KR100359256B1 - Improved method of preparing lansoprazole - Google Patents

Abstract

The present invention relates to an improved method for preparing lansoprazole. According to the method of the present invention, after reacting a hydroxymethylpyridine derivative as a starting material with a benzimidazole derivative in the presence of a phosphine compound and an azodicarboxylate compound, Lansoprazole (2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl of the following structural formula (1) by oxidizing the resulting compound in the presence of an organic radical catalyst -1H-benzimidazole) can be conveniently prepared in high yield.

(One)

Description

Improved manufacturing method of lansoprazole {IMPROVED METHOD OF PREPARING LANSOPRAZOLE}

The present invention relates to lansoprazole (2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimi from the starting hydroxymethylpyridine derivative. Dazole) in a high yield.

Lansoprazole is useful for the treatment of gastric ulcer, duodenal ulcer and gastritis because it acts to inhibit gastric acid secretion and to protect the gastric membrane.

Methods for preparing lansoprazole are disclosed in US Pat. No. 4,628,098 and Korean Pat. No. 92-2128. Looking specifically at this with reference to Scheme 1, to prepare a pyridine derivative of the following formula (4) having a leaving group by reacting the hydroxymethylpyridine derivative of the following structural formula (3) as a starting material with thionyl chloride, The compound of formula (4) is reacted with the benzimidazole derivative of formula (5) to synthesize the compound of formula (2) and the compound of formula (2) is oxidized to prepare the desired lansoprazole of formula (1). .

However, in this method, since the compound of formula (4) produced as an intermediate is very unstable and easily decomposed, a large amount of side reactions are generated when reacting with the benzimidazole derivative of formula (5). Has the disadvantage of obtaining a compound of in a low yield of about 68%.

In addition, in the oxidation process for converting the compound of formula (2) to lansoprazole of formula (1), European Patent Nos. 134,400 and UK Patent No. 2,134,523, including US Pat. No. 4,628,098 and Korean Pat. Discloses m-chloroperbenzoic acid as an oxidant, and Spanish Patents 550,057, 540,147 and 539,793 disclose sodium periodate, iodosomethylbenzene and iodosobenzene, respectively, Oxidizers have the problem of being expensive and uneconomical for industrial use, as well as low yields (approximately 60 to 80%) by producing large amounts of byproducts in use.

In order to secure the disadvantage of the oxidation reaction, a method for producing lansoprazole, characterized in that the oxidation reaction with hydrogen peroxide in the presence of a vanadium compound is disclosed in Korean Patent No. 96-47. This method can improve the yield of the desired compound by inhibiting the production of by-products during the oxidation reaction, but it is difficult to apply to mass production because the price problem of the oxidant is still not solved.

Accordingly, the present inventors have continued the research, and in the presence of a phosphine compound and an azodicarboxylate compound, by directly reacting the starting material with the compound of the formula (5), the structural formula (2) can be obtained in high yield without using the compound of the formula (4). In addition to being able to produce compounds of the present invention, it is found that the desired lansoprazole can be produced in high yield by oxidizing the compound of formula (2) with an oxidizing agent in the presence of a specific catalyst in the subsequent oxidation process. It became.

It is an object of the present invention to provide an improved process for the efficient and simple preparation of lansoprazole.

In the present invention according to the above object,

(a) reacting a hydroxymethylpyridine derivative of formula (3) with a benzimidazole derivative of formula (5) in the presence of a phosphine compound and an azodicarboxylate compound to produce a compound of formula (2) Steps, and

(b) reacting the compound of formula (2) produced in step (a) with an oxidizing agent in a mixed solvent of water and an organic solvent containing a phase transfer catalyst in the presence of an organic radical catalyst

It provides a method for producing lansoprazole of the following structural formula (1) comprising a.

Formula 1

(One)

(3)

(5)

(2)

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

Representative method of the present invention is as follows.

In Scheme 2, the hydroxymethylpyridine derivative of Structural Formula (3), which is a starting material of the present invention, may be prepared according to a known method (see US Pat. No. 4,698,333), and the method is described in Schemes 3a and 3b. It can be summarized in one way.

For Scheme 3a, the nitro compound is reacted with 2,2,2-trifluoroethanol in the presence of a base and then with acetic anhydride, followed by hydrolysis to synthesize the compound of formula (3); For Scheme 3b, the nitro compound is reacted with 2,2,2-trifluoroethanol, methylated with dimethyl sulfate and the free radicals are used to synthesize the compound of formula (3). However, according to the method of Scheme 3b, about 60% of the compounds having a hydroxymethyl group substituted at the 6-position of the pyridine parent instead of the target compound of the structural formula (3) having the hydroxymethyl group substituted at the 2-position of the pyridine parent There is a problem that the generated selectivity is poor.

According to step (a) of the process for preparing lansoprazole of the present invention, the starting material (compound of formula (3)) is converted into a compound having a leaving group (compound of formula (4) of Scheme 1) and heated to reflux in the presence of a base. Unlike conventional methods for reacting with benzimidazole derivatives of formula (5) under conditions, by reacting with benzimidazole derivatives of formula (5) directly in the presence of a phosphine compound and an azodicarboxylate compound To prepare a compound.

Specifically, in step (a) according to the method of the present invention, the hydroxymethylpyridine derivative of formula (3), the benzimidazole derivative of formula (5) and the phosphine compound are dissolved in a suitable organic solvent, and then added thereto. The azodicarboxylate compound was slowly added and reacted at 0 ° C. to room temperature for 1 to 2 hours to produce 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2 of formula (2). -Pyridyl] methylthio-1H-benzimidazole can be prepared in high yield (95% or more). At this time, the benzimidazole derivative of formula (5) may be used in a 1 to 1.2 molar ratio with respect to the hydroxymethylpyridine derivative of formula (3). Such reactions can be carried out by the reaction mechanism of the Mitsnov reaction type (for example, triphenylphosphine / diethylazodicarboxylate (Ph ₃ P / DEAD)), as shown in the following continuous schemes 4a to 4c. It can be explained that the application to the coupling (coupling) reaction.

Where

R is an ethyl group,

R ^* is a 3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl group.

Organic solvents usable in the step (a) according to the method of the present invention include carbon chlorides such as dichloromethane, chloroform, 1,2-dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether and dioxane; Ketones such as methyl isobutyl ketone; Nitriles such as acetonitrile; And amides such as dimethylacetamide, dimethylformamide, and the like, and at least one member is selected. Particularly, a solvent capable of reacting the reactants in a homogeneous state is preferable.

In addition, representative examples of the phosphine compound used in the present invention include triethyl phosphine, trimethyl phosphine, tributyl phosphine and triphenyl phosphine, and the like, preferably triphenyl phosphine. The phosphine compound may be used in an amount of 1 to 1.5 equivalents, preferably 1.1 equivalents, relative to the compound of formula (3).

Representative examples of the azodicarboxylate compounds used in the present invention include diisopropyl azodicarboxylate and diethyl azodicarboxylate (DEAD), and the like. To 1.5 equivalent ratio, preferably 1.1 equivalent ratio.

The compound of formula (2) prepared in step (a) can be recovered as a crystal simply by filtering after pH adjustment, without the purification process by conventional column chromatography.

Subsequently, by step (b) according to the method of the present invention, the compound of formula (2) produced in step (a) in the mixed solvent of water and organic solvent containing a phase transfer catalyst in the presence of an organic radical catalyst Oxidation can produce the desired lansoprazole.

Specifically, in step (b) according to the method of the present invention, the compound of formula (2) is reacted with an oxidizing agent at 0 to 20 ° C. in a mixed solvent of water and an organic solvent containing a phase transfer catalyst in the presence of a catalytic amount of an organic radical catalyst. By reacting for 2 to 4 hours, the desired lansoprazole of Structural Formula 1 can be obtained in high yield (90% or more). At this time, sodium hypochlorite, which is a low-cost oxidizing agent, may be usefully used as an oxidizing agent, and by-products (for example, the compound represented by the following Chemical Formula 6) produced when using m-chloroperbenzoic acid or without a catalyst are used. It can be suppressed to less than 0.1%.

(6)

Representative examples of the organic radical catalyst used in the present invention include diphenyl nitrosyl radical, di-tert-alkyl nitrosyl radical, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) free radical catalyst And 4-methoxy-TEMPO free radicals, and the like, with 1 mol% catalytic amount being used for the compound of formula (2).

The oxidizing agent used in the present invention may be used in an amount of 1 to 3 equivalents, preferably 2.2 equivalents, relative to the compound of formula (2).

In addition, the step (b) oxidation process according to the present invention is carried out under a mixed solvent of water and an organic solvent, that is, two-phase, it is possible to add a phase transfer catalyst in a solvent to increase the reaction yield. At this time, water and the organic solvent may be mixed in a weight ratio of 1: 1 to 2, examples of the phase transfer catalyst used are tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide and tetrabutyl ammonium iodide, etc. Examples of the organic solvent used may be the same as the examples of the solvent used in the step (a).

Lansoprazole, the final target compound prepared in step (b), can be separated from the organic phase and simply recovered by recrystallization, and the unreacted oxidant remains in the water phase and can be easily removed.

As described above, according to the method for preparing lansoprazole of the present invention, a target compound can be obtained in a high yield through a simple purification process in a short time under mild reaction conditions, and by shortening the existing process by one step and enabling a low-cost oxidizing agent to be used. It can increase the economic efficiency and lead to the industrial mass production of lansoprazole.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited by the embodiment.

Example 1: of 2- [3-methyl-4- (2,2,2, -trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole (compound of formula (2)) Manufacturing (step (a))

6.63 g (30 mmol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine in 100 ml of tetrahydrofuran, 4.5 g (30 mmol) of 2-mercaptobenzimidazole, After dissolving 8.67 g (33 mmol) of triphenyl phosphine, a solution of 5.75 g (33 mmol) of diethyl azodicarboxylate (DEAD) in 30 ml of tetrahydrofuran was slowly added dropwise at room temperature. After stirring the reaction solution for 1 hour, the solvent was removed by distillation under reduced pressure. Then, 100 ml of ethyl acetate was added to the residue, followed by extraction twice with 50 ml of an aqueous 1N hydrochloric acid solution. The aqueous layer was washed with 50 ml of diethyl ether, then neutralized to pH 7 using 1N-NaOH aqueous solution, and the resulting crystals were filtered, washed with water and dried to give 10.06 g of a white title compound (monohydrate) (yield: 90.3). %) Was obtained.

Melting Point: 142 ° C to 144 ° C

Mass: m / z = 354.1 (M + 1) ⁺ , 321.1, 235.9, 119.0

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 2.33 (s, 3H), 4.40 to 4.47 (q, 2H), 4.44 (s, 2H), 6.72 to 6.74 (d, 1H), 7.17 to 7.20 (m, 2H), 7.53 to 7.56 (m, 2H), 8.41 to 8.43 (d, 1H)

Example 2: 2- [3-methyl-4- (2,2,2, -trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (compound of formula 1, lansoprazole) Preparation of (Step (b))

4.46 g of 2- [3-methyl-4- (2,2,2, -trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole (monohydrate) prepared in Example 1 (12 mmol) and 18.74 mg (1 mol%) of TEMPO free radical as catalyst were dissolved in 40 ml of tetrahydrofuran, followed by addition of a solution of 166.76 mg (5 mol%) of tetrabutyl ammonium chloride in 20 ml of distilled water. After the reaction solution was cooled to 0 ° C., an aqueous solution of 13.6 ml (12% solution, 2.2 equivalents) of sodium hypochlorite dissolved in 20 ml of distilled water was added dropwise to the reaction solution at 0 ° C. for 2 hours, and stirred at the same temperature for 10 minutes. The reaction solution was further stirred at 20 ° C. for 10 minutes. Subsequently, the aqueous layer of the reaction solution was extracted with 40 ml of ethyl acetate, and the organic layer of the reaction solution was washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of saturated brine, dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from acetone / hexane to give 3.99 g (yield: 90%) of white-light brown titled compound (lansoprazole).

Melting Point: 164-165 ° C (Decomposition)

Mass: m / z = 392.1 (M + Na) ⁺ , 370.05 (M + 1) ⁺ , 354.1, 252, 119.0

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 2.20 (s, 3H), 4.33 to 4.41 (q, 2H), 4.73 to 4.88 (q, 2H), 6.66 to 6.68 (d, 1H), 7.26 -7.30 (m, 2H), 7.51-7.71 (m, 2H), 8.34-8.36 (d, 1H)

Comparative Example 1

A crude product was prepared in the same manner as in Example 2, except that no catalyst was used in the oxidation reaction. The resulting crude product was separated by silica gel column and recrystallized to give 2.79 g (yield 63%) of white-light brown title compound (lansoprazole). Melting point and ¹ H-NMR were consistent with the analysis results of Example 2.

Comparative Example 2

2.23 g of 2- [3-methyl-4- (2,2,2, -trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole (monohydrate) prepared in Example 1 (6 mmol) was dissolved in 20 ml of chloroform, and a solution of 1.24 g (1.2 equivalents) of m-chloroperbenzoic acid in 20 ml of chloroform was slowly added dropwise at 5 DEG C or lower, and then stirred at the same temperature for about 10 minutes. After the reaction was completed, the reaction mixture was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting crude product was separated by silica gel column and recrystallized to obtain 1.33 g (yield: 60%) of white-light brown title compound (lansoprazole). Melting point and ¹ H-NMR were consistent with the analysis results of Example 2.

Impurity generation rate analysis

The lansoprazole obtained in Example 2, Comparative Example 1 and Comparative Example 2 was subjected to high performance liquid chromatography (HPLC) to determine the yield of lansoprazole according to oxidation and recrystallization, and the results are shown in Table 1 below.

<HPLC condition>

Column: Capcell pak C ₁₈ (150 × 4.6mm inner diameter)

Measurement wavelength: 254nm

Mobile phase: 40% acetonitrile with 0.1 mol KH ₂ PO ₄

division % Area in HPLC RT (minutes) Example 2 Comparative Example 1 Comparative Example 2 Lansoprazole 2.839 98.0973 92.1528 85.6436 Compound of formula 6 3.595 0.0834 3.0078 9.5431 Compound of formula 2 5.842 1.8193 4.8394 5.4133 yield 90% 83% 80%

From Table 1, compared to the embodiment according to the present invention, when sodium hypochlorite was used as an oxidizing agent without using a catalyst (Comparative Example 1) and when conventional m-chloroperbenzoic acid was used as an oxidizing agent (Comparative Example 2) It can be seen that the yield of the desired compound lansoprazole is much inferior as a large amount of the compound of formula 6 is produced as a by-product.

According to the lansoprazole production method of the present invention, the target compound can be obtained in high yield through a simple purification process in a short time under mild reaction conditions, and the economic efficiency is improved by shortening the existing process by one step and enabling the use of a low-cost oxidizing agent. It can bring about mass production.

Claims (7)

(a) reacting a hydroxymethylpyridine derivative of formula (3) with a benzimidazole derivative of formula (5) in the presence of a phosphine compound and an azodicarboxylate compound to produce a compound of formula (2) Steps, and (b) reacting the compound of formula (2) produced in step (a) with an oxidizing agent in a mixed solvent of water and an organic solvent containing a phase transfer catalyst in the presence of an organic radical catalyst Including, Lansoprazole production method of the following structural formula (1). Formula 1 (One) Formula 2 (3) Formula 3 (5) Formula 4 (2) The method of claim 1, Step (a) is carried out at 0 ° C. to room temperature for 1 to 2 hours. The method of claim 1, The phosphine compound is characterized in that at least one selected from the group consisting of triethyl phosphine, trimethyl phosphine, tributyl phosphine and triphenyl phosphine. The method of claim 1, And wherein the azodicarboxylate compound is diisopropyl azodicarboxylate or diethyl azodicarboxylate (DEAD). The method of claim 1, Organic radical catalysts include diphenyl nitrosyl radicals, di-tert-alkyl nitrosyl radicals, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) free radicals and 4-methoxy-TEMPO free radicals. At least one selected from the group consisting of. The method of claim 1, Sodium hypochlorite is used as an oxidizing agent in a ratio of 1 to 3 equivalents relative to the compound of formula (2). The method of claim 1, Wherein the phase transfer catalyst is selected from the group consisting of tetrabutyl ammonium fluoride, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide and tetrabutyl ammonium iodide.