KR20110109638A - Method for manufacturing olmesartan cilexetil - Google Patents

Abstract

The present invention provides a method for producing olmesartan cilexetil with low generation of impurities and economical.

Description

Method for manufacturing olmesartan cilexetil {Method for manufacturing olmesartan cilexetil}

The present invention relates to a process for preparing olmesartan cilexetil. In particular, the present invention relates to a process suitable for mass production of olmesartan cilexetil in high purity.

Olmesartan is an angiotensin II receptor antagonist and is an imidazole family of drugs used for the treatment or prevention of hypertension, arteriosclerosis or hemorrhagic heart failure. However, the bioavailability of olmesartan is extremely low, and in order to overcome such low bioavailability, prodrug-type olmesartan medoxomil has been developed and commercially available (Daewoong Pharmaceutical, Olmetec Tablet ™).

However, the bioavailability of olmesartan medoxomil is also extremely low at about 26%, and thus, development of an olmesartan derivative having improved bioavailability is needed. The patent application (Korean Patent Application No. 10-2009-0099599) was made with a surprising discovery that it is very superior to Olmesartan Medoxoid.

On the other hand, less impurities are produced in the process of preparing olmesartan cilexetil and a more suitable production method is required.

Therefore, the technical problem to be achieved by the present invention is the production of olmesartan cilexetil represented by the following general formula (1) is less impurities, less easy to follow-up operations such as purification, more suitable for mass production, the production cost is relatively low To provide a way.

In order to achieve the above technical problem, the present invention reacts (S1) 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid with 1-haloethyl cyclohexyl carbonate. To prepare 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester, (S2) said 4- 5- (4 '-(halomethyl) diphenyl- to (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester Binding the 2-yl) -1-protecting group-1H-tetrazole, and (S3) removing the protecting group; olmesartan cilexetil or a pharmaceutically acceptable thereof Provided are methods for preparing the salts.

In the production method according to the invention, bromo, chloro, fluoro, iodo and the like can be used as the halo, of which double bromo and chloro are preferred.

The present invention also provides 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester represented by the following formula (2) and 1- (cyclohexyloxycarbonyloxy) ethyl-4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H) represented by formula (3) Olmesatan cilexetil or a pharmaceutical thereof, which provides -tetrazol-5-yl) diphenyl-4-yl) methyl) -1H-imidazol-5-carboxyester and also uses one of them It provides a method for preparing an acceptable salt.

"Pharmaceutically acceptable salts" of the present invention refer to salts that are made from non-toxic or less acid or base. When the compounds of the present invention are relatively basic, acid addition salts can 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 propionic acid, isobutyl acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic, fumaric acid, manderic acid, phthalic acid, benzenesulfonic acid, p-torylsul Phonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphorous acid Salts formed of, and the like, but are not limited thereto. It also includes, but is 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 tetrazole refers to a group known in the art for protecting the amino group of tetrazole against unwanted reactions during the synthesis process. The protecting group is used to protect the site during the reaction at another reaction site and can then be removed. For example, protecting groups commonly used in the field of the present invention 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 (Alloc ), Carbamate protecting groups such as 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl carbamate (Cbz) and the like; Formyl, acetyl, propionyl, butyryl, isobutyryl, trihaloacetyl, benzoyl, 4-methoxybenzoyl, nitrophenylacetyl, phenylacetyl, phenoxyacetyl, 4-tert-butylphenoxyacetyl Amide protecting groups such as 4-isopropylphenoxyacetyl, (dimethylamino) methylene and the like; Sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; And imine and cyclic imde protecting groups such as phthalimido and dithiasuccinoyl may be used, but are not limited thereto. In the manufacturing method according to the present invention, protecting groups Low trityl group was more preferred. Thus, more preferably, the 5- (4 '-(halomethyl) diphenyl-2-yl) -1-protecting group-1H-tetrazol is 5- (4'-(halomethyl) diphenyl-2 -Yl) -1-trityl-1H-tetrazole is provided.

More preferably, step (S1) of the preparation method of the present invention is carried out in the presence of an alkylamine. As such alkylamine, triethylamine, trimethylamine, tripropylamine, ethylamine, diethylamine, diisopropylethylamine, and the like may be used alone or in combination of two or more thereof, but the present invention is not limited thereto. no.

More preferably, in the production method of the present invention, the 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid is 4- (1-hydroxy-1-methylethyl ) -2-propyl-imidazole-5-carboxylic acid alkyl esters are reacted with alkali metal hydroxides (more preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), wherein the alkyl of the alkyl esters has 1 carbon atom. It is more preferable that it is alkyl of 5-5.

Therefore, more preferably, olmesartan cilexetil is produced by the production method of the present invention represented by Scheme 1 below.

<Scheme 1>

By way of example, the manufacturing method according to the present invention has the following advantages, but the present invention is not limited to these predicted advantages.

<Scheme 2>

First, when the chloroethyl cyclohexyl carbonate is reacted with an acid of tritylol mesatan as shown in Scheme 2, when the reaction occurs under a metal base (K ₂ CO ₃ , KI, NaOH, KOH, NaH, etc.), the lactone is generated as a side reaction. In the production method according to the present invention, lactone is not produced because alkylamine such as diethisopropylamine is used without using a metal base.

In addition, it is more preferable to substitute chloroethyl cyclohexyl carbonate unit price and diphenyl in the imidazole group in the same manner as in the preparation method according to the present invention, instead of replacing chloroethyl cyclohexyl carbonate in olmesatan after preparing olmesartan. Considering the cost of tetrazole, it is much more economical and more suitable for mass production.

<Scheme 3>

In addition, as shown in Scheme 3, hydrolysis of the tritylol mesatan ester with a metal base (NaOH, KOH, etc.) produces a small amount of olmesatonic acid and when reacted with an excess of chloroethyl cyclohexyl carbonate, the 'CCC of Scheme 3 While a large amount of impurity such as substituted olmethic acid cilexetil 'is produced, the preparation method according to the present invention generates the above impurity by first substituting chloroethyl cyclohexyl carbonate for imidazole and then trityldiphenyltetrazole. There is an advantage that is not.

The present invention provides a process for preparing olmesartan cilexetil with less impurities and economics.

Hereinafter, examples and the like will be described in detail to help understand 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 present invention are provided to more fully describe the present invention to those skilled in the art.

EXAMPLES Preparation of Olmesartan cilexetil

Olmesartan cilexetil was prepared according to the following reaction scheme.

Scheme 1

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

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

ESI-MS: 213.4 [M + H] ⁺ .

¹ H-NMR (DMSO- d ₆ , 400 MHz): 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

4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid (5 g, 23.6 mmol) was dissolved in 40 ml of dimethyl acetamide at room temperature, followed by diisopropylethylamine. (4.52 ml, 28.3 mmol) was added slowly dropwise. After 15 minutes, 1-chloroethyl cyclohexyl carbonate (4.52 ml, 24.7 mmol) was slowly added dropwise, followed by stirring at 60 ° C. for 1.5-2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and distilled water, and the next reaction was carried out separately without purification (6.39 g, 71%).

ESI-MS: 383.5 [M + H] ⁺ .

¹ H-NMR (CDCl _{3 -} d ₁ , 400 MHz): 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 (m, 3H), 1.30-1.22 (m , 3H), 0.99 (t, 3H, J = 7.3 and 7.4 Hz).

Example  3: 1- ( Cyclohexyloxycarbonyloxy ) Ethyl-4- (2- Hydroxypropane -2-yl) -2-propyl-1-((2 '-(1- Trityl -1H- Tetrazole -5 days) Diphenyl -4- days) methyl ) -1H-L Midazole -5- Carboxyl Ester  synthesis

4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester (2.27 g 5.9 mmol), potassium carbonate powder (1.64) g 11.9 mmol), and trityl biphenylbromide (3.2 g 5.7 mmol) were dissolved in 15 ml dimethyl acetamide and stirred at 60 ° C. for 3 hours. After completion of the reaction, the solid was produced using distilled water at 0 ℃, and then filtered. Compound 4 (3.8 g, 76%) was obtained after separation and purification using column chromatography (EtOAc: n -Hexane = 1: 5).

ESI-MS: 859.1 [M + H] ⁺ .

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

Example  4: 1- ( Cyclohexyl Oxy  Carbonyl Oxy ) Ethyl-1-((2 '-(1H-) Tetra Sol-5-day) Diphenyl -4- days) methyl ) -4- (2- Hydroxypropane -2-yl) -2-propyl-1H- Imidazole -5-carboxylic acid ester

Then, 58 mL of acetone: water 3.5: 1 mixed solution was diluted with 1- (cyclohexyloxycarbonyloxy) ethyl-4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 ' -(1-trityl-1H-tetrazol-5-yl) diphenyl-4-yl) methyl) -1H-imidazole-5-carboxyester (10 g, 11.6 mmol) and 2.95 mL of hydrochloric acid were added. Stir 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 trityolethanol. Thereafter, the mixture was concentrated under reduced pressure to remove acetone. The remaining water layer was adjusted to pH 5 with sodium bicarbonate and extracted with ethyl acetate. Anhydrous magnesium sulfate was added to the clear ethyl acetate extract, dried, and concentrated under reduced pressure. The mixture was separated by column chromatography (acetate: normalhexane = 1: 2) to give the white title compound 1- (cyclohexyl oxycarbonyl oxy) ethyl-1-((2 '-(1H-tetrazol-5-). Il) diphenyl-4-yl) methyl) -4- (2-hydroxypropan-2-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 = 7.9 Hz, 2H), 6.91 (d, J = 7.9 Hz, 2H), 6.75 (q, J = 2.7 Hz, 1H), 5.42 (s, 2H), 5.14 (s, 1H), 4.49 (m, 1H), 2.59 (t, J = 7.6 Hz, 2H), 1.82-1.23 (m, 21H), 0.87 (t , J = 7.6 Hz, 3H).

Claims (6)

(S1) 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid and 1-haloethyl cyclohexyl carbonate to react 4- (1-hydroxy-1- Preparing methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester,
(S2) H of tetrazol to 4- (1-hydroxy-1-methylethyl) -2-propyl-imidazole-5-carboxylic acid-1-cyclohexyloxycarbonyl-ethyl ester as a protecting group Binding a protected 5- (4 '-(halomethyl) diphenyl-2-yl) -1-protecting group-1 H-tetrazole, and
(S3) removing the protecting group
Method for producing olmesartan cilexetil or a pharmaceutically acceptable salt thereof, characterized in that it comprises a. The 5- (4 ′-(halomethyl) diphenyl-2-yl) -1-protecting group-1H-tetrazol of claim 1, wherein H of the tetrazole is protected with a protecting group. Methyl) diphenyl-2-yl) -1-trityl-1H-tetrazole. The method 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).
<Formula 2>

1- (cyclohexyloxycarbonyloxy) ethyl-4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-) 1H-tetrazol-5-yl) diphenyl-4-yl) methyl) -1H-imidazole-5-carboxyester.
<Formula 3>

A method for producing olmesartan cilexetil, wherein the compound of claim 4 or 5 is used.