KR102246226B1 - Manufacturing method of losartan metabolite exp-3174 - Google Patents

Abstract

The present invention provides a production method capable of producing a losartan metabolite EXP-3174 with high purity and high yield, using inexpensive starting materials and under mild reaction conditions.

Description

Manufacturing method of the losartan metabolite EXP-3174 {MANUFACTURING METHOD OF LOSARTAN METABOLITE EXP-3174}

The present invention relates to a method of preparing the losartan metabolite EXP-3174 in high yield.

Losartan, a compound represented by the following formula (1), is an angiotensin II receptor antagonist and is well known as an antihypertensive agent. The oral bioavailability of losartan is around 33% and shows rapid absorption. However, losartan has a short excretion half-life of about 2 hours, and thus has a problem in that it has a blood pressure lowering effect only temporarily.

식 (1)

Equation (1)

On the other hand, the losartan metabolite EXP-3174 of the following formula (2) has a long excretion half-life of about 6 to 9 hours, enabling effective treatment of hypertension with a continuous blood pressure lowering effect, and has an antagonistic activity against angiotensin receptors compared to rosartan. It is known to be about 10 to 40 times stronger:

식 (2)

Equation (2)

The synthesis of the losartan metabolite EXP-3174 is described in Tetrahedron Letters 44 (2003) 1149-1152. According to this document, EXP-3174 is _{prepared by reacting losartan and MnO 2} in an aqueous solution under microwave irradiation conditions. According to this reaction, the yield is about 64%. However, this reaction produced a very large amount of by-products, requiring a purification process using HPLC.

In addition, in Korean Laid-Open Patent Publication 10-2008-0096707 (2008.10.31) and US 2008/0090885A1, rosartan and rosartan salts are used as starting materials, and KMnO ₄ is used as an oxidizing agent to form 5-hydroxymethyl groups as 5-carboxyl groups. A method of making EXP-3174 by oxidation is described. However, these methods require the use of expensive losartan and losartan salts sold as products as starting materials. _{In addition, since KMnO 4} with very strong oxidizing power is used, the selectivity during the oxidation reaction is low, and a large amount of impurities are generated by oxidation other than the desired location, and such impurities are not easily removed and the purity of the final product is low, making purification very difficult. There is this.

The present invention was conceived to solve the problems of the prior art, and the object of the present invention is to prepare a losartan metabolite EXP-3174 with high purity and high yield under mild reaction conditions and using inexpensive starting materials. It is to provide a manufacturing method.

According to an aspect of the present invention

(a) reacting a compound of the following formula 1 with a compound of the following formula 2 in the presence of a base to prepare a compound of the following formula 3;

(b) reacting the compound of Formula 3 in _{a solution containing sodium azide (NaN 3} ), a salt, and a polar aprotic solvent to prepare a compound of Formula 4; And

(c) hydrolyzing the compound of Formula 4; It is possible to provide a method for preparing the losartan metabolite EXP-3174 of Formula 5, including:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In the above formula, X ₁ is Cl, Br, I or -Ots (Octadecyl-trichloro-sillane),

R ₁ is methyl, ethyl, propyl or butyl.

According to the manufacturing method according to an exemplary embodiment of the present invention, it is possible to produce an economical and high yield of the rosartan metabolite EXP-3174, which is effective as a blood pressure lowering agent.

The effects of the present invention are not limited to the above-described effects, and effects that are not mentioned will be clearly understood by those skilled in the art from the present specification and the accompanying drawings.

Throughout the present specification, when a certain part "includes" a certain component, it means that other components may be further included rather than excluding other components unless otherwise stated.

Hereinafter, the present invention will be described in more detail.

The preparation method of the losartan metabolite EXP-3174 of the following Formula 5 according to an exemplary embodiment of the present invention is (a) reacting a compound of Formula 1 with a compound of Formula 2 in the presence of a base to prepare a compound of Formula 3 below. step; (b) reacting the compound of Formula 3 in _{a solution containing sodium azide (NaN 3} ), a salt, and a polar aprotic solvent to prepare a compound of Formula 4; And (c) hydrolyzing the compound of Formula 4;

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In the above formula, X ₁ is Cl, Br, I or -Ots (Octadecyl-trichloro-sillane),

R ₁ is methyl, ethyl, propyl or butyl.

When the compound of Formula 1 and the compound of Formula 2 are reacted in the presence of a base in step (a), NH of Formula 1 and X ₁ of Formula 2 are bonded to each other to prepare the compound of Formula 3.

According to an exemplary embodiment of the present invention, step (a) may be performed under a phase transfer catalyst. The phase transfer catalyst may be one of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride (TBAC), and tetrabutyl ammonium iodide (TBAI), and tetrabutyl ammonium bromide is preferred.

According to an exemplary embodiment of the present invention, the base in step (a) may be an alkali metal hydroxide, specifically lithium hydroxide, sodium hydroxide, or potassium hydroxide. Among them, sodium hydroxide is preferred.

According to an exemplary embodiment of the present invention, the reaction temperature in step (a) may be 40°C to 80°C, and the reaction time may be 15 to 20 hours. When the chemical reaction proceeds within the temperature and time range, the target compound of Formula 3 may be obtained in high yield.

In the step (b), when the compound of Formula 3 is reacted in _{a solution containing sodium azide (NaN 3} ), a salt and a polar aprotic solvent, the cyano group of Formula 3 reacts with sodium azide to form a nitrogen ring structure. To form the compound of Formula 4 is prepared.

According to an exemplary embodiment of the present invention, the polar aprotic solvent in step (b) may be N-methyl pyrrolidinone (NMP), dimethylformamide (DMF), or dimethyl sulfoxide (DMSO). Among them, N-methyl pyrrolidinone is preferred.

According to an exemplary embodiment of the present invention, the salt of step (b) may be pyridine hydrochloride, triethylamine hydrochloride, piperidine acetate, or dialkylamine hydrochloride. Among them, triethylamine hydrochloride is preferred.

According to an exemplary embodiment of the present invention, the reaction temperature in step (b) may be 90°C to 130°C. Specifically, 100°C to 120°C is preferable, and 110°C to 120°C is more preferable.

According to an exemplary embodiment of the present invention, the reaction time of step (b) may be 30 to 50 hours. Specifically, 35 to 45 hours are preferable, and 40 to 45 hours are more preferable.

When the chemical reaction proceeds within the temperature and time range, the target compound of Formula 4 may be obtained in high yield.

The step (c) corresponds to the step of hydrolyzing the ester group of the compound of Formula 4 to prepare the losartan metabolite EXP-3174 of Formula 5, which is a compound in the form of a carboxy group, as a final product.

According to an exemplary embodiment of the present invention, step (c) may be performed in the presence of a base. The base may be an alkali metal hydroxide, specifically lithium hydroxide, sodium hydroxide, or potassium hydroxide. Among them, sodium hydroxide is preferred.

According to an exemplary embodiment of the present invention, the reaction time of step (c) may be 15 to 25 hours. In addition, according to another exemplary embodiment of the present invention, the reaction temperature in step (c) may be 80°C to 90°C.

When the chemical reaction proceeds within the above temperature and time range, the target product, losartan metabolite EXP-3174, can be obtained in high yield.

The losartan metabolite EXP-3174 obtained in step (c) may be used as it is or may be used after further purification.

According to an exemplary embodiment of the present invention, the compound of Formula 1 may be prepared by oxidative esterification of the compound of Formula 6 below.

[Formula 6]

The oxidative esterification reaction is a step of converting the aldehyde group of Formula 6 to an ester group by oxidative esterification, and is reacted by adding alcohol. Specifically, the aldehyde group is oxidized to become a carboxyl group, and the compound of Formula 2 is prepared by esterification with an alcohol.

According to an exemplary embodiment of the present invention, the oxidative esterification reaction may be a Corey-Gilman-Ganem oxidation reaction. Specifically, it may be a reaction of oxidizing and esterifying an aldehyde group by adding _{MnO 2} as an oxidizing agent and adding alcohol.

According to an exemplary embodiment of the present invention, the alcohol is not particularly limited, but a C1 to C4 alcohol such as methanol, ethanol, propanol or butanol is preferable, and ethanol is most preferable to minimize steric hindrance.

According to an exemplary embodiment of the present invention, the oxidative esterification reaction may be performed under heating and reflux conditions, and the reaction time may be 12 to 50 hours.

According to an exemplary embodiment of the present invention, a losartan metabolite EXP-3174 can be prepared in high yield and high purity.

Hereinafter, examples will be described in detail in order to describe the present invention in detail. However, the embodiments according to the present invention may be modified into various other forms, and the scope of the present invention is not construed as being limited to the embodiments described below. Examples of the present specification are provided to more completely describe the present invention to those of ordinary skill in the art.

Example 1

The method for preparing the losartan metabolite EXP-3174 according to an exemplary embodiment of the present invention is shown step by step in Scheme 1 below.

(a) Ethyl 2-butyl-4-chloro-1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate (chemical formula Preparation of 3-1)

Ethyl 2-butyl-4-chloro-1H-imidazole-5-carboxylate (Formula 1-1, CAS 136540-89-1, Reference: European Journal of Medicinal chemistry, 50, 2012, 90 /Rare chemicals building blocks sold ) 2.68 g (11.28 mmol) and 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile 3.68 g (Chemical Formula 2-1, 3.54 mmol) were dissolved in 35 mL of toluene, 1 N NaOH 17 mL (16.92 mmol) and tetrabutyl ammonium bromide (TBAB) 1.27 g (3.95 mmol) were added, followed by heating and stirring at 60° C. for 20 hours. After the reaction was completed, the flask was cooled at room temperature and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated. The concentrated crude product was purified by flash column chromatography (EtOAc: Hex: MeOH = 1: 4: 0.05) and concentrated to obtain ethyl 2-butyl-4-chloro-1-((2'-cyano-[1,1). '-Biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate (Chemical Formula 3-1, pale yellow solid) was obtained in a yield of 75%.

1H NMR (CDCl3, 400MHz) δ 7.76 (d, J = 7.3 Hz, 1H), 7.65 (t, J = 8.2 Hz, 1H), 7.53-7.43 (m, 4H), 7.11 (d, J = 8.1 Hz, 2H), 5.61 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 1.75-1.67 (m, 2H), 1.41-1.31 (m, 5H) ), 0.89 (t, J = 7.3 Hz, 3H)

(b) ethyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-im Preparation of dazole-5-carboxylate (Chemical Formula 4-1)

Ethyl 2-butyl-4-chloro-1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxyl obtained from (a) above Dissolve 600 mg (Chemical Formula 3-1, 0.14 mmol) in 0.6 mL of toluene, and add _{43.7 mg (0.57 mmol) of NaN 3} and 78.3 mg (0.57 mmol) of trimethylamine hydrochloride and 0.06 mL (0.57 mmol) of NMP. Then, it was heated to reflux at 60°C. After 43 hours, it was confirmed that the reaction was complete, and the reaction vessel was cooled at room temperature. To the reaction mixture cooled at room temperature, _{10 mL of saturated NH 4} Cl solution was added, followed by extraction three times with 10 mL of dichloromethane (DCM). The extracted organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The concentrated crude product was purified by flash column chromatography (CH ₂ Cl ₂ : MeOH = 10: 1) and concentrated to ethyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'). -Biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylate (Formula 4-1, brown oil formulation) was obtained in a yield of 80%.

1H NMR (CDCl3, 400MHz) δ 8.00 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 6.9 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 5.52 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 1.66 (quint, J = 7.7 Hz, 2H), 1.39-1.25 (m, 5H), 0.88 (t, J = 7.3 Hz, 3H)

(c) Preparation of losartan metabolite EXP-3174

Ethyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro- obtained in (b) above 1H-imidazole-5-carboxylate 40 mg (Chemical Formula 4-1, 0.086 mmol) was dissolved in 0.6 mL of ethanol, and 0.14 mL (0.26 mmol) of 2 N NaOH was added, followed by heating at 90 °C to reflux. After 20 hours, when the reaction was completed, the reaction vessel was cooled to room temperature. After cooling the reaction vessel to 0 °C again, 1 N HCl was added dropwise until the pH of the solution became 3-4, and extracted twice with 15 ml of EtOAc. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The concentrated crude product was purified by flash column chromatography (EtOAc: MeOH = 2: 1) and concentrated to obtain a losartan metabolite EXP-3174 (white solid) in a yield of 90%.

1H NMR (MeOD, 400MHz) δ 7.59 (d, J = 7.5 Hz, 1H), 7.53-7.42 (m, 3H), 7.07 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 5.71 (s, 2H), 2.61 (t, J = 7.7 Hz, 2H), 1.55 (quint, J = 7.6 Hz, 2H), 1.34-1.28 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H)

Claims (11)

(a) reacting a compound of the following formula 1 with a compound of the following formula 2 in the presence of a base to prepare a compound of the following formula 3;
(b) reacting the compound of Formula 3 in _{a solution containing sodium azide (NaN 3} ), a salt, and a polar aprotic solvent to prepare a compound of Formula 4; And
(c) hydrolyzing the compound of Formula 4;
Including,
The base of step (a) is an alkali metal hydroxide,
The polar aprotic solvent of step (b) is N-methyl pyrrolidinone (NMP), dimethylformamide (DMF) or dimethyl sulfoxide (DMSO),
The salt of step (b) is pyridine hydrochloride, triethylamine hydrochloride, piperidine acetate or dialkylamine hydrochloride.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In the above formula, X ₁ is Cl, Br or I,
R ₁ is methyl, ethyl, propyl or butyl.
The method according to claim 1,
The step (a) is a method for producing a losartan metabolite EXP-3174, which proceeds under a phase transfer catalyst.
The method according to claim 2,
The phase transfer catalyst is tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride (TBAC), or tetrabutyl ammonium iodide (TBAI).
delete delete delete The method according to claim 1,
The step (c) is a method for producing a losartan metabolite EXP-3174 in the presence of a base.
The method according to claim 1,
The reaction time of the step (c) is 15 to 25 hours, a method for producing a losartan metabolite EXP-3174.
The method according to claim 1,
The reaction temperature of the step (c) is 80 ℃ to 90 ℃ method of producing a losartan metabolite EXP-3174.
The method according to claim 1,
The method of preparing the losartan metabolite EXP-3174, wherein the compound of Formula 1 is prepared by oxidative esterification of the compound of Formula 6 below.
[Formula 6]

The method of claim 10,
The oxidative esterification reaction is carried out by adding methanol, ethanol, propanol or butanol to prepare a losartan metabolite EXP-3174.