TW201217363A - Process for obtaining olmesartan medoxomil - Google Patents

Abstract

The invention relates to a process for obtaining olmesartan medoxomil by the reaction of sodium 5-(1-hydroxy-1-methylethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylate, obtained by the reaction between ethyl 5-(1-hydroxy-1-methylethyl)-2-propyl-3H-imidazole-4-carboxylate from and 5-(4'-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole followed by saponification, with 4-(chloromethyl)-5-methyl-1, 3-dioxol-2-one, deprotection and purification.

Description

201217363 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for obtaining olmesartan medosamine (VI). Olmesartan medosamine (VI) chemically corresponds to 4 (2-hydroxypropion-2-yl)-2-propyl-1-({4-[2-(2Η-1,2,3,4- Tetrazolium-5-yl)phenyl]phenyl)indenyl)-1Η-imidyl-5-carboxylic acid (5-methyl-2-oxo-2H-1,3-dioxole- 4-Base) oxime ester' and it is an angiotensin η receptor blocker. It is used as an antihypertensive drug in clinical practice. Its structural formula is:

(VI) [Prior Art] Patent US Pat. No. 5,616,599 describes 5-(dihydroxy-1-methylethyl)_2-propyl-3-[2,-(l-trityl-1) ugly having the formula (ΙΠ) - tetrazole _5_yl)biphenylmethyl]-3f. Synthesis of -4-carboxylic acid ethyl ester

The synthesis of the compound of the formula (III) in olmesartan medosamine (VI) 4 201217363 is an intermediate product in the alkylation of the oxime, hydrazine-dimethyl decylamine compound (I). The synthesis of (III) is carried out using sodium hydride as a base and imidazole nitrogen of the compound of the formula (11).

Ph3C

The purification method involves several separations with water and ethyl acetate. The column is purified by column chromatography and finally crystallized. The yield was 80%. The article published in L Med. Chem. (1996), 39(1), 323 38 also describes the use of a third butanol unloading test by the same reaction in hydrazine, dimethyl dimethyl acetamide. The synthesis (111) 'purification method also involves several times of separation with water and acetic acid, purification by column chromatography and finally crystallization. The yield was 80%. Similarly, the patent application, 〇 2〇〇 8〇43996, also describes the reaction in N,N-dimethylacetamide, but using sodium hydroxide, gas oxidizing or potassium carbonate as the base. The yield of this step was not mentioned because the olmesartan medosalmi was synthesized without separating any intermediate product. Therefore, it is apparent that a solvent having a toxicity lower than N,N-dimethylacetamide or N,N-dimethylformamide is required in the synthesis of the intermediate product (ΙΠ). Both solvents have toxic effects on reproduction. 201217363 Another aspect of the invention obtains (ιπ) by using a less toxic solvent, but performing the same reaction in the presence of a base for a longer reaction time. This is the case in the following inventions: Patent ΕΡ 181 6131 describes the use of carbonic acid unloading as a test, which is paid back (7) after 7 hours in B guess. The separation was carried out by cooling the product, transitioning and suspending it in water for 1.5 hours, followed by the intermediate product (ΙΠ). The yield was 89% 专利 Patent Shen Qing case W02007 148344 and patent EP 1 91 6246 describe the synthesis of (m) in acetone using carbonic acid unloading and desertification. The reaction was held for 10-16 hours under reflux. The separation method is to filter the substance to remove salts, to distill acetone and to recrystallize acetonitrile or decyl alcohol. The yield of the patent application '344 is 94. /. And the yield of the patent '246 is 8〇_85〇/〇. Patent Shenqing W02007048361 describes the synthesis of (III) in an acetone:polyethylene glycol mixture in the presence of potash for up to 11 hours of boiling. The yield was 85%. The pct patent application WO2008043996 describes the synthesis of (ΙΠ) in dimethyl hydrazine at room temperature using sodium hydroxide as a base for 12 hours. The intermediate product (ΙΠ) thus obtained was used in the next step without isolation. Although WO2007148344, W02007048361, ΕΡ1816131 and ΕΡ1916246 describe the synthesis of (III) in a solvent having a toxicity less than ν,ν-dimercaptoacetamide or ν,ν-dimethylformamide, the total reaction time is from 7 to 16 hour. This is why it is necessary to shorten the reaction time in the preparation of a non-toxic solvent to optimize the industrialization of the process. Patent US5616599 describes the synthesis of 5-(1-hydroxyl) having the formula (V)

S 201217363 decylethyl)-2-propyl-3-[2'-(l-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylindenyl]-3H-imidazole- 5-nonanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-yl decyl ester,

(V) as an intermediate in the synthesis of olmesartan medosamine (VI). The synthesis is carried out by reacting the previously mentioned intermediate (III) with a compound of the formula (IV), which is saponified (III) with lithium hydroxide in dioxane to obtain the formula (III- The lithium salt of Li) is then carried out.

7 201217363 After (III-Li) was isolated, potassium carbonate was used as an assay, and it was alkylated with (IV) in n n dimethylacetamide. The final crystallization step is carried out in diisopropyl mystery or acetic acid in vinegar. The yield was 87%. Similarly, the patent EP 1816131 describes the preparation of (v), but this time sodium hydroxide is used in N,N-dimethylacetamide to form a sodium salt of the formula (ni_Na).

The unseparated salt (III-Na) was alkylated with (IV) in N,N-dimercaptoacetamide using potassium carbonate as the base. The intermediate product (v) thus obtained was used in the next step without isolation. The yield was 75%. Application WO200843996 describes the same reaction in which sodium hydroxide is used to form a salt (ni-Na) in hydrazine, hydrazine-dimercaptoacetamide, but this time diisopropylethylamine or potassium butoxide is used as the base. The salt is alkylated with (IV) in hydrazine, hydrazine-dimercaptoacetamide diisopropylethylamine. In this application, the intermediate (III) is starting from (I) and (II) and is synthesized on the spot without isolation. A similar reaction diagram is described in the patent ΕΡ 19 16246. The salt (III-Li) was obtained by refluxing (III) in tetrahydrofuran for 15 hours using lithium hydroxide as a base. The (V) can be produced by alkylation of the previously isolated salt (III-Li) in hydrazine, hydrazine-dimercaptoacetamide in the presence of triethylamine in a yield of 75-80%. There is therefore a need for a process for synthesizing (v) using a solvent which is less toxic than N,N-dimercaptoacetamide or dioxin 8 201217363. The synthesis of (v) is described in the corp. patent application, WO 2,7,48,361, wherein potassium hydroxide is used in tetrahydrofuran for up to 24 hours to prepare a salt of formula (III-K:).

The reaction of the salt (III-K) with (IV) was carried out in methyl ethyl ketone and in the presence of potassium iodide for 7.5 hours. The solvent used in the crystallization is ethanol. The yield was 86 〇/〇. Although W02007048361 describes the synthesis of (v) in a non-toxic solvent, the completion time for the formation of the salt is 24 hours' and the reaction completion time for the alkylation step is 7.5 hours. It is therefore necessary to achieve a method of obtaining (v) which is optimized for industrial use because of the use of a non-toxic solvent and with a short reaction time. Because the solvents N,N-dimercaptoacetamide, N,N-dimethylamine and one burn are used in the current state of the art 如上f the art as described above, belonging to the CMR group. Group (Guangzhou Pain, Chuanbian and Qilanli Drugs) (Regulations of the European Parliament and the Council on the Classification, Labelling and Packaging of Substances and Mixtures (EC) No. 1272/2008 (December 16, 2008) (Regulation (EC) No. 1272/2008 of the European Parliament and Council of 16 December 2008 on the Classification, Labelling and Packaging of Substances and Mixtures), its amendments and revocations refer to 201217363 Orders 67/548/EEC and 1999/45/EC and Amendments to Regulations ( Ε〇第i9〇7/2〇〇6”), so it is appropriate to find a way to optimize industrialization by shortening manufacturing time and using safer alternative solvents. Patent US5616599 is described at 60. (: Deprotection of the trityl derivative (v) in the final product (VJ) in aqueous acetic acid. Once the reaction is complete, the mixture is cooled, water is added and the triphenylmethanol is removed by filtration. The product was removed from the ethyl acetate. The residue was crystallized from ethyl acetate. The yield of this step was 8 1 〇 / 〇. Patent application US 2 〇 06 014 887 〇 also describes (V) is deprotected in an acetic acid hopper solution at 6 〇〇c to produce (VI). Similarly, the patent application W〇2〇〇7〇47838 describes _(7) deprotection at 58 under aqueous acetic acid To produce (VI). The method is to cool the reaction mixture, add sodium vapor solution and filtrate to remove triphenylmethanol, then add di-methane, and separate it from the aqueous phase. Then distill the organic solvent and finally the residue from acetone Crystallization. The yield of this step is 76 〇.. Patent EP 1 9 1 6246 also describes the (v) de-sucking in aqueous acetic acid to produce (VI). Once the reaction is complete, the mixture is cooled and water is added. The trityl alcohol is removed by hydrazine. The acetic acid is distilled and the residue is blocked from isopropanol.

曰B These four documents describe two options for removing acetic acid: a steaming plant to produce a final product (VI) without acetic acid. Because deprotection requires: a large amount of acetic acid' therefore must prevent the reaction from being "neutralized" due to the large amount of salt produced. When the residue is obtained from distilled acetic acid, in order to ensure complete removal of acetic acid by 10 201217363, f benzene or ethyl acetate must be added. b) Extraction of (VI) from aqueous acetic acid medium using -chloro-Hyun (a highly volatile toxic solvent, also belonging to the CMR group). There is therefore a need for a process for synthesizing (VI) which does not use an aqueous acetic acid solution and avoids the production of the final product via distillation, thereby making the process more suitable for industrialization. Patent application W〇2〇〇7017135 is described at 24-26. (: Deprotection of (V) in the presence of HCl in an ethyl acetate:ethanol mixture for 3 hours. Once the reaction is complete, add water and adjust the pH to NaOH with NaOH. Ester extraction. The solvent is removed at low pressure until it produces a residue, then ethyl acetate is added, followed by distillation again. The outlet body is crystallized from ethyl acetate (75 / yield). Obtaining (VI) requires at least 2 〇 volume, this application The volume in the case is the following ratio: volume = number of milliliters of solvent (ml) / gram of solute (g) Patent application W〇2〇 (m48344 described in toluene: guilty, ethyl acetate: HCi or heptane: a mixture of HC1 In the case of (v) deprotection, when toluene or heptane is used, after adjusting the pH of the organic phase to 5 〇 _65 with potassium carbonate solution, the phases are separated and the aqueous phase is extracted with ethyl acetate. Each phase: Partially illuminate the acetic acid § to allow (VI) day or day, or to completely crystallize the residue from propylamine. When using ethyl acetate as the counter: (d) 丨 when adjusting the pH Never separate the phases before. Produce at least 29 times the volume. And by 201217363 Application No. 2008043996 describes the deprotection of (V) in a mixture of n,n-diamine:HC1. The base of the ugly side is trimmed. The cold reaction material is decanted to the oxime and the triphenyl sterol is filtered off. The residue is cooled, and the mixture is extracted with a gas-fired product. The second gas pit is removed and the residue is crystallized from C. It is also described that (ν) is deprotected in an aqueous acetic acid medium. To be at least 18 volumes. When using inorganic acid synthesis (VI), use a toxic solvent (ν, ν-dimercaptoacetamide or di-methane, all CMR), or more than 2 〇 volume. Manufacture (VI) in a non-toxic solvent, reducing the required volume and avoiding the distillation, in order to make the process more suitable for industrialization. Patent application US20060258727, US20060074117, US20070054948 and US7528258 are described in the presence of H2S04 at 4 (TC) Deprotection of (V) in a mixture of acetone:water (1:1 v/v). Trityl alcohol was precipitated by adding water and removed by filtration. NaHC03 was added to the filtrate and the mixture was cooled to ambient temperature. According to (vi). When using inorganic acid pairs V) Deprotection, (VI) described in the patent US Pat. No. 7,528,258, to prepare a volume required for the reduction operation. SUMMARY OF THE INVENTION The present invention provides a novel and olmesartan medosamine (VI) according to FIG. Favorable industrial methods:

S 12 201217363

In this application, volume = number of milliliters of solvent (mL) / gram of solute (g). Compared with the current state of the art, the most important features of the present invention and the preferred oxidative oxygen. First step: synthesis of (III) a) use of a non-toxic solvent (non-CMR): tetrahydrofuran, disulfoxide, c, butyl , methyl tertiary butyl mystery, toluene, ethyl acetate or a mixture thereof. 1 has been shortened. Actual ±, & completed within 2 hours of 'special reaction even as a solvent, no: 吏, dimethyl argon or four is not the third butyl alcohol unloading test time: using non-toxic solvents, However, it is reported in the best technical state 13 201217363 7 -16 hours. The combined use of potassium t-butoxide and a non-toxic solvent in the present invention unexpectedly and advantageously shortens the reaction time. c) Product separation involves very easy handling, such as cooling the reaction mass, distilling the solvent in the presence of water, and filtering. d) Obtain a product with high yield (95%) and good purity (> 93%). Second step: Synthesis of (V) a) Use of a non-toxic solvent (non-CMR): tetrahydrofuran, 2-mercaptotetrahydrofuran, monoterpenoid, acetone or a mixture thereof. b) The reaction time for producing the salt and alkylating the salt with (IV) is shortened. Thus, in addition to the use of a non-toxic solvent, it takes only 2 hours to form the salt, rather than the 24 hours described in the current state of the art, while the alkylation step takes only 2.5 hours, rather than the current state of the art. 7.5 hours. c) The reagent can be better utilized because a product having a high yield (85%) and a good purity (> 95%) is obtained per equivalent (?) using 1 · 〗 〖(IV) 〇 d ). Third step: Synthesis of (VI) a) Use a non-toxic solvent (non-cmR): methanol, toluene, acetonitrile or a mixture thereof. b) The product crystallizes from toluene' which allows removal of the triphenylmethanol which is soluble in the solvent without loss of product in the mother liquor. Thus, the process of the present invention requires up to 14 volumes in this step. c) Obtain a product with high yield (85% deprotection and 90% recrystallization) and greater purity (>99.5%) than 201217363. Thus, in summary and in short, the method of the present invention does not use a carcinogenic, mutagenic or reproductive toxicity solvent, and the reaction time is shortened and the amount of solvent is reduced, all of which are advantageous for the industrialization of the process. [Embodiment] One object of the present invention is to provide a method for obtaining olmesartan medosamine (VI),

It contains the following steps: In the presence of a butanol clock and in a medium comprising a solvent selected from the group consisting of ethyl acetate, acetone such as methyl sulfoxide, butyl hydrazine, methyl tert-butyl ether, tetrahydrofuran, and toluene and a mixture Compounds of formula (I) with a compound of formula (Π)

15 0) 201217363

(Π) formed by saponifying (i) in the presence of sodium hydroxide and in a medium comprising a solvent selected from the group consisting of dimethyl sulfoxide, 2-methyltetrahydrofuran, and tetrahydrofuran, and mixtures thereof Compound,

To produce an intermediate salt of formula (III-Na),

It reacts with the compound of formula (IV) in the presence of potassium carbonate in a medium comprising a solvent selected from the group consisting of acetone, dimethyl sulfoxide, 2-methyltetrahydrofuran, and tetrahydrofuran, and mixtures thereof.

S 16 (IV)201217363

Cl (iii ) deprotects the compound of formula (V) produced in (π) in a medium comprising an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, acid, nitric acid and sulfuric acid and an aqueous solution of acetone or acetonitrile ,

The crystallization is then carried out by adding toluene, adjusting the pH of the aqueous phase to remove acetone or acetonitrile at low pressure and filtering to separate the resulting compound and or a mixture of acetonitrile and methanol, or under reflux to subsequently crystallize (VI 4.5-6.0 (VI) (^) by a final purification of a medium comprising a mixture of acetonitrile and a mixture of C, in a preferred embodiment, a mixture of diterpene and hard. In another preferred embodiment, in another preferred embodiment In the example, the medium of step (i) comprises acetone and the reaction of step (i) is carried out under reflux. The reaction solvent is removed at a low pressure after adding water to the product in water at 17 17 1717363. In another preferred embodiment In the present example, the compound of formula (III) is not used in the next step of the process. It is understood that in another preferred embodiment, the medium of step (ii) comprises __〇一碉碉•, dimethyl ya a mixture with tetrahydrofuran, a mixture of dimethyl sulfoxide and 2-methyltetrahydrofuran, a mixture of dimethyl sulfoxide and acetone, a mixture of dimethyl sulfoxide, tetrahydrofuran and acetone, and dimethyl sulfoxide, 2·曱A mixture of tetrahydrofuran and acetone. In another preferred embodiment, the medium of step (ii) comprises a mixture of tetrahydrofuran and disulfoxide at a ratio of 2:3 to saponify (ιπ). In another preferred embodiment, The temperature for the saponification (ιπ) in the step (Η) is 45-75. In another preferred embodiment, the step „. ^ 匕χ JT Aixiang (ii) contains tetrahydrofuran and dimethylene. Shifengzhi 3.7.1 5 Bu Bu, Xuan··gt;, 曰人• · Mixture of ratios to use (IV) alkylation (III-Na). ^Other - preferred embodiment, step (u The alkylation temperature between (m_Na) and (ιν) is 6 〇 _ 7.5. It is in the other step (ii) - more than the four gas "Shi Bijia good specific case, after 1.5 hours Adding the compound diluted in tetrafurfuran to (III-Na) is added to (III-Na). In step (u), the other compound (IV Na, Xiu " human body) The ratio of (ΠΙ-Na) to the amount of ΠΙ-Na is between 1 〇 and 15 ii) The compound (V) crystallizes from ethyl acetate in another preferred embodiment. The medium of i) contains hydrochloric acid and in another preferred embodiment, the step (i)

S 18 201217363 Aqueous solution of acetonitrile. In another preferred embodiment, the temperature is between 25 ° C and 25 ° C. In another preferred embodiment, the hydrochloric acid equivalent is carried out. The deprotection of step (iii) is carried out in the deprotection step 4-6 of the step (iii). In another preferred embodiment, only % T, in the step (m), when the trityl group is dissolved in toluene, The compound Γ (VI ) is crystallized in the solvent to separate the trityl group from the medium. In another preferred embodiment of the self-experimental carbonate or bicarbonate, the pH of the step (iii) is 'the base is potassium carbonate, and the sodium carbonate is adjusted in the saturated solution of the other hydrogencarbonate of step (iii). Adjust with the base. In another preferred embodiment, hydrogencarbonate or sodium bicarbonate. In a preferred embodiment, the pH is alkaline. In a further preferred embodiment of step ((1)), the positive value is adjusted with a saturated solution of sodium arsenate. In another preferred embodiment the crystal system is carried out with acetonitrile. Example - Re-blocking ethyl (ethyl)-2-propyl-3-[2,-(l-triyl]-3H-imidazol-4-furoate ethyl ester in the step (VI) Example 1- 8: Preparation of 5_(1•hydroxyindolylphenyl-1H-tetrasyl-5-yl)-stupid _4_yl-(III) 19 201217363

Example 1 5.15 g of (Π) and 2.51 g (1" equivalent) of (1) were suspended in 12.3 ml of acetone. The mixture was cooled to 〇_5〇c to add 丨14 g (1" equivalent) of potassium t-butoxide. The mixture was then heated under reflux. At the beginning of the reflux, 〇.5 ml of dimethyl sulfoxide was added over about 30 minutes. The reaction was completed in the next 2 hours. The mixture was cooled to ambient temperature in about 1 hour. Then 24.6 ml of water was added and acetone was distilled. The mixture was cooled to 〇5, filtered, washed with water and dried in a heat cabinet. 6.34 g of (III) (97% yield) was obtained. The solid obtained by HpLC analysis showed a purity of more than 93%. Example 2 Ug (υ and 0.47 g (1.0 eq.) potassium tert-butoxide were suspended in 5 ml of dimethyl sulfoxide. Then, 2 (II) (1 〇 equivalent) was added over 1 hour at ambient temperature. The mixture was stirred at ambient temperature for 5 hours. The mixture was filtered, washed with water and dried in a heating cabinet. The obtained "(1)...❶/❶ yield" was analyzed by inhibition. The purity is shown to be greater than 80%.# Example 3 and 0.46 g ° 1.0 g of (I), 2.08 g of (Π) (〇9 equivalent) (1,0 equivalent) potassium butoxide can be suspended in 10 ml. Tetrahydrocethane in 20 201217363 This alpha was heated to /Furton for 2 hours. HpLc analysis revealed the formation of 6 states. (III). Example 4 5. 〇g of (I), u, 6g ( II) (1.0 eq.) and 2,8 g of potassium butoxide potassium suspension in 25 ml of methyl ethyl ketone. The mixture was heated to 50%. After 6.0 hours, the reaction was analyzed by β Ηρπ to reveal the formation (out). Example 5 1.0 g of (I), 2 〇 8 g of (π) (〇9 eq.) and 〇 (1.0 詈) of the -6th potassium alkoxide were suspended in 10 ml of decyl tertiary butyl ether. The compound reached boiling. 梃m. Then 2 mL of dimethyl sulphate was added over 30 minutes, and the reaction was a butylene in 3.5 hours. HPLC analysis revealed the formation of 59% of (III). Example 6 g (I) and 10.44 g (II) (0.9 eq.) μ are floated in 25 ml of toluene. The current I I is cooled to less than l〇t, and 2 34 (1_〇 equivalent) is added. The third butanol was completed within a known time. HPLC analysis revealed the formation of a pendulum. The mixture was heated to 551 and 5 ml of diterpenoids were added. The reaction was at 4% 79 79% (III) 〇 Example 7 1.0 g (I), Λο .08 g (π) (0.9 eq.) and 〇46 g (1·〇 equivalent) of the third 醆 醆 μ seed were suspended in 1 ml of ethyl acetate. The compound reached boiling. The reaction was completed in an hour. The HPLC analysis revealed that 21% of (III) was formed. | ah, not taking Example 8 21 201217363 will be ..., 2.32g (Π) (1_〇 equivalent) and 〇. 47 g (1·0 tianli) potassium butoxide was suspended in 丨〇ml of acetone. The mixture was heated under reflux. The reaction was completed in 2.0 hours. HpLC analysis revealed the formation of 82% of (III). Example: base q methyl ethyl) 2 propyl small [2 匕 (1-monobenzyl-li / - tetrazol-5-yl) biphenyl _4 methyl] _3 ugly imidazole _4 Preparation of 5-mercapto-2-yloxy[1'3]dioxol 4 carboxylic acid ethyl ester (v)

(V) Example 9 6.20 g of (III) was suspended in a mixture of Η"ml tetrahydrofuran: dioxin (2:3' V/V). The mixture was cooled to 17 Torr to add 〇·45 g (1.3 eq.) of sodium aroxide. The mixture is then heated to 6 &>c. After 2 hours, 1.55 g (1.1 equivalents) of potassium carbonate was added to the mixture. The full house was heated to 7 ° C, and 1.4 1 g of (IV) dissolved in 丨6 2 such as tetrahydrofuran was added to the mixture over 1.5 hours. The reaction was completed in 1 hour. The mixture was cooled to room temperature. The whole was then washed 3 times with a 29% aqueous solution of sodium sulphate. Finally, the organic solvent was distilled and 丨8 6 mi of ethyl acetate was added. Finally, (V) was crystallized from ethyl acetate by cooling. Cool the mixture to 〇_5

S 201217363 °c 'over the 遽, used solid. The obtained solid was obtained, and the acetic acid and the hexane were washed, and then dried in a heating cabinet to obtain 5.54 g (V) (80% yield). The purity is greater than 97% by pjPLC. Example 1 2 2·〇 g of broad (III) and 0·18 g (1.66 equivalent) of sodium hydroxide were suspended in 5 ml of dimethylene. ^ Wind: a mixture of 2-mercaptotetrahydrofuran (3:2, ν/ν). The mixture was then added to 埶, 芏: > υ υ, and held for 1 hour. The receiver is heated and mixed under reflux. And add hydrazine, 46 g potassium carbonate. It was dissolved in 1 〇 ml of 2-methylperic cough over 1.25 hours. South China's G.5g (IV). It is necessary to complete the reaction! Hours (76% of (V) ' is known by HpLC). EXAMPLES 2.08 (ΙΠ) and 〇·18 g (1.6 equivalents) of sodium hydroxide were suspended in 5 ml of dimethyl sulfoxide. The mixture was stirred at room temperature for 2 hours. The mixture was then heated under back and 〇 54 g of potassium carbonate was added. 58 g of (〇) dissolved in 10 ml of monothyl sulfoxide was added to the mixture over 3 minutes. It takes 5 hours to complete the reaction (75% (v), known by HpLc). Example 12 2,0 g of (III) and 〇18 曰 8 g of U.6. sodium hydroxide were suspended in 8 ml of diterpenoid. The mixture was stirred for 2 hours under the uterus, ® A, τ brother τ 至 / / dish. The mixture was then heated to 5 full and 0.54 g of potassium carbonate was added. The reaction mixture was placed under reflux, and (IV) dissolved in 2 〇 ml (4) of 58 g was added over 1.5 hours. It takes 2_75 hours to complete the reaction (9% (v), MpLc knows). The mixture was filtered to remove. Tian Wei ^ Yu, now. Wash the salt with 5 ml of acetone and add 20 ml of ethyl acetate and 5 ml of water. The blister is separated from the water. Add 20 ml of n-heptane to 23 201217363. The acetone was removed by distillation. The mixture was cooled to. -5 ° C, the solid formed by filtration was dried by washing with 5 ml of n-heptane. It was obtained on the evening of eve, and the person was heating the plant handle (yield). The solids were analyzed by muscle c, showing a purity of 95%.丄 (Μ例例13·14 : 4-(2_ propyl propyl R propyl 5 carboxylic acid ^ 1,2,3,4-tetras-7 yl) phenyl] phenyl} methyl ). The taste of salicylic acid (S, methyl-2·sideoxy-2 ugly (VI) preparation of lining (4) _4· base)

Example 13 3·8§ g (ν) was suspended in 92 ml of B. However, to 5 1 , > / H * The mixture was cooled to 24.6 ml of 6N HC1. At 5〇c, it was pulled for 2 hours. Mix the mixture ", σ 150(6) benzene. The pH was adjusted to 5 7 with potassium bicarbonate. The mixture was passed through to remove part of the produced product. 展, 展王 07 1 was washed with 30 ml of acetonitrile. "From the various phases. Evaporate the acetonitrile present in the organic phase. Cool the mixture and = filter. The solid was washed with toluene and water. Dry in a heating cabinet (W). Obtained 16.66 g of (VI) (85% yield). Further Example 14 43.0 g of (7) was suspended in 13 〇 ml of B guess +. Cooling mixture

24 201217363 to 〇-5 °C and add 6NHC1 of 35 claws. The mixture was given 2 hours at 7_8t. Add 215 ml of toluene. The pH was adjusted to 4.8 with a saturated solution of sodium bicarbonate. Separate the phases. The aqueous phase was extracted with a mixture of 215 ml of toluene and 43 g of acetonitrile. The organic phases were combined and washed with 43 mL water. The acetonitrile present in the organic phase is distilled. The mixture was cooled to 〇5 < t and filtered. The solid was washed with toluene and water and washed again with toluene. Dry in a heating cabinet (VI). 24 67 g of (VI) (82% yield) was obtained. Example 15-17: 4-(2-Hydroxypropan-2-yl)_2-propyl-1-({4-[2-(2孖-1,2,3,4-tetrazol-5-yl) Purification of phenyl]phenyl}methyl)_1 ugly-imidazole-5-carboxylic acid (5-methyl-2. oxo-2-opened dioxol-4-yl) decyl ester (VI) Example 15 15.06 g of (VI) were dissolved in 130 ml of acetonitrile under reflux and cooled to 0-5 ° C for filtration, washed with acetonitrile and water and finally dried. The yield was 93%. Example 16 4.7 g of (VI) were dissolved in 32.9 ml of acetonitrile and 4.7 ml of decyl alcohol under reflux. The mixture was cooled to 0-5 ° C, filtered, washed with acetonitrile and dried in a heating cabinet. The yield was 80%. Example 17 5.0 g of (VI) was dissolved in 35 ml of acetonitrile and 5 ml of acetone under reflux. The mixture was cooled to 0-5 ° C, filtered, washed with acetonitrile and dried in a heating cabinet. The yield was 89%. 25 201217363 [Simple description of the diagram] None [Key component symbol description] None

S 26

Claims (1)

201217363 VII. The scope of application for patents: 1. The method of obtaining omesartan medoxomil (VI), It comprises the following steps: (1) in the presence of potassium t-butoxide and comprising a mixture selected from the group consisting of ethyl acetate, acetone, dimethyl sulfoxide, methyl ethyl ketone, decyl butyl ether, tetrahydrofuran and toluene and mixtures thereof Alkylation of a compound of formula (I) with a compound of the formula (I) in a solvent medium (11) in the presence of sodium oxysulfide and in the presence of a mixture comprising a mixture of dimethyltetrahydrofuran and tetrahydrofuran, and a mixture thereof, formed by the formula (called saponification (1) The solvent of the compound of the media 27 201217363 To produce an intermediate salt of the formula (ΠΙ-Na), It reacts with the compound of formula (IV) in the presence of potassium carbonate in a medium comprising a solvent selected from the group consisting of acetone, dimethyl hydrazine, 2-mercaptotetrahydrofuran and tetrahydrofuran, and mixtures thereof, YV〇(IV) (iii) deprotecting a compound produced in formula (V) with (ii) in a medium comprising an aqueous solution of a mineral acid selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid and acetone or acetonitrile, δ 28 201217363 Subsequently, crystallization is carried out by adding toluene, the pH of the aqueous phase is adjusted to 4.5-6.0', the acetone or acetonitrile is removed at low pressure and filtered to separate the obtained compound (VI); and (W) is dissolved in acetonitrile by refluxing, The final purification is carried out by crystallizing (VI) in a medium of a mixture of acetonitrile and methanol or a mixture of acetonitrile oxime &gt;w, ”. 2. The method of claim </ RTI> is characterized by the step (. The medium comprises a mixture of acetone and dimethyl sulfoxide. The method of claim 1, wherein the medium of step (ii) comprises dimethyl sulfite, dimethyl hydrazine and tetrahydroanthracene. a mixture of a person, a mixture of dif-methyltetra(4), a dimethyl methion and a ketone, a mixture of hydrazine, tetrahydrotetramine and propylamine, a mixture of imipenem, 2-methyltetrahydrofuran and acetone. 4. The method of claim 1, wherein the medium comprises an aqueous solution of hydrochloric acid and acetonitrile. 5. If the patent is applied to the side of the item i, the characteristic of the ρ ίί is selected from the test. Carbonate or bicarbonate on 6. Please Method patentable scope as item 5, wherein the entire circumferential Chi ^. Potassium, sodium carbonate, potassium bicarbonate or sodium bicarbonate. ~ Is carbonate 29