WO2007133040A1

WO2007133040A1 - Method for preparing losartan

Info

Publication number: WO2007133040A1
Application number: PCT/KR2007/002380
Authority: WO
Inventors: Sun Young Jang; Sung Bum Kim; Sangmin Yun; Han Kyong Kim; Kwee Hyun Suh
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2006-05-15
Filing date: 2007-05-15
Publication date: 2007-11-22
Also published as: KR20070110617A; KR100809159B1

Abstract

The present invention relates to a simple and efficient method for preparing losartan, which comprises the steps of reacting a nitrile compound with triethylamine hydrochloride and sodium azide in an organic solvent; and crystallizing losartan directly from the reaction solution.

Description

METHOD FOR PREPARING LOSARTAN

Technical Field

[1] The present invention relates to an improved method for preparing losartan. Background Art [2] Losartan (2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-(lH - tetrazole-5-yl)biphenyl-4-yl)methyl]imidazole) of formula (J) was disclosed for the first time in U.S. Patent No. 5,138,069, and some other methods for preparing losartan have been disclosed in U.S, Patent Nos. 5,138,069, 4,820,843, 5,155,118 and 5,130,439; and International Patent Publication Nos. WO95/17396 and WO2005/23758; and a potassium salt thereof has been used for treating hypertension due to its effect as an angiotensin II receptor blocker.

[3]

[5] (I) [6] [7] One of important steps in the method for preparing losartan is the introduction of the tetrazole group. U.S. Patent No. 5,155,118 discloses a method of preparing losartan, which comprises the steps of reacting a nitrile compound of formula (II) with azido- trialkyltin, or with sodium azide and chlorotrialkyltin to prepare a tetrazole derivative protected by a trialkyltin group, and allowing the resulting tetrazole derivative to react with trityl chloride (Ph C-Cl) to produce a tetrazole derivative protected by a trityl group, followed by removal of the trityl group.

[8]

[10] (H)

[H] [12] Further, U.S. Patent No. 4,820,843 discloses a method of preparing losartan, which comprises the steps of reacting a nitrile compound of formula (III) with azido- trialkyltin, or with sodium azide and chlorotrialkyltin, to prepare a tetrazole derivative and letting the resulting tetrazole derivative to react with trityl chloride to prepare a tetrazole derivative protected by a trityl group, followed by conducting a series of follow-up steps.

[13]

[16] [17] However, the above-mentioned methods require azidotributyltin having strong toxicity, and when the compound of formula (II) is used as a starting material, highly toxic tin oxide may remain in the losartan product. Further, when the compound of formula (HI) is used as a starting material, a large number of reaction steps must be employed, lowering the efficiency of the overall process.

[18] A classical method for preparing a tetrazole compound directly from a nitrile compound comprises the step of reacting a nitrile compound with sodium azide in N,N-dimethylformamide at 120°C, in the presence of lithium chloride or ammonium chloride {see Finnegan et al, J. Am, Chem, Soc, 80, 3908-3911, 1958).

[19] U.S. Patent No. 5,138,069 and International Patent Publication WO95/17396 disclose a method for preparing losartan from the compound of formula (II), using reaction conditions similar to those of said classical method. However, this method has the disadvantages that the yield of losartan is very low and the content of impurities is very high even when sodium azide is used in an excessive amount. Besides, this method generates large amounts of by-products and is hampered by a risk of explosion of sublimable ammonium azide generated during the reaction.

[20] Bernstein et al. have reported a method for preparing a tetrazole compound in a moderate yield, which comprises the step of reacting specific nitrile compounds with triethylamine and sodium azide in the presence of N-methyl-2-pyrrolidinone at a higher temperature of 150°C, and extracting the reaction mixture with organic solvents exhaustively. However, it appeared that this method is not applicable for the func- tionalized compounds like formula (II), generating a large amount of by-products under the above conditions.

[21]

Disclosure of Invention Technical Problem

[22] Accordingly, it is an object of the present invention to provide a method of preparing high purity losartan by using the nitrile compound of formula (II) in a high yield.

Technical Solution

[23] In accordance with an aspect of the present invention, there is provided a method for preparing losartan of formula (I), which comprises the steps of reacting the nitrile compound of formula (II) with triethylamine hydrochloride and sodium azide in a polar organic solvent, and crystallizing losartan directly from the resulting mixture.

[25] (I)

[27] (H) [28] [29]

Mode for the Invention [30] Specifically, the inventive method of preparing losartan of formula (I) comprises the step of reacting the nitrile compound of formula (II) with triethylamine hydrochloride and sodium azide in a polar organic solvent at a temperature ranging from 105 to 135°C.

[31] The nitrile compound of formula (II) may be prepared by the method disclosed in

U.S. patent No. 5,138,069.

[32] The polar organic solvent used in the present invention is preferably

N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, and a mixture thererof . The preferred amount of the organic solvent ranges from 2 to 6 ml per 1 g of the nitrile compound of formula (II).

[33] Sodium azide may be employed in an amount ranging from 1 to 5 molar equivalents based on the nitrile compound, and triethylamine hydrochloride may be employed in an amount ranging from 1 to 1.5 molar equivalents based on sodium azide.

[34] The reaction time is about 5 to 48 hours, although it varies depending on the amounts of the organic solvent, triethylamine hydrochlroride and sodium azide, as well as the reaction temperature.

[35] The reaction temperature may range from 105°C to 135°C. It needs to keep the reaction temperature at higher than 105°C for the reaction to proceed efficiently, and if over 135°C, by-products may be generated.

[36] After converting the nitrile compound of formula (II) into a tetrazole compound, the desired product, losartan, exists in the reaction solution as a salt of triethylamine. Accordingly, the inventive method further comprises the step of crystallizing losartan. In accordance with the present invention, the crystallization may be carried out directly from the above reaction solution by adding water and acetone to the reaction solution and adjusting the pH of the resulting mixture to 2 to 5 with hydrochloric acid.

[37] Unless acetone is added to the reaction solution, losartan can not be crystallized from the reaction solution. Acetone may be employed in an amount ranging from 0.5 to 3.5 ml per 1 ml of the organic solvent used in the reaction. When the amount of acetone is less than 0.5 ml, the purity of losartan may be lowered due to incomplete crystallization, and when more than 3.5 ml, the yield of the product may be unsatisfactory.

[38] Water is added to the reaction solution to dissolve unreacted triethylamine hydrochloride and sodium azide, and it may be employed in an amount of ranging from 1.5 to 3.5 ml per 1 ml of an organic solvent.

[39] The inventive method comprising reacting the nitrile compound of formula (II) with triethylamine hydrochloride and sodium azide in an organic solvent and crystallizing losartan directly from the resulting reaction solution solves some of the problems of the conventional method for preparing a tetrazole compound from a nitrile compound. For example, additional multi-purification processes are not required. That is, a con- ventional method that uses a water-miscible polar solvent as a reaction solvent requires the steps of extracting a reaction solution exhaustively with a water-immiscible organic solvent to collect the desired product dissolved in the polar organic solvent layer mixed with water, concentrating the resulting extract and crystallizing the desired product using an appropriate organic solvent.

[40] Further, the inventive method capable of directly crystallizing losartan from the reaction solution by way of adding acetone and water provides a benefit as compared to that using an aromatic hydrocarbon solvent such as toluene. For example, when the nitrile compound of formula (II) is converted to a tetrazole compound, losartan, in the presence of an aromatic hydrocarbon solvent, the reaction rate is very slow, insoluble materials in the form of black tar are generated, and losartan can not be crystallized directly from the reaction solution.

[41] Thus, the inventive method can be beneficially applied to the conversion of a nitrile compound of formula (II) to a tetrazole compound.

[42] In the present invention, a small amount of losartan may be seeded to the reaction solution at the time of adjusting the pH of the solution to induce a facile crystallization. Further, if necessary, the desired product, losartan may be further treated with activated carbon in an appropriate solvent, or can be recrystallized to obtain higher product purity.

[43] According to the present invention, losartan having a high degree of purity can be easily prepared from a nitrile compound of formula (II) at a relatively low temperature in a high yield. HPLC analysis of losartan prepared by the inventive method shows a purity of more than 95% of purity and a yield of more than 70%.

[44] Losartan thus prepared can be beneficially used for the preparation of a pharmaceutical composition for treating hypertension after converting into a potassium salt to a conventional method.

[45]

[46] The present invention will be described in further detail with reference to Examples.

However, it should be understood that the present invention is not restricted by the specific Examples.

[47]

[48] Reference example: Preparation of

2-n-butyl-4-chloro-5-hydroxymethyl-l-[r2'-cyanobiphenyl-4-yl^')methyllimidazole (the compound of formula GTi)

[49] 600 g of 2-butyl-4-chloro-lH-imidazole-5-carboxaldehyde prepared by the method of U.S. patent No. 4,355,040 and 858 g of 4'-bromomethyl-2-biphenylcarbonitrile were added to N,N-dimethylacetamide (4,800 ml) and then 457 g of potassium carbonate was slowly added thereto, followed by stirring the resulting solution at room temperature for 5 hours. Methanol (1,800 ml) was added thereto and the resulting mixture was cooled to 5°C. Then, 47.1 g of sodium borohydride was slowly added thereto while maintaining the temperature of the mixture at under 10°C or lower, and then stirred at room temperature for an hour. Water (6,000 ml) was slowly added to the resulting mixture to induce the precipitation of a solid material, which was filtered, washed with a mixed solution of water and methanol, and dried at 40°C to obtain 1,110 g of the title compound as a white crystalline powder.

[50]

[51] Melting point: 158°C to 161°C

[52] ¹H-NMR (CDCl₃, ppm): 7.8 (IH, d), 7.68 (IH, t), 7.5 (4H, m), 7.1 (2H, d), 5.3 (2H, s), 4.6 (2H, s), 2.7 (IH, br), 2.6 (2H, m), 1.7 (2H, m), 1.4 (2H, m), 0.9 (3H, t).

[53]

[54] Example 1 : Preparation of losartan (the compound of formula (T))

[55]

[56] 100 g of 2-n-butyl-4-chloro-5-hydroxymethyl- 1 - [(2'-cyanobiphenyl-4-yl)methyl] imidazole (263 mmol) prepared in Reference Example, 72.4 g of triethylamine hydrochloride (526 mmol, 2 mole equivalents) and 34.2 g of sodium azide (526 mmol, 2 mole equivalents) were successively added to N-methyl-2-pyrrolidinone (300 ml), and the resulting mixture was kept at 120°C for 12 hours and then cooled to 80°C. Purified water (600 ml) and acetone (600 ml) were added to the resulting solution and 6N hydrogen chloride aqueous solution was added thereto to adjust the pH to 4.0. Then, 100 mg of losartan was seeded thereto and stirred for 6 hours while slowly cooling to room temperature to allow the formation of a solid material. 6N hydrogen chloride aqueous solution was added thereto to adjust the pH to 3.5. The resulting suspension was cooled to 5°C and stirred for 3 hours. The resulting precipitates were filtered under a reduced pressure, washed with a mixture of 300 ml of purified water and 100 ml of acetone, and dried at 45°C, to obtain 82.5 g of the title compound (yield: 76 %) as a tiny yellow solid.

[57]

[58] Melting point: 185°C to 187°C

[59] Purity: 97.0% (HPLC)

[60] ¹H-NMR (CDCl₃, ppm): 7.65 (2H, m), 7.5 (2H, m), 7.0 (4H, m), 5.2 (2H, s), 4.3 (2H, s), 2.4 (2H, m), 1.4 (2H, m), 1.2 (2H, m), 0.8 (3H, t).

[61]

[62] Example 2-15

[63] Losartan was obtained by a method similar to that used in Example 1 using 100 g of

2-n-butyl-4-chloro-5-hydroxymethyl-l-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-m ethanol (263 mmol) as a starting material while varying the reaction conditions as shown in Table 1.

[64] Table 1 [Table 1]

[65] Example 16: preparation of losartan potassium (potassium salt of the compound of formula (I)

[66] [67] 85 g of losartan was suspended in isopropanol (250 ml), and a solution prepared by dissolving 12.1 g of potassium hydroxide in methanol (85 ml) was slowly added thereto, followed by stirring for 30 minutes at room temperature. The resulting solution was filtered to remove insoluble materials and the filtrate was refluxed while adding cyclohexane (1,000 ml) thereto. Then, the resulting mixture was distilled to remove 340 ml of solvent and the residue containing solids was slowly cooled to room temperature. After stirring for 4 hours, the solid material was filtered, washed with a mixture of isopropanol and cyclohexane, and dried at 45 °C, to obtain 87.3 g of the title compound (yield: 90 %).

[68]

[69] Melting point: 269°C to 274°C

[70] ¹H-NMR (DMSO-d₆, ppm): 7.65 (IH, m), 7.4 (2H, m), 7.3 (IH, m), 7.15 (2H, d),

6.95 (2H, d), 5.45 (IH, br), 5.3 (2H, s), 4.4 (2H, s), 2.54 (2H, m), 1.55 (2H, m), 1.31 (2H, m), 0.9 (3H, t).

[71]

[72] While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

[73]

Claims

[1] A method for preparing losartan of formula (I)

ω

, which comprises the steps of reacting the compound of formula (II)

(H) with triethylamine hydrochloride and sodium azide in a polar organic solvent at a temperature ranging from 105 to 135 °C, the polar organic solvent being selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide,

N-methyl-2-pyrrolidinone and dimethylsulfoxide; adding water and acetone to the resulting reaction solution; and adjusting the pH of the resulting mixture to 2 to 5 to induce the crystallization of losartan.

[2] The method of claim 1, wherein the polar organic solvent is employed in an amount ranging from 2 to 6 ml per 1 g of the compound of formula (II). [3] The method of claim 1, wherein sodium azide is employed in an amount ranging from 1 to 5 molar equivalents based on the compound of formula (II). [4] The method of claim 1, wherein triethylamine hydrochloride is employed in an amount ranging from 1 to 1.5 molar equivalents based on sodium azide. [5] The method of claim 1, wherein water is employed in an amount ranging from

1.5 to 3.5 ml per 1 ml of the polar organic solvent. [6] The method of claim 1, wherein acetone is employed in an amount ranging from

0.5 to 3.5 ml per 1 ml of the polar organic solvent.