HK1073844B - Method for the production and purification of 1,7' - dimethyl - 2'- propyl - 2,5'- bi-1h-benzimidazole - Google Patents

Description

Preparation and purification method of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bi-1H-benzimidazole

The present invention relates to a method for the preparation and purification of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole which can be used industrially.

Background

J.med.chem. (1993), 36(25), 4040-51 and international patent application WO0063158 disclose a process for the preparation of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole from the reaction of 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid and N-methyl-o-phenylene-diamine dihydrochloride.

1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is valuable as an intermediate for the industrial synthesis of drugs, in particular the drug Telmisartan (Telmisartan) (future drugs 1997, 22(10), 1112-1116). High purity is required for this purpose. The purification processes disclosed in the above documents using ethyl acetate and diethyl ether are not suitable for large industrial processes, such as diethyl ether, which presents safety problems and requires a high level of operational expenditure on the basis of its toxicity, its tendency to form peroxides and its vapour, and the risk of explosion due to electron discharge.

It is therefore an object of the present invention to provide a process which can be used industrially to purify 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole prepared by the above-described synthetic process and obtained in its variants as proposed in the present patent specification.

Detailed Description

It was surprisingly found that 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole of high purity can be obtained in a process suitable for industrial use if carbon is used for the main purification step.

The present invention therefore relates to a process which can be used industrially for the purification of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole prepared by reacting 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid or a salt thereof with N-methyl-o-phenylene-diamine or a salt thereof, in which the crude product is treated with carbon.

In a preferred process according to the invention, 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid and N-methyl-o-phenylene-diamine or their salts, especially in the form of their salts, preferably in the form of their phosphates, chlorides or bromides, especially preferably in the form of their phosphates or chlorides, especially preferably in the form of their phosphates, are reacted in the presence of methanesulfonic acid and phosphorus pentoxide.

In another preferred method, the reaction is carried out at a temperature of 125-145 ℃.

In a particularly preferred process, the purification step is carried out by adding the reaction mixture to charcoal after the reaction, hydrolysis and adjustment of the pH have ended.

Another particularly preferred process is one in which the purification step is carried out using charcoal at a temperature of 70-80 ℃.

In a particularly valuable process, the purification step is carried out at a pH of 0.7 to 1.2.

In another particularly valuable process, the amount of carbon used in the purification step is 5 to 20% by weight of the 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid used.

In a particularly preferred method, the purification steps after filtration and centrifugation of the reaction mixture are repeated one to three times.

In another particularly preferred process, the purification by treatment with charcoal is followed in turn by the following steps:

a) adding an organic solvent into the mixture, and adding a solvent,

b) adding a base to adjust the pH to 5 to 6,

c) the aqueous phase is separated and the aqueous phase,

d) the 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is separated from the organic phase by crystallization and subsequent filtration or centrifugation.

In another preferred process, isopropanol is used as organic solvent in step a).

Also particularly preferred is a process in which the base is added in step b) at a temperature of from 70 to 80 ℃.

Also particularly preferred is a process in which the crystallization in step d) is carried out by adding water.

1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is used in particular for the preparation of Telmisartan (Telmisartan). Telmisartan (Telmisartan) was prepared according to the method described in future drugs 1997, 22(10), 1112-1116 according to the following Synthesis Panel I:

synthesis of FIG. I:

schemes A, B, C, D and E below are particularly preferred embodiments of the process of the present invention.

Scheme A:

to an organic acid solution, in particular methanesulfonic acid, phosphorus pentoxide, thionyl chloride, sulfuryl chloride, acetic anhydride or polyphosphoric acid, preferably methanesulfonic acid, phosphorus pentoxide or thionyl chloride, and/or mixtures or dilutions thereof with an inert organic solvent, preferably N-methylpyrrolidone, o-, m-or p-xylene, particularly preferably N-methylpyrrolidone, 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC) and N-methyl-o-phenylene-diamine (NMPD) or salts thereof are metered in succession with stirring at a temperature of 100 ℃ to 160 ℃, preferably 115 ℃ to 150 ℃, in particular 125 ℃ to 145 ℃, particularly preferably about 135 ℃. The molar ratio of PMBC to NMPD is 1.0: 0.5 to 1.0: 2.0, preferably 1.0: 0.7 to 1.0 to 1.5, particularly preferably 1.0: 1.0.

The amounts of organic acid and organic solvent were determined based on the amount of PMBC used. Up to 10 mol, preferably from 2 to 8 mol, particularly preferably about 7 mol, of organic acid and up to 2 mol, preferably from 0.5 to 1.5 mol, particularly preferably about 1 mol, of phosphorus pentoxide are used per mole of PMBC.

After the addition has been completed, the mixture is stirred at a temperature of 100 ℃ and 160 ℃, preferably 125 ℃ and 145 ℃, in particular 135 ℃ for a period of up to 10 hours, preferably 1 to 4 hours, particularly preferably 3 hours. Subsequently, for the hydrolysis of the excess acid components (anhydride, hydrochloric acid), water is metered in at a temperature of up to 100 ℃, preferably up to 90 ℃, in a ratio of 1.0: 2.0 to 1.0: 0.1, preferably 1.0: 1.4 to 1.0: 0.2, to the amount of organic acid used, for example phosphorus pentoxide.

After complete hydrolysis, the pH is adjusted to 0.2 to 1.8, preferably 0.5 to 1.5, particularly preferably 0.7 to 1.2, particularly preferably 0.9, by adding a base, preferably sodium hydroxide, sodium carbonate or an amine, particularly preferably sodium hydroxide, sodium carbonate, ammonia, pyridine or triethylamine, particularly preferably sodium hydroxide solution or ammonia, particularly preferably sodium hydroxide. The temperature of the reaction mixture during the addition should not exceed 100 ℃, preferably be below 90 ℃ and particularly preferably be between 70 and 80 ℃.

At a constant temperature range, the reaction mixture is mixed for purification with carbon, preferably activated carbon, preferably "dried activated carbon", "wet activated carbon" or "activated carbon granules", particularly preferably "dried activated carbon" of SX2, SX or L2S. The activated carbon preferably used in the process of the invention is, for example, available from Norit, Atofina or Begerow. The amount of carbon used per purification step is 5 to 20% by weight, preferably 6 to 15% by weight, particularly preferably 8 to 12% by weight, and particularly preferably about 10% by weight, based on the amount of PMBC used. The reaction mixture mixed with the carbon is stirred at a temperature of up to 90 ℃, preferably from 50 to 80 ℃, particularly preferably from 70 to 75 ℃ for at least 5 minutes, preferably from 5 to 60 minutes, preferably from 8 to 50 minutes, particularly preferably from 10 to 30 minutes, and subsequently filtered or centrifuged, preferably filtered. The purification step is repeated 1 to 10 times, preferably 1 to 5 times, particularly preferably 1 to 3 times, in particular 2 times, with the filtered or centrifuged reaction mixture.

Subsequently, an organic solvent, preferably n-butanol, tert-butanol, 2-methyl-propanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, tetrahydrofuran or toluene, preferably n-butanol or isopropanol, particularly preferably isopropanol, is added to the reaction mixture with stirring. The amount of solvent is determined by the amount of PMBC previously used in the process and should be in the range of 1: 1 to 20: 1, preferably 1: 1 to 10: 1, particularly preferably 1: 1 to 5: 1, especially 3: 1.

After the addition of the solvent has been completed, a base, in particular sodium hydroxide, sodium carbonate or an amine such as ammonia, pyridine or triethylamine, in particular sodium hydroxide or ammonia, in particular sodium hydroxide, is metered in at a temperature of up to 100 ℃, preferably from 50 to 90 ℃, particularly preferably from 70 to 80 ℃ and particularly preferably about 75 ℃ in order to adjust the pH to 4 to 8, in particular from 5 to 7, particularly preferably about 5 to 6. The precipitate is stirred for at least 5 minutes, preferably 10 to 30 minutes, while maintaining a constant temperature range. After the phase separation was complete, the aqueous phase was separated and discarded.

For crystallization of the product, acetone, acetate or water, preferably acetone or water, particularly preferably water, is metered into the organic phase at room temperature or at elevated temperature, preferably at reflux. The amount of water used corresponds to 50 to 200% by volume, preferably 70 to 150% by volume, predominantly 80 to 130% by volume, particularly preferably 120% by volume, based on the amount of organic solvent used.

After the addition of water has been completed, the precipitate is cooled to a temperature of at most 40 ℃, in particular 5 to 30 ℃, particularly preferably 10 to 20 ℃, particularly preferably 15 ℃.

The precipitate may be filtered or centrifuged to isolate the product. The product thus obtained can be treated with a wash solution comprising water and one or more organic solvents selected from acetone, n-butanol, tert-butanol, cyclohexane, dichloromethane, ethyl acetate, isopropanol, methanol, 2-methyl-propanol, n-propanol, tetrahydrofuran, toluene or xylene, preferably acetone, isopropanol or ethyl acetate, particularly preferably isopropanol. The washing liquid generally has a volume ratio of organic solvent/water of from 1: 0 to 1: 10, in particular from 1: 1 to 1: 8, particularly preferably from 1: 1.5 to 1: 6, particularly preferably 1: 2. The product is subsequently washed again with water and dried at a temperature of up to 110 ℃, preferably up to 100 ℃, particularly preferably from 75 to 90 ℃, preferably under vacuum.

Scheme B:

variant A, no carbon is added to the reaction solution or the reaction solution is added to carbon, but the strongly acidic reaction solution is filtered through a carbon-filled vessel or column (Kartuschen) at a pH of about 0.2 to 1.8, preferably 0.5 to 1.5, particularly preferably 0.7 to 1.2, particularly preferably 0.9. The filtrate was purified by extraction with an organic solvent and further processed as described in scheme a.

Scheme C:

in an alternative to treating the acid with charcoal to a strongly acidic reaction solution, the organic product solution may be treated with charcoal, for example by adding charcoal to the organic solution, adding the solution to the charcoal or by filtration through the charcoal, and further treated as described in scheme a.

Scheme D:

variants A, B or C, extraction with large amounts of organic solvent, can also be carried out at lower temperatures and this can be reduced again before precipitation.

Scheme E:

another possible method for obtaining the pure product 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is to include: after the reaction and hydrolysis by adding sufficient base, in particular sodium hydroxide, sodium carbonate or an amine such as ammonia, pyridine or triethylamine, particularly preferably sodium hydroxide or ammonia, or by adding the reaction solution to a lye, the reaction product is precipitated directly. After subsequent filtration, the crude product may be dried and dissolved in an organic acid or an organic solvent or a mixture thereof, the organic solvent being selected from methanesulfonic acid, isopropanol, n-butanol, ethyl acetate, methanol or toluene, preferably methanesulfonic acid or isopropanol, and subjected to a carbon purification step and subsequent further treatments as described in scheme a. If methanesulfonic acid is used, the precipitation can be carried out by adding an alcoholic, for example methanolated, sodium hydroxide solution or by introducing the product solution into an alcoholic, for example methanolated, sodium hydroxide solution. Ascorbic acid or BHT (2, 6-bis-tert-butyl-4-methoxyphenol) may be added to this embodiment, with ascorbic acid being preferred.

The following examples are presented to illustrate the preparation and purification of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole. It is merely representative of possible approaches and is not limiting of the present disclosure.

Example 1 (scheme A)

Preparation and purification of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole

70kg of phosphorus pentoxide (at 115-145 ℃) were dissolved in 300kg of methanesulfonic acid. To this solution 100kg of 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC) and 90kg of N-methyl-o-phenylene-diamine (NMPD) were added at 145 ℃ 125 ℃. The reaction mixture was stirred at this temperature for 4 hours and then cooled to about 80 ℃. The mixture was quenched with about 350 liters of water. About 180kg of 50% sodium hydroxide solution was added to adjust the pH to about 1. The strongly acidic reaction solution was mixed with about 10kg of activated carbon and stirred at 70-80 ℃ for at least 5 minutes. The charcoal was then filtered off and washed with water. The charcoal treatment of the solution was repeated 3 times. To the filtrate, about 400 liters of isopropanol were added with stirring and the pH was adjusted to about 5-6 by adding about 190kg of 50% sodium hydroxide solution. Upon subsequent phase separation, the lower aqueous phase was separated and discarded. To precipitate the product, about 420 l of water are metered into the organic phase under reflux. The precipitate was cooled to about 20 ℃. The precipitated product was centrifuged and washed with about 280 liters of a 2: 1 mixture of water and isopropanol, followed by about 70 liters of water. The isolated product was dried in vacuo at up to 90 ℃ for at least 5 hours. Its HPLC purity was at least 99.5 area%. The yield was about 85% based on the PMBC used.

Example 2 (scheme E)

Preparation and purification of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole

70kg of phosphorus pentoxide were dissolved in 300kg of methanesulfonic acid at 115-145 ℃. To this solution 100kg of 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid (PMBC) and 90kg of N-methyl-o-phenylene-diamine (NMPD) were added at 145 ℃ at 125 ℃. The reaction mixture was stirred at this temperature for 4 hours and then cooled to about 80 ℃. The mixture was quenched with about 540 liters of water. To precipitate the product, the pH is adjusted to 5-6 with about 370kg of 50% sodium hydroxide solution at 50-60 ℃. The precipitated product was filtered off by centrifugation, washed with 780-1040 l of water and dried at maximum 90 ℃ in vacuo, giving a yield of about 85-100% based on the PMBC used.

150kg of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole and 3kg of ascorbic acid (optionally) are suspended in 285 l of water and mixed with 94kg of methanesulfonic acid. To the strongly acidic solution about 10kg of activated carbon was added and the suspension was stirred at 50-60 ℃ for at least 5 minutes. The charcoal was then filtered off and washed with water. The charcoal treatment of the solution was repeated 6 times. To precipitate the product, the filtrate is added, with stirring, to a solution of about 88kg of 45% sodium hydroxide solution and 150 l of methanol at 60-80 ℃. Alternatively, methanolized sodium hydroxide solution may be added to the filtrate. It is then cooled to 10-25 ℃ and the pH is adjusted to about 9-12 with sodium hydroxide solution. The product was then centrifuged and washed with about 700 liters of water. The isolated product was dried in vacuo at up to 90 ℃. Its HPLC purity was about 99 area%. The yield was about 85% based on the 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole used.

Example 3 (scheme C)

Purification of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole

150kg of 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole were dissolved in 750 l of isopropanol at 70-80 ℃ and mixed with 7kg of charcoal. After stirring for at least 5 minutes, the char is separated and washed with about 70 liters of isopropanol and about 145 liters of water. The charcoal treatment was repeated 3 times. To precipitate the product, about 420 l of water are metered into the organic phase under reflux. The precipitate was cooled to about 20 ℃. The precipitated product was centrifuged and washed with about 400 liters of a 2: 1 mixture of water and isopropanol, followed by about 70 liters of water. The isolated product was dried in vacuo at up to 90 ℃ for at least 5 hours. Its HPLC purity was at least 99.5 area%. The yield was 85-95% based on 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole used.

Claims (36)

1. A process for purifying 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole prepared by reacting 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid or a salt thereof with N-methyl-o-phenylene-diamine or a salt thereof, characterized in that: after the chemical reaction, hydrolysis and pH adjustment are complete, the reaction product is treated with charcoal.

2. A process according to claim 1, characterized in that 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid and N-methyl-o-phenylene-diamine or a salt thereof are reacted in the presence of methanesulfonic acid and phosphorus pentoxide.

3. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of 125-145 ℃.

4. The process as claimed in claim 2, wherein the reaction is carried out at a temperature of 125-145 ℃.

5. The process according to claim 1, wherein the reaction mixture is added to the char or the char is added to the reaction mixture after the reaction, hydrolysis and pH adjustment have been completed.

6. The process according to claim 2, characterized in that after the reaction, hydrolysis and pH adjustment, the reaction mixture is added to charcoal or charcoal is added to the reaction mixture.

7. A process according to claim 3, characterized in that after the reaction, hydrolysis and adjustment of the pH has ended, the reaction mixture is added to charcoal or charcoal is added to the reaction mixture.

8. The process according to claim 4, characterized in that the reaction mixture is added to the char or the char is added to the reaction mixture after the reaction, hydrolysis and pH adjustment have been completed.

9. A process according to claim 5, characterized in that the char treatment is carried out at a temperature of 70-80 ℃.

10. The process according to claim 6, characterized in that the reaction mixture is added to the char or the char is added to the reaction mixture after the reaction, hydrolysis and pH adjustment have been completed.

11. The process according to claim 7, characterized in that after the reaction, hydrolysis and pH adjustment, the reaction mixture is added to charcoal or charcoal is added to the reaction mixture.

12. The process according to claim 8, characterized in that after the reaction, hydrolysis and pH adjustment, the reaction mixture is added to charcoal or charcoal is added to the reaction mixture.

13. A method according to any of claims 1-12, characterized in that the char treatment is carried out at a pH of 0.7-1.2.

14. A method according to any one of claims 1-12, characterized in that the amount of char used is 5-20% by weight of the 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid used.

15. A process according to claim 13, characterized in that the amount of carbon used is 5-20% by weight of the 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid used.

16. The process according to any one of claims 1 to 12, characterized in that the purification step after filtration or centrifugation of the reaction mixture is repeated one to three times.

17. The process according to claim 13, characterized in that the purification step after filtration or centrifugation of the reaction mixture is repeated one to three times.

18. The process according to claim 15, characterized in that the purification step after filtration or centrifugation of the reaction mixture is repeated one to three times.

19. Process according to any one of claims 1 to 12, characterized in that the following steps are carried out in sequence after purification by treatment with charcoal:

a) adding an organic solvent into the mixture, and adding a solvent,

b) adding an alkali to adjust the pH value to 5-6,

c) separating the aqueous phase

d) The 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is separated from the organic phase by crystallization and subsequent filtration or centrifugation.

20. The process according to claim 13, characterized in that the following steps are carried out in sequence after purification by treatment with charcoal:

a) adding an organic solvent into the mixture, and adding a solvent,

b) adding an alkali to adjust the pH value to 5-6,

c) separating the aqueous phase

d) The 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is separated from the organic phase by crystallization and subsequent filtration or centrifugation.

21. The process according to claim 15, characterized in that the purification by treatment with charcoal is followed by the following steps in sequence:

a) adding an organic solvent into the mixture, and adding a solvent,

b) adding an alkali to adjust the pH value to 5-6,

c) separating the aqueous phase

d) The 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is separated from the organic phase by crystallization and subsequent filtration or centrifugation.

22. The process according to claim 18, characterized in that the purification by treatment with charcoal is followed by the following steps in sequence:

a) adding an organic solvent into the mixture, and adding a solvent,

b) adding an alkali to adjust the pH value to 5-6,

c) separating the aqueous phase

d) The 1, 7' -dimethyl-2 ' -propyl-2, 5' -bis-1H-benzimidazole is separated from the organic phase by crystallization and subsequent filtration or centrifugation.

23. The process according to claim 19, characterized in that isopropanol is used as organic solvent in step a).

24. The process according to claim 20, characterized in that isopropanol is used as organic solvent in step a).

25. The process according to claim 21, characterized in that isopropanol is used as organic solvent in step a).

26. The process according to claim 22, characterized in that isopropanol is used as organic solvent in step a).

27. The process according to claim 19, characterized in that the addition of the base in step b) is carried out at a temperature of 70-80 ℃.

28. The process according to claim 22, characterized in that the addition of the base in step b) is carried out at a temperature of 70-80 ℃.

29. The process according to claim 23, characterized in that the addition of the base in step b) is carried out at a temperature of 70-80 ℃.

30. The process according to claim 26, characterized in that the addition of the base in step b) is carried out at a temperature of 70-80 ℃.

31. The process according to claim 19, characterized in that in step d) the crystallization is carried out by adding water.

32. The process according to claim 22, characterized in that in step d) the crystallization is carried out by adding water.

33. The process according to claim 23, characterized in that in step d) the crystallization is carried out by adding water.

34. The process according to claim 26, characterized in that in step d) the crystallization is carried out by adding water.

35. The process according to claim 27, characterized in that in step d) the crystallization is carried out by adding water.

36. The process according to claim 30, characterized in that in step d) the crystallization is carried out by adding water.