution of the well stirred residue at room temperature in 4ml of ethyl acetate was added heptane (24ml) over 30 minutes, 2 hours after the addition, the off-white solid was filtered off under nitrogen and washed with 5ml of heptane, and the wet product was dried under vacuum at 70-80 ℃ for 2 days to yield 2.7g of montelukast sodium. Yield: 100 percent.

Example 25: preparation of montelukast sodium

1.15L of toluene was added to 115.2g of montelukast acid (e.e.: 99.9%). The mixture was cooled to 2-10 ℃ and 313.3ml of NaOH in methanol (0.5M) were added over 15 minutes, then the mixture was warmed to room temperature and stirred for 30 minutes, after which time 1.5L of solvent was distilled off under reduced pressure at 30 ℃ and then 2.4L of toluene was added to the crude product and distillation was restarted until a final volume of 300ml was obtained. The crude solution obtained is added to 1L of heptane over 1 hour at room temperature with stirring, 18 hours after the addition, the off-white solid is filtered off under nitrogen and washed with 500ml of heptane, and the wet product is dried under vacuum at 75 ℃ for 3 days to yield 120g of montelukast sodium. Yield: 100 percent. e.e.: 99.9 percent.

Example 26: preparation of montelukast from the L- (+) -alpha-phenylglycinol salt of montelukast Methanol solvates of L- (+) -alpha-phenylglycinol salt of (A)

4.0g of L- (+) - α -phenylglycinol salt of montelukast (HPLC: 98.2%) was suspended in 24ml of methanol and stirred at room temperature until a solution was obtained. The solution was kept at room temperature and a white solid precipitated out rapidly. The slurry was then cooled to 0 ℃, the solid filtered off and dried in vacuo to yield 3.2g of the title compound. Yield: 79% HPLC: 99.3%. DSC (peak): 91.9 ℃ and 104.0 ℃. H-RMN (6 d-DMSO): 0.6% (mol/mol) MeOH.

Example 27: preparation of montelukast from the L- (+) -alpha-phenylglycinol salt of montelukast Ethanol solvates of L- (+) -alpha-phenylglycinol salt of (A)

4.0g of L- (+) -alpha-phenylglycinol salt of montelukast (HPLC: 98.2%) are suspended in 40ml of ethanol, the suspension is heated to 60 ℃ until a solution is obtained, the solution is cooled to 20 ℃ and kept at room temperature with stirring until a large amount of solid precipitates out. The slurry was cooled to 0 deg.C, the solid filtered off and dried in vacuo to yield 3.35g of the title compound. Yield: HPLC, 81%: 99.2%. DSC (peak): 89.2 ℃, 95.1 ℃ H-RMN (6 d-DMSO): 0.6% (mol/mol) EtOH. The X-ray diffraction pattern is shown in fig. 4.

Example 28: preparation of montelukast from the L- (+) -alpha-phenylglycinol salt of montelukast 2-propanol solvates of L- (+) -alpha-phenylglycinol salt of (A)

4.0g of L- (+) -alpha-phenylglycinol salt of montelukast (HPLC: 98.8%) are suspended in 40ml of 2-propanol, the suspension is heated to 60 ℃ until a solution is obtained, the solution is cooled to 20 ℃ and kept at room temperature under stirring until a large amount of solid precipitates out. The slurry was cooled to 0 ℃, the solid filtered off and dried in vacuo to yield 3.64g of the title compound. Yield: 86%, HPLC: 99.3%. DSC (peak): H-RMN (6 d-DMSO): 0.6% (mol/mol) 2-propanol. The X-ray diffraction pattern is shown in fig. 5.

Example 29: preparation of tert-butylamine salt of montelukast

1.0g of montelukast free acid (purity by HPLC: 97.6%; e.e: 96.8%) is suspended in 10ml of acetone, 0.25g of tert-butylamine is added in one portion, after stirring for 4 hours at room temperature, the mixture is filtered under vacuum, the filter cake is washed three times with 2ml of acetone, and the solid obtained is dried under vacuum at 25 ℃ for 24 hours to give 0.68g of the title compound. (yield: 60%; purity by HPLC: 98.6%; e.e.: 97.7%).

Example 30: preparation of L- (+) -alpha-phenylglycinol salt of montelukast

The solution obtained in example 3, corresponding to 10g of montelukast acid (purity by HPLC: 89.1%; e.e.: 99.1%), was mixed with 2.4g of L- (+) - α -phenylglycinol. The resulting suspension was heated to 70 ℃ and after 10 minutes the mixture was cooled to room temperature, stirred for 1 hour and filtered under vacuum, and the filter cake was washed twice with 10ml of toluene and dried under vacuum at 25 ℃. 10.7g of the title compound are obtained. Yield: purity of HPLC: 98.3 area%. e.e.: 99.6 percent.

Claims (17)

1. A process for the purification of montelukast or its pharmaceutical salts or solvates thereof, including any stereoisomer or mixture thereof, which comprises converting montelukast acid or its solvate thereof, including any stereoisomer or mixture thereof, in the presence of a suitable solvent, into an amine salt selected from the group consisting of: tris- (hydroxymethyl) aminomethane salts, L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salts and L- (+) - α -phenylglycinol salts.

2. The purification process of claim 1, wherein the amine salt is selected from the group consisting of: l- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salt and L- (+) - α -phenylglycinol salt.

3. The purification process of claim 2, wherein the L- (+) - α -phenylglycinol salt of montelukast is a solvate selected from the group consisting of: solvates of methanol, ethanol and 2-propanol.

4. The purification process of any one of claims 1 to 3, wherein the solvent is selected from the group consisting of: (C)₂-C₈) -ethers, (C)₄-C₈) -alkyl esters, (C)₆-C₈) -an aromatic hydrocarbon; (C)₆-C₈) -non-aromatic hydrocarbons, (C)₂-C₅) -alcohols and mixtures thereof.

5. The purification process of claim 4, wherein the solvent is selected from the group consisting of: toluene, ethyl acetate, ethanol, 2-propanol and mixtures thereof.

6. The purification process according to any one of claims 1-5, further comprising a prior purification step comprising subjecting the montelukast or impurities thereof to a specific set of selective solvent extraction operations comprising at least one washing of the aqueous phase containing the crude montelukast in salt form with an organic solvent at a pH ranging from 12.0 to 13.5 and at a temperature ranging from 10 ℃ to about 5 ℃ below the boiling point of the mixture.

7. The purification process of claim 6, wherein the set of solvent extraction operations comprises the steps of:

(a) subjecting the aqueous phase comprising crude montelukast in salt form to at least one wash with an organic solvent at a pH of 12.0 to 13.5 and at a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture, and then separating the aqueous phase comprising montelukast in salt form;

(b) optionally, subjecting the aqueous phase of step (a) to one or more washes with an organic solvent at a pH of 8.5 to 10.0 and at a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture, and isolating an aqueous phase comprising montelukast in salt form;

(c) extracting purified montelukast from the aqueous phase of step (a) or (b) with an organic solvent at a pH of 4.5 to 8.0 and at a temperature of 10 ℃ to about 5 ℃ below the boiling point of the mixture, and separating an organic phase comprising montelukast acid; and

(d) optionally, isolating montelukast as the acid from the organic phase of step (c).

8. The purification process of any one of claims 6 to 7, wherein the organic solvent is selected from the group consisting of: (C)₂-C₈) -ethers, (C)₆-C₈) -an aromatic hydrocarbon; (C)₁-C₃) -chlorine-containing solvents and mixtures thereof.

9. The purification process of claim 8, wherein the solvent is selected from the group consisting of: toluene, t-butyl methyl ether, tetrahydrofuran and mixtures thereof.

10. The purification process of any one of claims 6 to 9, wherein at least two washes are performed at a pH of 12.0 to 13.5 and at a temperature of 20 ℃ to 60 ℃.

11. Purification process according to any one of claims 6 to 10, in which the extraction of step (b) is carried out at a pH equal to 9.0 to 9.5 and at a temperature ranging from 20 ℃ to 60 ℃.

12. The purification process of any one of the preceding claims, comprising:

(a) treating an amine salt of montelukast as defined in claim 1 with an acid to obtain montelukast acid; and optionally (c) a second set of instructions,

(b) the product thus obtained is treated with an ion source and the corresponding pharmaceutically acceptable salt is isolated.

13. The method of claim 12, wherein the ion is sodium and the pharmaceutically acceptable salt is a sodium salt.

14. The tris- (hydroxymethyl) aminomethane salt of montelukast.

15. L- (+) -threo-2-amino-1-phenyl-1, 3-propanediol salt of montelukast.

16. L- (+) - α -phenylglycinol salt of montelukast.

17. A solvate of L- (+) - α -phenylglycinol salt of montelukast selected from: solvates of methanol, ethanol and 2-propanol.