WO2014036686A1

WO2014036686A1 - Olmesartan medoxomil preparation method

Info

Publication number: WO2014036686A1
Application number: PCT/CN2012/080967
Authority: WO
Inventors: 李金亮; 赵楠; 谢益明
Original assignee: 上海迪赛诺化学制药有限公司; 上海迪赛诺药业有限公司
Priority date: 2012-09-04
Filing date: 2012-09-04
Publication date: 2014-03-13

Abstract

An olmesartan medoxomil preparation method, the method comprising the step of deprotecting a compound of formula V in an organic solvent containing p-toluenesulphonic acid, the compound of formula V having a structure as shown in the specification. The method of the present invention uses cheap and readily available raw materials, and has a moderate reaction condition, high reaction selectivity, high yield and few by-products, thus being suitable for industrialized production.

Description

Preparation method of olmesartan medoxomil

Technical field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of olmesartan medoxomil. Background technique

Olmesartan Medoxomil, chemical name 4-(1-hydroxy-1-methylethyl)-2-propyl small _{ 4-[2-(tetrazol-5-yl)phenyl]benzene Methyl imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, the structural formula is:

Olmesartan Medoxomil is a prodrug of olmesartan, an angiotensin II receptor antagonist that exerts antihypertensive effects by affecting the renin-angiotensin-aldosterone system, and has been listed by the World Health Organization and the International Hypertension League. It is one of the six major antihypertensive drugs.

US5616599A first disclosed two methods for synthesizing olmesartan medoxomil, respectively:

Wherein, in the last step of the route 1, when the trityl protecting group is removed under 75% acetic acid aqueous solution, a small amount of the ester-based hydrolyzate-olmesartan can be detected, and the final product obtained from this route is olmesartan medoxomil disclosed in US7528258B2. The content of olmesartan is about 2.2% (HPLC purity), which affects the purification of the final product. Regarding this step reaction, the existing methods are basically carried out under acid water conditions, and it is easy to cause the ester bond to be broken, and the hydrolysate olmesartan is produced. In addition, Yan Xinhong et al reported that the total yield of the two-step reaction of saponification and esterification was 81% (虞心红, Tang Jian, Wen Xinmin, Mao Qinghua, Shen Yongjia. Synthesis of antihypertensive drug olmesartan. Journal of East China University of Science and Technology (Nature) Scientific Edition), 2005, 31(2), 189-192.

In the second step of the route 2, the ester group is easily hydrolyzed under alkaline conditions, and the trityl olmesartan by-product is easily obtained.

In addition, when removing the trityl protecting group from the two routes, the acetic acid used is at least 10 times more equivalent than the reactant. The post-treatment requires neutralization with a base, resulting in a large amount of waste liquid, increasing post-treatment costs and environmental protection pressure. .

Therefore, there is still a need in the art to provide a novel process for the preparation of olmesartan medoxomil. Summary of the invention

The object of the present invention is to overcome the deficiencies of the prior art and to provide a novel method for preparing olmesartan medoxomil. In a first aspect of the invention, there is provided a process for the preparation of olmesartan medoxomil comprising the compound of formula V in the presence of p-toluenesulfonic acid

In another preferred embodiment, the organic solvent comprises acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, acetonitrile or a mixture of two or more thereof. Solvent.

In another preferred embodiment, the organic solvent is acetone, methanol or a mixed solvent of the two.

In another preferred embodiment, the molar ratio of the compound of the formula V to p-toluenesulfonic acid is 1: 0.01-20; preferably, 1: 0.01-10, more preferably 1: 0.01-1, or even 1 : 0.05-0.5

In another preferred embodiment, the molar ratio of the compound of the formula V to p-toluenesulfonic acid is 1 : 0.02 - 0.8, preferably 1 : 0.05 to 0.15, more preferably 1: 0.1.

In another preferred embodiment, the reaction temperature of the deprotection reaction is from 0 ° C to 100 ° C. Preferably, the reaction temperature of the deprotection reaction is from 5 ° C to 80 ° C, more preferably, The reaction temperature for the deprotection reaction is from 10 ° C to 60 ° C.

In another

(a) a compound of formula II in an organic solvent, an alkali metal hydroxide, an alkali metal alkoxide, or an alkali metal Hydrolysis to obtain a hydrazine compound in the presence of a mixture of a hydroxide and an alkali metal alkoxide;

(b) adding the compound of the formula IV to the reaction mixture obtained in the step (a) without isolation, to obtain a compound of the formula V;

Wherein is an alkyl group of _-5 ; X is a halogen.

In another preferred embodiment, X is fluorine, chlorine, bromine or iodine.

In another preferred embodiment, the R is ethyl or methyl. Preferably, said R is an ethyl group.

In another preferred embodiment, the X is chlorine or bromine. Preferably, said X is chlorine.

In another preferred embodiment, the organic solvent in the step (a) includes acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, acetonitrile or Two or more mixed solvents. Preferably, the organic solvent is acetone, methanol or a mixed solvent of the two.

In another preferred embodiment, the molar ratio of the hydrazine compound, the compound of formula IV, to the alkali metal hydroxide, or to the alkali metal alkoxide, or to the mixture of the alkali metal hydroxide and the alkali metal alkoxide It is 1: 1 to 6: 1 to 5; preferably, the molar ratio is 1: 2-5: 1.5 to 4.

In another preferred embodiment, the molar ratio of the hydrazine compound, the compound of the formula IV, and the hydroxide of the alkali metal is 1: 1 to 6: 1 to 5; preferably, the molar ratio is 1: 2-5. : 1.5 to 4.

In another preferred embodiment, the molar ratio of the hydrazine compound, the compound of the formula IV, and the alcoholate of the alkali metal is 1:1 to 6:1 to 5; preferably, the molar ratio is 1:2-5: 1.5 to 4.

In another preferred embodiment, the molar ratio of the hydrazine compound, the compound of the formula IV, and the mixture of the alkali metal hydroxide and the alkali metal alkoxide is 1:1 to 6:1 to 5; preferably, The molar ratio is 1: 2-5: 1.5~4.

In another preferred embodiment, the alkali metal hydroxide in the step (b) comprises sodium hydroxide, potassium hydroxide or a mixture of the two; preferably, sodium hydroxide.

In another preferred embodiment, the alkali metal alkoxide includes sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or a mixture of two or more thereof. Preferably, the alkali metal alkoxide is sodium methoxide.

In another preferred embodiment, the reaction temperature of the step (a) is 0 to 60 ° C; and the reaction temperature of the step (b) is 35 to 100 ° C.

In another preferred embodiment, the reaction of the step (a) is 10 to 60 ° C; and the reaction temperature of the step (b) is 35 to 60 ° C.

In another preferred embodiment, after the addition of the compound of the formula IV is completed, the temperature is raised to 35 to 100 ° C to carry out the reaction. It is preferred to raise the temperature to 40 to 60 °C.

In another preferred embodiment, the method further includes the steps of:

(c) The reaction mixture obtained in the step (b) was cooled to room temperature, and washed with water. In another preferred embodiment, the ratio of the amount of water added to the amount of the substance of the formula compound is from 10 to 200:1, preferably from 50 to 150:1.

In another preferred embodiment, in the step (b), when the compound of the formula IV is added, the catalyst is added to the system. In another preferred embodiment, the catalyst is potassium iodide or sodium iodide. More preferred is potassium iodide.

In another preferred embodiment, the ratio of the amount of the catalyst added to the amount of the substance of the hydrazine compound is 0.0005 to 5: 1, preferably 0.0008 to 3: 1, more preferably 0.001 to 1:1. In a second aspect of the invention, there is provided a method of preparing a compound of formula V, comprising the steps of:

(a) a compound of the formula II is hydrolyzed in an organic solvent in the presence of a mixture of an alkali metal hydroxide, an alkali metal alkoxide, or an alkali metal hydroxide and an alkali metal alkoxide to obtain a hydrazine compound;

Wherein is an alkyl group of _-5 ; X is a halogen.

In another preferred embodiment, X is fluorine, chlorine, bromine or iodine.

In another preferred embodiment, a hydrazine compound, a compound of formula IV, a hydroxide with an alkali metal, or an alkali metal The molar ratio of the alcoholate or the mixture of the alkali metal hydroxide and the alkali metal alkoxide is 1:1 to 6:1 to 5; preferably, the molar ratio is 1:2-5: 1.5 to 4.

In another preferred embodiment, the reaction of the step (a) is 0 to 60 ° C; and the reaction temperature of the step (b) is 35 to 100 ° C.

In another preferred embodiment, the method further includes the steps of:

(c) The reaction mixture obtained in the step (b) was cooled to room temperature, and washed with water.

In another preferred embodiment, the ratio of the amount of water added to the amount of the substance of the formula compound is from 10 to 200:1, preferably from 50 to 150:1.

In another preferred embodiment, in the step (b), when the compound of the formula IV is added, the catalyst is added to the system. In another preferred embodiment, the catalyst added is potassium iodide or sodium iodide. More preferred is potassium iodide.

In another preferred embodiment, the ratio of the amount of the catalyst added to the amount of the substance of the hydrazine compound is 0.0005 to 5:1, preferably 0.0008 to 3:1, more preferably 0.001 to 1:1. The invention has the advantages that the raw material is cheap and easy to obtain, the reaction selectivity is high, the reaction condition is mild, the yield is high, and the by-products are few, which is suitable for industrial production. It should be understood that within the scope of the present invention, the above various technical features of the present invention and the specific description below (as in the embodiment) The various technical features described can be combined with each other to form a new or preferred technical solution. Due to space limitations, it will not be repeated here. detailed description

The inventors of the present application have extensively and intensively studied, and unexpectedly found that the compound of the formula V is deprotected in an organic solvent containing p-toluenesulfonic acid to obtain olmesartan medoxomil, which can be a side reaction product - Omeisha The content of tanzan is controlled below 1%. The organic solvent used has a low boiling point, is easily recovered by distillation, and uses a catalyst amount of acid, which is simple in post-treatment, low in cost, and does not cause pollution and waste. On the basis of this, the present invention has been completed. Herein, the alkyl group of d- ₅ means a straight or branched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Base, pentyl, etc.

Herein, room temperature means a temperature condition of about 20 ° C (20 ± 1 ° C). Compound of formula V

In the present invention, "compounds of formula V", "compounds of formula V", "key intermediates of formula V", "compounds of formula V", and "compound V" are used interchangeably and mean The compound having the structure of formula V is a key intermediate in the synthesis of olmesartan medoxomil.

V

Preparation of compound of formula V

In the present invention, a preferred method for preparing a compound of formula V comprises the steps of:

Wherein 1 is an alkyl group of ₅ ; X is a halogen (including fluorine, chlorine, bromine or iodine).

The organic solvent in the step (a) includes acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, acetonitrile or a mixed solvent of two or more. Preferably, the organic solvent is acetone, methanol or a mixed solvent of the two.

The reaction of the step (a) is 0 to 60 ° C, preferably 10 to 60 ° C.

The alkali metal hydroxide in the step (b) includes sodium hydroxide, potassium hydroxide or a mixture of the two; the alkali metal alkoxide includes sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or both The above mixture.

In another preferred embodiment, the alkali metal hydroxide is sodium hydroxide.

In another preferred embodiment, the alkali metal alkoxide is sodium methoxide.

The molar ratio of the hydrazine compound, the compound of the formula IV, and the hydroxide of the alkali metal is from 1:1 to 6:1 to 5; preferably, the molar ratio is from 1:2 to 5: 1.5 to 4.

The molar ratio of the hydrazine compound, the compound of the formula IV, and the alcoholate of the alkali metal is 1 : 1 to 6: 1 to 5; preferably, the molar ratio is 1 : 2-5: 1.5 to 4.

The molar ratio of the hydrazine compound, the compound of the formula IV, and the mixture of the alkali metal hydroxide and the alkali metal alkoxide is 1:1 to 6:1 to 5; preferably, the molar ratio is 1:2. -5: 1.5~4.

The reaction temperature of the step (b) is 35 to 100 °C. In another preferred embodiment, when the compound of the formula IV is added, the reaction is carried out by raising the temperature to 35 to 100 °C. Preferably, the temperature is raised to 35 to 60 °C.

After the saponification reaction, the compound of the formula IV is directly added to the esterification reaction without isolation, and the yield is high, 〉85%, Even more than 90%.

The method also includes the steps of:

In another preferred embodiment, the ratio of the amount of water added to the amount of the substance of the formula compound is from 10 to 200:1, preferably from 50 to 150:1, more preferably 100:1.

In another preferred embodiment, in step (b), after the addition of the compound of formula IV is completed, the catalyst is added to the system. In another preferred embodiment, the catalyst added is potassium iodide or sodium iodide. More preferred is potassium iodide.

In another preferred embodiment, the ratio of the amount of the catalyst added to the amount of the substance of the hydrazine compound is 0.0005 to 5: 1, preferably 0.0008 to 3: 1, more preferably 0.001 to 1:1.

Further, the method further comprises the step of isolating and purifying the compound of formula V. Using a conventional method in the art, for example, the reaction system obtained in the step (c) is concentrated under reduced pressure to remove acetone, and the concentrate is extracted three times with ethyl acetate (e.g., 3 X 300 mL), and the organic phases are combined and saturated. Wash with sodium chloride solution (such as 300 mL), dry over anhydrous sodium sulfate for 2-4 h, remove sodium sulfate by filtration to obtain a filtrate, and then concentrate under reduced pressure to leave a small amount of ethyl acetate (about 1 times volume). Stir slowly, and cool with ice water bath. A large amount of solid is precipitated. Filter under reduced pressure to obtain crude light yellow solid. Add the crude product to ethyl acetate (such as 3 times volume), heat to dissolve, filter hot, remove a small amount of insoluble mechanical impurities. The filtrate is slowly stirred, naturally cooled to room temperature, continued to cool in an ice water bath, slowly stirred, gradually precipitated a large amount of solids, filtered under reduced pressure, the filtrate was removed, a small amount of n-heptane (such as about 200 mL) was washed, and filtered to dryness. Drying in a vacuum oven gave a white powdery solid compound of formula V. Compound of formula I

In the present invention, "the compound of the formula I", "the compound of the formula I", "compound 1", "the compound of the formula I", and "olmesartan medoxomil" are used interchangeably, and both have Olmesartan medoxomil of the structure of formula I.

Preparation of compounds of formula I

In the present invention, a process for the preparation of a compound of formula I comprises the step of deprotecting a compound of formula V in an organic solvent containing p-toluenesulfonic acid to give olmesartan medoxomil.

The organic solvent includes acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran,

N,N-dimethylformamide, diethyl ether, acetonitrile or a mixed solvent of two or more. Preferably, the organic solvent is acetone, methanol or a mixed solvent of the two. The low boiling organic solvent used is easily recovered by distillation. The organic solvent to be used may contain a trace amount of water, a water content of 0.1% by weight, preferably a water content of 0.05% by weight, or even 0.01% by weight, most preferably, an anhydrous organic solvent.

The molar ratio of the compound of the formula V to p-toluenesulfonic acid is from 1:0.01 to 20; preferably, from 1:0.01 to 10, more preferably from 1:0.01 to 1.

The amount of catalyst used is simple, low in cost, and does not cause pollution and waste.

The reaction temperature of the deprotection reaction is from 0 ° C to 100 ° C; preferably from 10 ° C to 60 ° C.

The water content in the p-toluenesulfonic acid used is usually from 8 to 10% by weight.

With the method of the present invention, the content of the ester reaction hydrolyzate olmesartan, a by-product of the reaction, can be controlled to less than 1% and less than 0.7%. The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in this specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equal or similar features. The invention is advantageous in that:

(1) A novel preparation method of olmesartan medoxomil is provided, which can effectively control the content of the by-product olmesartan below 1%.

(2) Using a catalyst amount of acid, the post-treatment is simple, the cost is low, and no pollution or waste is caused.

(3) It is easy to recover by distillation using a low-boiling organic solvent.

(4) After saponification, the compound of the formula V is directly produced in the synthesis system of the compound of the formula III without isolation, and the yield is high. The invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only. The starting materials or reagents used in the present invention are obtained by conventional methods or are commercially available unless otherwise specified. Preferably, the hydrazine compound is prepared by referring to J. Med. Chem., 1996, 39, 323-338, and the compound of the formula IV is commercially available, for example, the manufacturer is Xinxiang Hongchen Technology Co., Ltd. Example 1

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxy-1 -Methylethyl)imidazole-5-(5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (Compound of formula V)

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid ethyl ester (147.16g, 0.2mol) was suspended in acetone (100 mL), stirred rapidly for several minutes, the system was evenly dispersed, and sodium methoxide (22.05 g, 0.4 mol) was added. After stirring at room temperature, the reaction was monitored by TLC (petrole ether: ethyl acetate = 1 : 1) until the starting material disappeared. Stirring was continued at room temperature, and 4-chloromethyl-5-methyl-1,3-dioxocyclopenten-2-one (89.10 g, 0.6 mol) was added. After the addition was completed, the mixture was transferred to an oil bath and heated to 55 ° C. Reaction, TLC (dichloromethane: methanol = 10: 1) was used to monitor the end of the reaction (the intermediate product completely disappeared), and the reaction solution was cooled to room temperature, stirred, and added. Distilled water (500 mL), EtOAc (3 mL, EtOAc) 2-4h, the sodium sulfate was removed by filtration to obtain a filtrate. The filtrate was concentrated under reduced pressure to a small amount of ethyl acetate (about 1 times volume), slowly stirred, and cooled in an ice water bath. A large amount of solid was precipitated and filtered under reduced pressure. The crude product is obtained as a pale yellow solid. The crude product is added with an appropriate amount of ethyl acetate (about 4 times the volume), dissolved by heating, filtered while hot, and a small amount of insoluble mechanical impurities are removed. The filtrate is slowly stirred, naturally cooled to room temperature, and cooled in an ice water bath. Under the slow stirring, gradually precipitate a large amount of solids, filter under reduced pressure, remove the filtrate, wash the product with a small amount of n-heptane (about 200 mL), suction to dryness, vacuum drying oven, -0.09MPa/110 °C, dry 5-6h, Compound (V. l).

HPLC conditions:

Flow rate: F = 1.0 ml/min, column temperature: T = 30 ° C, detection wavelength: Y = 210 nm, column: ODS-3 250 x 4.6 nm 5 μηι. Solvent: Α = 0.05% Η ₃ ΡΟ ₄ , Β = acetonitrile. The retention time of the compound of formula V was 13.80 min.

Example 2

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxy-1 -methylethyl)imidine-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (compound of formula V)

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid ethyl ester (147.16 g, 0.2 mol) was suspended in acetone (100 mL), stirred rapidly for several minutes to uniformly disperse the system, and sodium hydroxide (33.33 g, 0.8 mol) was added. After the addition was completed, the mixture was stirred at room temperature, and the reaction was monitored by TLC (petrole ether: ethyl acetate = 1 : 1 ) until the material disappeared completely, stirring was continued at room temperature, and 4-chloromethyl-5-methyl-1,3- Dioxocyclopenten-2-one (148.5 g, 1 mol), after the completion of the reaction, the reaction was transferred to an oil bath, and the temperature was raised to 40 ° C. The reaction was terminated by TLC (dichloromethane: methanol = 10:1). The product disappeared completely. The reaction solution was cooled to room temperature. After stirring, distilled water (300 mL) was added, and the mixture was stirred for 30 min, concentrated under reduced pressure, acetone was removed, and the concentrate was extracted three times with ethyl acetate (3×300 mL). The phase was washed with a saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate (MgSO? Stir slowly, and cool with ice water bath. A large amount of solid is precipitated and filtered under reduced pressure to obtain a crude pale yellow solid. The crude product is added with an appropriate amount of ethyl acetate (about 3 times volume), dissolved by heating, filtered while hot, and removed. Insoluble mechanical impurities, the filtrate is slowly stirred, naturally cooled to room temperature, continued to cool in an ice water bath, slowly stirred, gradually precipitated a large amount of solids, filtered under reduced pressure, the filtrate was removed, a small amount of n-heptane (about 200 mL) Polyester product, suction filtration to dryness, vacuum drying oven, -0.09MPa/110 °C, drying for 5-6h, to obtain white powdery solid compound V compound (139.35g); yield: 87%, HPLC (detection The same procedure as in Example 1): 99.22%, mp: 102-104 ° C, ESI-MS (m/e): 802.06 (M+l). Example 3

L-[[[2'-2(trityl))-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(l-hydroxy-1 -methylethyl)imidine-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (compound of formula V)

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid ethyl ester (147.16 g, 0.2 mol) was suspended in methanol (100 mL), stirred rapidly for several minutes to make it evenly dispersed, and sodium methoxide (16.54 g, 0.3 mol) was added. After completion, transfer to an oil bath at 50 ° C for stirring, TLC (petroleum ether: ethyl acetate = 1 : 1). Monitor the reaction until the starting material disappears completely, continue stirring at 50 ° C, and add 4-chloromethyl-5- Methyl-1,3-dioxocyclopenten-2-one (59.4 g, 0.4 mol), after completion, TLC (dichloromethane: methanol = 10:1) was used to monitor the end of the reaction (intermediate product completely disappeared), The reaction solution was cooled to room temperature. After stirring, distilled water (200 mL) was added, and the mixture was stirred for further 30 min, and then concentrated under reduced pressure. Methanol was evaporated, and the mixture was extracted three times with ethyl acetate (3×200 mL). The sodium solution (200 mL) was washed, dried over anhydrous sodium sulfate for 2-4 hr, and then filtered and evaporated, and then filtered, evaporated, evaporated, evaporated, evaporated. After cooling, a large amount of solid precipitated, and vacuum filtration was carried out to obtain a crude pale yellow solid. The crude product was added with an appropriate amount of ethyl acetate (about 4 times volume), dissolved by heating, filtered while hot, and a small amount of insoluble mechanical impurities were removed, and the filtrate was slowly stirred. Naturally cool to room temperature, continue to cool in an ice water bath, slowly stir, gradually precipitate a large amount of solids, filter under reduced pressure, remove the filtrate, wash the product with a small amount of n-heptane (about 200 mL), suction to dryness, vacuum Drying in a dry box at -0.09 MPa / 110 ° C, drying for 5-6 h, to obtain a white powdery solid compound of formula V (145.20 g); Yield: 90.6%, HPLC (detection method as in Example 1): 99.26% , mp: 102-104 ° C, ESI-MS (m/e): 802.06 (M+l). Example 4

L-[[[2'-2(trityl))-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(l-hydroxy-1 -Methylethyl)imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (compound of formula V)

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid ethyl ester (147.16g, 0.2mol) was suspended in acetone (600mL), stirred rapidly for several minutes, the system was evenly dispersed, sodium methoxide (22.05g, 0.4mol) was added, room temperature Stirring, TLC (petroleum ether: ethyl acetate = 1 : 1) was monitored, until the starting material disappeared completely, and 4-chloromethyl-5-methyl-1,3-dioxocyclopenten-2-one was added. 74.25g, 0.5mol), after the addition, immediately add potassium iodide (3.35g, 0.02mol), transfer to an oil bath, warm to reflux state for about 1h, TLC (dichloromethane: methanol = 10: 1) to monitor the end of the reaction (middle The product completely disappeared).

After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed three times with acetone (3×60 mL). The filtrate was concentrated to give a brown oil, and a small solid precipitated: ethyl acetate (~100 mL), dissolved by heating; Solids were precipitated and the temperature was slowly stirred at 0-5 ° C for about 1 h; filtered under reduced pressure. The filter cake was washed with cold ethyl acetate (2 X 50 mL) and evaporated to give a pale yellow solid. In ethyl acetate (about 300mL), heat to boiling, dissolve it; remove the heat source, slowly stir to cool to room temperature; continue to cool with ice water bath, solid precipitation, and keep the temperature at 0-5 ° C Under stirring, slowly stirring for about 1 h; vacuum filtration to dryness, filter cake washed with cold ethyl acetate (2 X 50 mL), suction filtered to dryness; vacuum drying oven, -0.09 MPa / 50 ° C, dry to Constant weight, a white solid compound of formula V (149.1 g) was obtained; Yield: 93.1%, HPLC (detection method as in Example 1): 99.12%, mp: 102-104 °C, ESI-MS (m/e) : 802.06 (M+l ). Example 5

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid ethyl ester (147.16g, 0.2mol) was suspended in acetone (600mL), stirred rapidly for several minutes, the system was evenly dispersed, sodium methoxide (22.05g, 0.4mol) was added, room temperature Stirring, TLC (petroleum ether: ethyl acetate = 1 : 1) was monitored, until the starting material disappeared completely, and 4-chloromethyl-5-methyl-1,3-dioxocyclopenten-2-one was added. 74.25g, 0.5mol), immediately after the addition, add potassium iodide (0.335g, 0.002mol), transfer to an oil bath, warm to reflux for about 1.5h, TLC (dichloromethane: methanol = 10: 1). The product completely disappeared).

After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed three times with acetone (3×60 mL); the filtrate was concentrated to give a brown oil, and a small solid was precipitated: ethyl acetate (about 100 mL) was added and dissolved by heating; With slow stirring, naturally cool to room temperature; continue to cool with ice water bath, solid precipitation, and keep the temperature at 0-5 ° C, slowly stir for about 1h; vacuum filtration to dry, filter cake with cold acetic acid The ester (2 X 50 mL) was washed and dried to give a pale-yellow solid. The solid was suspended in ethyl acetate (about 300 mL) and heated to boiling to dissolve; remove the heat source, and slowly cool to room temperature; Continue to cool with ice water bath, solid precipitation, and keep the temperature at 0-5 ° C, slowly stir for about 1 h; vacuum filtration to dryness, filter cake washed with cold ethyl acetate (2 X 50 mL), suction filtration Dry to constant weight in a vacuum drying oven at -0.09 MPa / 50 ° C to give a white solid compound of formula V (146 g); Yield: 91.2%, HPLC (detection method as in Example 1): 99.29 %, mp: 102-104 °C , ESI- MS (m/e): 802.06 (M+l). Example 6

L-[[[2'-2(trityl))-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(l-hydroxy-1 -Methylethyl)-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (Compound of formula V)

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid ethyl ester (147.16g, 0.2mol) was suspended in acetone (600mL), stirred rapidly for several minutes, the system was evenly dispersed, sodium methoxide (22.05g, 0.4mol) was added, room temperature Stirring, TLC (petroleum ether: ethyl acetate = 1 : 1) The reaction was monitored until the starting material disappeared completely, and 4-chloromethyl-5-methyl-1,3-dioxocyclopenten-2-one (75.02 g, 0.5 mol) was added, and potassium iodide was added immediately after the addition. 33.5g, 0. 2mol), transferred to an oil bath, warmed to reflux state for about 1 h, TLC (dichloromethane: methanol = 10:1) The end of the reaction was monitored (intermediate product completely disappeared).

After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed three times with acetone (3×60 mL); the filtrate was concentrated to give a brown oil, and a small solid was precipitated: ethyl acetate (about 100 mL) was added and dissolved by heating; With slow stirring, naturally cool to room temperature; continue to cool with ice water bath, solid precipitation, and keep the temperature at 0-5 ° C, slowly stir for about 1h; vacuum filtration to dry, filter cake with cold acetic acid The ester (2 X 50 mL) was washed and dried to give a pale-yellow solid. The solid was suspended in ethyl acetate (about 300 mL) and heated to boiling to dissolve; remove the heat source, and slowly cool to room temperature; Continue to cool with ice water bath, solid precipitation, and keep the temperature at 0-5 ° C, slowly stir for about 1 h; vacuum filtration to dryness, filter cake washed with cold ethyl acetate (2 X 50 mL), suction filtration Dry to constant weight in a vacuum drying oven at -0.09 MPa / 50 ° C to give a white solid compound of formula V (143.5 g); Yield: 89.6%, HPLC (detection method as in Example 1): 99.13%, mp: 102-104 °C, ESI-MS (m/e): 802.06 (M+l). Example 7

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid methyl ester (140.57 g, 0.2 mol) was suspended in dichloromethane (600 mL) and stirred rapidly for several minutes. The system was uniformly dispersed, sodium methoxide (22.05 g, 0.4 mol) was added, and the mixture was stirred at room temperature, and the reaction was monitored by TLC (petrole ether: ethyl acetate = 1 : 1 ) until the starting material disappeared completely, and 4-bromomethyl-5- was added. Methyl-1,3-dioxocyclopenten-2-one (96.5 g, 0.5 mol), immediately after the addition, sodium iodide (30 g, 0.2 mol) was added, and the mixture was transferred to an oil bath and heated to reflux. About lh, TLC (dichloromethane: methanol = 10:1) The end of the reaction was monitored (intermediate product completely disappeared).

After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed with dichloromethane (3×60 mL). The filtrate was concentrated to give a brown oil, and a small solid precipitated: ethyl acetate (~100 mL), dissolved by heating; Take the heat source, slowly stir, and naturally cool to room temperature; continue to cool with ice water bath, solid precipitation, keep the temperature at 0-5 ° C, slowly stir for about 1h; vacuum filtration to dry, filter cake with cold Ethyl acetate (2 X 50 mL) was washed and dried to give a pale-yellow solid. The solid was suspended in ethyl acetate (about 300 mL) and heated to boiling to dissolve; remove the heat source, and slowly cool to cool. At room temperature; continue to cool with ice water bath, solid precipitated, and keep the temperature at 0-5 ° C, slowly stir for about 1 h; vacuum filtration to dryness, filter cake washed with cold ethyl acetate (2 X 50 mL). Filtering to dryness; drying in a vacuum oven at -0.09 MPa / 50 ° C to dry weight to give a white solid compound of formula V (145.3 g); Yield: 90.72%, HPLC (detection method same as Example 1) ): 99.22%, mp: 102-104 ° C, ESI-MS (m/e): 802.06 (M+l). Example 8

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) Ethyl imidazole-5-carboxylate (147.16 g, 0.2 mol) was suspended in acetone (100 mL), stirred rapidly for several minutes to uniformly disperse the system, sodium methoxide (11.02 g, 0.2 mol) and sodium hydroxide (16 g, 0.4 mol), after stirring at room temperature, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1 : 1) until the starting material disappeared. Stirring was continued at room temperature, and 4-bromomethyl-5-methyl-1,3-dioxocyclopenten-2-one (115.8 g, 0.6 mol) was added. After the addition was completed, the mixture was transferred to an oil bath and heated to 55 ° C. Reaction, TLC (dichloromethane: methanol = 10: 1) The end of the reaction was monitored (the intermediate product completely disappeared), the reaction mixture was cooled to room temperature, and stirred, and distilled water (500 mL) was added, and the mixture was evaporated. The acetone was concentrated with ethyl acetate (3×500 mL). The organic layer was combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate Reducing to a small amount of ethyl acetate (about 1 times the volume), stirring slowly, cooling with an ice water bath, a large amount of solid precipitated, and suction filtration under reduced pressure to give a crude pale yellow solid. About 4 times the volume), heated to dissolve, hot filtered, remove a small amount of insoluble mechanical impurities, the filtrate is slowly stirred, naturally cooled to room temperature, continue to cool in an ice water bath, slowly stirred, gradually precipitated a large amount of solids, vacuum filtration, Remove filter Liquid, a small amount of n-heptane (about 200mL), wash the product, vacuum filter to dry, vacuum drying oven, -0.09MPa/110 °C, dry for 5-6h, to obtain a white powdery solid compound V

( 145.13 g); Yield: 90.6%, HPLC (detection method as in Example 1): 99.35%, mp: 102-104 °C, ESI-MS (m/e): 802.06 (M+l). Example 9

Preparation of olmesartan medoxomil

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (80.98 g, O.lmol) suspended in acetone ( In 500 mL), p-toluenesulfonic acid TsOH (0.95 g, 5 mmol) was added at room temperature, transferred to an oil bath, and the temperature was raised to 50 ° C to carry out the reaction, and TLC (dichloromethane: methanol = 10:1) was monitored until the end of the reaction. Slowly add 5wt% NaOH solution, adjust the pH to neutral, concentrate under reduced pressure, remove methanol, add appropriate amount of distilled water (200mL), extract three times with ethyl acetate (3x200mL), combine the organic layer, with saturated chlorine Sodium solution (200mL), anhydrous sulfuric acid The sodium was dried for 2-3 h, and the sodium sulfate was filtered to remove the filtrate, and the filtrate was evaporated to dryness to give a yellow oil, which was then evaporated to dryness. The solid precipitated, filtered under reduced pressure, the filtrate was removed, and the product was washed with 10 mL of cold anhydrous ethanol, filtered to dryness, placed in a vacuum drying oven, dried at -0.09 MPa / 110 ° C, dried for 5-6 h, to obtain white Solid (47.48g), Yield: 85%, mp: 180-182°C, ESI-MS (m/e): 559.54 (M+l).

Product HPLC: olmesartan medoxomil 97.66%, ester-based hydrolyzate olmesartan 0.43%.

HPLC conditions:

Flow rate: F = 1.0 ml/min, column temperature: T = 30 ° C, detection wavelength: Y = 210 nm, column: ODS-3 250 x 4.6 nm 5 μηι. Solvent: Α = 0.05% Η ₃ ΡΟ ₄ , Β = acetonitrile. The retention time of olmesartan medoxomil was 11.57 min, and the retention time of the ester-based hydrolyzate was 6.37 min. Example 10

Preparation of olmesartan medoxomil

1-[[[2'-2(trityl))-2H-tetrazolyl-5-yl]biphenyl-4-yl]methyl]-2-propyl-4-(1-hydroxyl Methyl ethyl) imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxocyclopenten-4-yl)methyl ester (80.98 g, O.lmol) suspended in methanol

(500 mL), p-toluenesulfonic acid (1.91 g, O. Olmol), TLC (dichloromethane: methanol = 10:1) was added at room temperature to monitor the end of the reaction, slowly add 5% NaOH solution, adjust the pH to medium The organic layer was extracted with ethyl acetate (3×200 mL). The organic layer was combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate -3h, the sodium sulfate was removed by filtration, and the filtrate was evaporated to dryness to dryness crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Filtration under reduced pressure, removal of the filtrate, washing the product with 10 mL of cold absolute ethanol, suctioning to dryness, placing in a vacuum drying oven, drying at -0.09 MPa / 110 ° C for 5-6 h, giving a white solid

(44.69g), Yield: 80%, mp: 180-182°C, ESI-MS (m/e): 559.54 (M+l).

HPLC (detection conditions as in Example 9): olmesartan medoxomil 97.53%, ester-based hydrolyzate olmesartan 0.51%. Example 11

L-[[2'-2H-tetrazol-5-yl]biphenyl-4-methyl]-2-propyl-4-(l-hydroxy-1-methylethyl)imidazole-5-carboxylate Acid-(5-methyl-2-keto-1,3-dioxo-4-cyclopentenylmethyl ester

(500 mL), p-toluenesulfonic acid (9.56 g, 0.05 mol) was added at room temperature. After the addition, the temperature was raised to 35 ° C. The reaction was terminated by TLC (dichloromethane: methanol = 10:1). % NaOH solution, adjust the pH to neutral, concentrate under reduced pressure, remove methanol, add appropriate amount of distilled water (200 mL), extract three times with ethyl acetate (3×200 mL), and combine the organic layer with saturated sodium chloride solution ( 200 mL) Washed, dried over anhydrous sodium sulfate for 2-3 h, then filtered and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Stir slowly under a water bath until solids are precipitated, filter under reduced pressure, remove the filtrate, wash the product with 10 mL of cold absolute ethanol, filter to dryness, and place in a vacuum oven at -0.09 MPa / 110 °C. Drying for 5-6 h gave a white solid (45.80 g), yield: 82%, mp: 180-182 ° C, ESI-MS (m/e): 559.54

(M+l).

The product HPLC (detection conditions as in Example 9): olmesartan medoxomil 97.32%, ester-based hydrolyzate olmesartan 0.62%. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entirety as if they are individually incorporated by reference. In addition, it should be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the invention.

Claims

Rights request

1. A method for preparing olmesartan medoxomil, characterized in that the method includes adding a compound of formula V to a compound containing p-toluenesulfonic acid.

2. The method of claim 1, wherein the organic solvent includes acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, diethyl ether , acetonitrile or a mixture of two or more solvents.

3. The method of claim 1, wherein the molar ratio of the compound of formula V to p-toluenesulfonic acid is 1: 0.01~20.

4. The method of claim 1, wherein the reaction temperature of the deprotection reaction is 0°C~100°C.

5. Such as:

(a) The compound of formula II is hydrolyzed in an organic solvent in the presence of an alkali metal hydroxide, an alkali metal alcoholate, or a mixture of an alkali metal hydroxide and an alkali metal alcoholate to obtain a compound of formula II; (b) without separation, add the compound of formula IV to the reaction mixture obtained in step (a), and react to obtain the compound of formula V;

In the formula, is a _-5 alkyl group; X is halogen.

6. The method of claim 5, wherein the organic solvent in step (a) includes acetone, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethyl Formamide, diethyl ether, acetonitrile or a mixture of two or more solvents.

7. The method of claim 5, wherein the compound of formula II, the compound of formula IV, a hydroxide with an alkali metal, or an alcoholate with an alkali metal, or a hydroxide with an alkali metal and an alkali metal The molar ratio of the alcoholate mixture is 1:1~6:1~5.

8. The method of claim 5 or 7, wherein the alkali metal hydroxide in step (b) includes sodium hydroxide, potassium hydroxide or a mixture of both; the alkali metal hydroxide Alcoholates include sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide or a mixture of two or more.

9. The method of claim 5, wherein the reaction temperature of step (a) is 0~60°C; the reaction temperature of step (b) is 35~100°C.

10. The method of claim 5, characterized in that, the method further includes the steps of:

(c) Cool the reaction mixture obtained in step (b) to room temperature, add water and wash.

11. The method of claim 5, characterized in that, after adding the compound of formula IV in step (b), a catalyst is added to the system.

12. The method of claim 11, wherein the catalyst is potassium iodide or sodium iodide.

13. The method of claim 11, wherein the ratio of the amount of the catalyst to the compound of formula II is 0.0005~5:1.