KR101628758B1 - Method for manufacturing olmesartan cilexetil - Google Patents

Abstract

The present invention provides a method for producing omecatan cilexetil having less generation of impurities and being economical.

Description

Method for manufacturing olmesartan cilexetil < RTI ID = 0.0 >

The present invention relates to a process for the preparation of olmesartan cilexetil. Particularly, the present invention relates to a method suitable for mass production of olmecanthane cilexetil at high purity.

Olmesartan (olmesartan) is an angiotensin II receptor antagonist and is an imidazoline drug used for the treatment or prevention of hypertension, arteriosclerosis or hemorrhagic heart failure. However, the bioavailability of olmesartan is extremely low. To overcome this low bioavailability, prodrug form olmesatin medoxomil has been developed and marketed (Daewoong Pharm, Olmetec Tablet).

However, the bioavailability of olmesatan medoxomil is also extremely low to about 26%, and it is necessary to develop an omethatan derivative having improved bioavailability. As a result of many studies, the present inventors have found that the osmetacan celecetyl bio- We made a patent application (Korean Patent Application No. 10-2009-0099599) by remarkable discovery that it is very superior to Olmeta Satan Medoxomil.

On the other hand, there is a need for a production method which is less impurities and more suitable for mass production in the process of producing olmesartan cilexetil.

Accordingly, it is an object of the present invention to provide a process for producing omethatan cilexetil represented by the following formula (1), which is less impurities and which is simpler in subsequent operations such as purification, more suitable for mass production, Method.

In order to accomplish the above object, the present invention provides a process for the preparation of (S1) 4- (1-hydroxy-1-methylethyl) -2-propyl- imidazole- 1-cyclohexyloxycarbonyl-ethyl ester, (S2) reacting the 4- (1-hydroxy-1-methylethyl) (4'- (halomethyl) diphenyl-piperidine-l-carboxylic acid) was added to a solution of (1-hydroxy- 2-yl) -1-protecting group-1 H-tetrazole, and (S3) removing the protecting group, or a pharmaceutically acceptable salt thereof, A method for producing a salt is provided.

In the production method according to the present invention, the halo may be bromo, chloro, fluoro, iodo or the like, preferably bromo and chloro.

The present invention also provides 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl- 2-propyl-1 - ((2 '- (1-trityl-1 H (2-hydroxypropan-2-yl) -Tetrazol-5-yl) diphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate and also using one of these, olmesartan cilexetil or its pharmaceutical Lt; / RTI > acceptable salt.

The term "pharmaceutically acceptable salts " of the present invention refers to salts prepared with little or no toxicity or with acids or bases. When the compounds of the present invention are relatively basic, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid and a suitable inert solvent. Pharmaceutically acceptable acid addition salts include those derived from organic acids such as propionic acid, isobutyric acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, sueric, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, Phosphoric acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydrogen iodide, phosphorous acid, And the like, but are not limited thereto. But are not limited to, salts of amino acids such as arginate and analogs of organic acids such as glucuronic or galactunoric acids.

In the present invention, the "protecting group" of the tetrazole refers to a group known in the art for protecting the amino group of the tetrazole against undesired reactions during the synthesis process. The protecting group may be used to protect the site during the reaction at the other reaction site, and then removed. For example, the protecting groups commonly used in the art to which the present invention pertains are described in "Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999)".

Examples of such amino group protecting groups include 2-trimethylcarbonyl (Teoc), 1-methyl-1- (4-biphenylyl) carbonyl (Bpoc), t-butoxycarbonyl (BOC), allyloxycarbonyl Carbamate protecting groups such as 9-fluorenylmethyloxycarbonyl (Fmoc), benzylcarbamate (Cbz) and the like; But are not limited to, formyl, acetyl, propionyl, butyryl, isobutyryl, trihaloacetyl, benzoyl, 4-methoxybenzoyl, nitrophenylacetyl, phenylacetyl, phenoxyacetyl, , 4-isopropylphenoxyacetyl, (dimethylamino) methylene, and the like; Sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; And imine and cyclic imide protecting groups such as phthalimido and dithiasuccinoyl may be used but the present invention is not limited thereto and in the production method according to the present invention, More preferred is a trityl group. Thus, more preferably, the present invention relates to the use of 5- (4'- (halomethyl) diphenyl-2-yl) -1- -Yl) -1-trityl-1H-tetrazole. ≪ / RTI >

More preferably, step (S1) of the process of the present invention is carried out in the presence of an alkylamine. Examples of such alkylamines include triethylamine, trimethylamine, tripropylamine, ethylamine, diethylamine, diisopropylethylamine, and the like, or a mixture of two or more thereof. However, the present invention is not limited thereto no.

More preferably, in the process of the present invention, the 4- (1-hydroxy-1-methylethyl) -2-propyl- imidazole-5-carboxylic acid is 4- (1-hydroxy- ) -Propyl-imidazole-5-carboxylic acid alkyl ester is reacted with an alkali metal hydroxide (more preferably, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like) And more preferably an alkyl of 1 to 5 carbon atoms.

Therefore, more preferably, olmesartan cilexetil is produced by the production method of the present invention represented by the following reaction formula (1).

<Reaction Scheme 1>

Illustratively, the manufacturing method according to the present invention has the following advantages, but the present invention is not limited to these expected advantages.

<Reaction Scheme 2>

When the reaction is carried out under a metal base (K ₂ CO ₃ , KI, NaOH, KOH, NaH or the like) when chloroethylcyclohexyl carbonate is reacted with an acid of tritylolmesatan as shown in the reaction scheme 2, the lactone is formed as a side reaction In the production process according to the present invention, alkylamine such as diethyl isopropylamine is used without using a metal base, so lactone is not produced.

Further, it is more preferable to replace chlorethylcyclohexylcarbonate with an imidazolyl group in the same manner as the production process according to the present invention by replacing chlorosuccinimide with chlorethylcyclohexylcarbonate, Considering the unit cost of tetrazole, it is much more economical and more suitable for mass production.

<Reaction Scheme 3>

Also, as shown in Scheme 3, hydrolysis of tritylolmesatane ester with a metal base (NaOH, KOH, or the like) produces a small amount of olmesartanic acid. When this is reacted with excess chloroethylcyclohexylcarbonate, The present invention provides a method for producing impurities such as cilexetil substituted meta meta, while replacing trimethyldicyclohexyl carbonate with imidazole followed by trityldiphenyltetrazole generates impurities such as It is advantageous.

The present invention provides a process for preparing omecatan cilexetil with less impurities and being economical.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

EXAMPLES Preparation of olmesartan cilexetil

Olmetecane cilexetil was prepared according to the following reaction scheme.

[Reaction Scheme 1]

Example  1: 4- (1-Hydroxy-1- Methyl ethyl ) -2-propyl- Imidazole -5- Carboxylic acid  synthesis

(20.0 g, 83.2 mmol) and sodium hydroxide powder (6.6 g, 165.0 mmol) were added to a solution of 4- (1-hydroxy-1-methylethyl) -2-propyl- imidazole- Dissolved in 100 ml of acetone and distilled water, and then refluxed with stirring at 110 ° C for 3 hours. After cooling to room temperature, acetone was removed by concentration under reduced pressure. The distilled water layer was titrated with 5 N HCl with acid at 0 ° C, and the solid was filtered and dried to obtain Compound 2 (14.46 g, 82%).

ESI-MS: 213.4 [M + H] &lt; ⁺ &gt;.

_{^{1 H-NMR (DMSO- d 6}} , 400MHz): δ 4.37 ~ 3.78 (brs, 1H), 2.62 (t, 2H, J = 7.4 and 7.5 Hz), 2.51-2.50 (brs, 1H), 1.70 ~ 1.60 ( m, 2H), 1.47-1.40 (m, 6H), 0.87 (t, 3H J = 7.3 and 7.4 Hz).

Example  2: 4- (1-Hydroxy-1- Methyl ethyl ) -2-propyl- Imidazole -5- Carboxylic acid -One- Cyclohexyloxycarbonyl - ethyl ester synthesis

After dissolving 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid (5 g, 23.6 mmol) in 40 ml of dimethylacetamide at room temperature, diisopropylethylamine (4.52 ml, 28.3 mmol) was slowly added dropwise. After 15 minutes, 1-chloroethylcyclohexyl carbonate (4.52 ml, 24.7 mmol) was slowly added dropwise, and the mixture was stirred at 60 ° C for 1.5-2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and distilled water, and the following reaction was carried out without separation and purification (6.39 g, 71%).

ESI-MS: 383.5 [M + H] &lt; ⁺ &gt;.

_{^{1 H-NMR (CDCl 3 -}} d 1, 400MHz): δ 9.53 (brs, 1H), 7.00 ~ 6.96 (m, 1H), 5.35 (s, 1H), 4.68 ~ 4.63 (m, 1H), 2.69 (t 2H, J = 7.6 Hz), 1.97-1.91 (m, 2H), 1.77-1.73 (m, 5H), 1.63-1.60 (m, 6H), 1.55-1.43 , 3H), 0.99 (t, 3H, J = 7.3 and 7.4 Hz).

Example  3: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl-4- (2- Hydroxypropane Yl) -2-propyl-1 - ((2 ' - (1- Trityl -1H- Tetrazole -5 days) Diphenyl Yl) methyl ) -1H- Midazol -5- Carboxylate  synthesis

5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester (2.27 g, 5.9 mmol) and potassium carbonate powder (1.64 g, g 11.9 mmol) and trityl biphenyl bromide (3.2 g, 5.7 mmol) were dissolved in 15 ml of dimethylacetamide, and the mixture was stirred at 60 ° C for 3 hours. After completion of the reaction, solid was formed at 0 ° C using distilled water, and then filtered. Compound 4 (3.8 g, 76%) was obtained after purification by separation using a column chromatography (EtOAc: n- Hexane = 1: 5).

ESI-MS: 859.1 [M + H] &lt; ⁺ &gt;.

^{1 H NMR (300 MHz, DMSO} ) d 7.75 (d, J = 7.5Hz, 1H), 7.62 (t, J = 7.5Hz, 1H), 7.51 (t, J = 7.5Hz, 1H), 7.43-7.30 ( m, 10H), 7.04 (d , J = 4.1Hz, 2H), 6.90-6.84 (m, 8H), 6.73 (q, J = 5.4Hz, 1H) 5.36 (s, 2H), 5.16 (s, 1H) , 4.46 (m, 1H), 2.45 (t, J = 7.8Hz, 2H), 1.75-1.68 (m, 2H), 1.55-1.15 (m, 20H) 1.17 (t, J = 7.2Hz, 2H), 0.75 (t, J = 7.8 Hz, 3H)

Example  4: 1- ( Cyclohexyl Oxy  Carbonyl Oxy ) Ethyl-1 - ((2 ' - (lH- Tetra 5-yl) Diphenyl Yl) methyl ) -4- (2- Hydroxypropane Yl) -2-propyl-lH- Imidazole -5-carboxylic acid &lt; / RTI &gt; ester

Thereafter, a solution of 1- (cyclohexyloxycarbonyloxy) ethyl-4- (2-hydroxypropan-2-yl) Yl) methyl) -1H-imidazole-5-carboxylate (10 g, 11.6 mmol) and hydrochloric acid (2.95 mL) were added to a solution of The mixture was stirred at room temperature for 4 hours. 174 mL of water was added dropwise to the contents, stirred for 30 minutes, and then filtered to remove tritylmethanol. Thereafter, the acetone was removed by concentration under reduced pressure. The remaining water layer was adjusted to pH 5 with sodium bicarbonate and extracted with ethyl acetate. The clear ethyl acetate extract was dried by adding anhydrous magnesium sulfate, and concentrated under reduced pressure. This mixture was subjected to column chromatography (acetate: n-hexane = 1: 2) to obtain the title compound 1- (cyclohexyloxycarbonyloxy) ethyl- Yl) -2-propyl-1H-imidazole-5-carboxylic acid ester (6.8 g, 91.9%) was obtained .

^{1 H NMR (300 MHz, DMSO} ) d 7.70-7.51 (m, 4H), 7.07 (d, J = 7.9Hz, 2H), 6.91 (d, J = 7.9Hz, 2H), 6.75 (q, J = 2.7 1H), 5.42 (s, 2H), 5.14 (s, IH), 4.49 (m, IH), 2.59 (t, J = 7.6Hz, 2H), 1.82-1.23 , J = 7.6 Hz, 3H).

Claims (6)

(S1) Reaction of 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid with 1-haloethylcyclohexylcarbonate gave 4- Methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester,
(S2) To a solution of the 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl- Coupling the protected 5- (4 '- (halomethyl) diphenyl-2-yl) -1-protecting group-1H-tetrazole, and
(S3) removing the protecting group
&Lt; RTI ID = 0.0 &gt; olmesartan &lt; / RTI &gt; cilexetil or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein the 5- (4'- (halomethyl) diphenyl-2-yl) -1-protecting group-1H-tetrazole in which the H of the tetrazole is protected is 5- (4 ' Methyl) diphenyl-2-yl) -1-trityl-1H-tetrazole. 2. The process according to claim 1, wherein the reaction of step (S1) is carried out in the presence of an alkylamine. 4- (1-Hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester represented by the following formula 2
(2)

(1-cyclohexyloxycarbonyloxy) ethyl-4- (2-hydroxypropan-2-yl) Yl) methyl) -1H-imidazole-5-carboxylate.
(3)

A process for preparing olemetan cilexetil characterized by using the compound of claim 4 or 5.