WO2004083213A1

WO2004083213A1 - 4,6-dihydrofuro[3,4-d]imidazole-6-one derivatives and their salts and process for the preparation of the same

Info

Publication number: WO2004083213A1
Application number: PCT/CN2004/000199
Authority: WO
Inventors: Fuli Zhang; Taizhi Wu
Original assignee: Shanghai Institute Of Pharmaceutical Industry
Priority date: 2003-03-21
Filing date: 2004-03-12
Publication date: 2004-09-30
Also published as: CN1467209A; CN1197866C

Abstract

The present invention relates to compounds represented by the following formula (A) and their pharmaceutically acceptable salts and process for the preparation of the same, wherein, the definition of R11, R2, R3, R4 and compounds of formula (A), their pharmaceutically acceptable salts and process for the preparation of the same are described in the specification. One objective of this invention is to provide a kind of novel 4,6-dihydrofuro[3,4-d]imidazole-6-one derivatives (formula (A)) and their salts, another objective thereof is to provide intermediates for the preparation of angiotensin II receptor antagonist (for example, olmesartan medoxomil).

Description

4,6-dihydrofuro `` 3.4-dl imidazol-6-one derivative and its salt and preparation method TECHNICAL FIELD

The present invention relates to a series of 4,6-dihydrofuro [3,4-d] imidazole-6-one derivatives, pharmaceutically acceptable salts thereof, and a method for preparing such compounds. Background technique

4,6-Dihydrofuro [3,4-d] imidazol-6-one derivatives and their pharmaceutically acceptable salts are a new class of compounds that can be used as angiotensin II receptor antagonists (eg: Olmesartan medoxomil) is an important intermediate. Japanese JP (31) 27098, European Patent EP503785, CN106563 A ₃ CN1381453A, Journal of MedicalChemistiy, 1996, Vol. 39, No: 1 323-338 have been reported on the preparation method of olmesartan medoxomil, In the preparation of angiotensin II receptor antagonists (such as olmesartan medoxomil), the used intermediates have many by-products, harsh reaction conditions, difficult subsequent separation, and low yields. Summary of the invention

The technical problem to be solved by the present invention is to provide a new class of 4,6-dihydrofuro [3,4-d] imidazol-6-one derivatives (general formula (A)) and salts and preparation methods thereof, Overcome the shortcomings of the existing technology and meet the needs of relevant departments.

The 4,6-dihydrofuro [3,4-d] imidazole-6-one derivative of the present invention is a compound having the following general formula (A):

General formula (A)

RR ₂ and R ₃ represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, and RR ₂ and R ₃ may be the same or different; R ₄ represents a hydrogen atom or a substituent represented by formula (B):

Equation (B)

Wherein: R ₅ represents carboxylic acid, tetrazol-5-yl, cyano, protected carboxyl, protected tetrazol-5-yl, carbamoyl or fluorenylcarbamoyl;

The compound of the present invention must contain at least one basic nitrogen atom in the imidazole ring, and thus can form a salt with an acid. Examples of such acid salts are: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and salts with organic acids such as maleic acid, fumaric acid, tartaric acid and lemon.

Preferred compounds include:

Compound (I) Compound (II) Compound απ;> The method for preparing the compound of the present invention includes the following steps:

The compound having the general formula of the formula (C) is subjected to a condensation reaction with a condensing agent in a solvent, and then the product of the formula (D) obtained by purification is collected by a conventional method, such as recrystallization, column chromatography, and a thin layer is prepared. Chromatography.

Formula (C)

The compound represented by formula (C) was prepared by the method disclosed in the journal Journal of Medical chemistry, 1996, Vol. 39, No: 1 323-338.

The reaction is usually carried out preferably in the presence of a solvent. The nature of the solvent used is not particularly limited, as long as there is no side reaction to the reaction or the reagents used. The solvent used can dissolve or dissolve the reactants to a certain extent. Suitable solvents include hydrocarbons , Such as benzene or xylene, toluene or alkane, halogenated hydrocarbon; ethers such as tetrahydrofuran, propyl ether, ether, dioxane; ketones such as acetone, methyl ethyl ketone; sulfoxides, such as dimethyl sulfoxide; Amides, such as N, N-dimethylformamide, N, N-diethylformamide, N, N-dimethylacetamide; pyridine; cyanide.

The nature of the condensing agent used in the reaction is not important, and any condensing agent that can catalyze the esterification or acylation on oxygen can be used for the reaction. Any dehydrating agent used in the esterification reaction can also be used in the reaction. The carboxyl group at the 5-position can also be formed into an active ester or an acid anhydride, and then condensed with a hydroxyl group at the 4-position 1-hydroxy-1-methylethyl group to form a lactone. Preferred reagents include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; carbodiimides such as dicyclohexylcarbodiimide; acids and anhydrides: trifluoroacetic acid, trifluoroacetic anhydride; and dichloroimine Sulfone. The reaction temperature can be within a certain width, and the precise temperature is not very important for the reaction. Usually -20 ° to 100 ° (, preferably 0 ° C to 50 ° C, the reaction time varies depending on the reaction temperature of the solvent, and is usually preferably 1 to 56 hours. The general reaction formula is:

Formula (E)

Wherein: X represents halogen, R ₅ represents carboxylic acid, tetrazol-5-yl, cyano, protected carboxyl, protected tetrazol-5-yl, carbamoyl or alkylcarbamoyl.

The compound of formula (E) may be a commercially available product.

The reaction formula is:

Formula (D) Formula (E)

The reaction is usually carried out preferably in an inert solvent and preferably under basic conditions. There are no particular restrictions on the nature of the solvent used, as long as there are no side reactions to the reaction or reagents used. The solvent used is capable of dissolving or to some extent the reactants. Suitable solvents include hydrocarbons, preferably aromatic hydrocarbons such as benzene or xylene or toluene; ethers such as tetrahydrofuran, propyl ether, diethyl ether or dioxane; alcohols such as methanol, ethanol, isopropanol or tert-butanol ; Amides, such as N, N-dimethylformamide, N, N-diethylformamide, or N, N-dimethylacetamide; Ketones, such as acetone or methyl ethyl ketone; Cyanides , Such as acetonitrile; sulfoxides, such as dimethyl sulfoxide. Among them, amides, sulfoxides, ketones or eyes are preferred.

The nature of the base used in the reaction is not important, and any base capable of reacting with the acid X-X can be used in the reaction. Preferred bases include alkali metal carbonates, such as: sodium carbonate, potassium carbonate; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate; alkali metal hydrides, such as sodium hydride, potassium hydride, lithium hydride; alkali metals Alkoxides, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium methoxide; alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide. Preferred are alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides or alkali metal alkoxides.

The reaction can take place over a wide range of temperatures, and the precise temperature is not critical to the reaction. Usually -20 ° C to 10 ° C, preferably 0 to 60 ° C, the reaction time varies depending on the reaction temperature of the solvent, usually 30 minutes to 24 hours, preferably 1 to 16 hours.

After completion of the reaction, the desired compound can be recovered from the reaction mixture by a conventional method. For example, a suitable recovery method includes: distilling off the solvent under reduced pressure, mixing the residue with water, extracting with a water-insoluble solvent such as ethyl acetate, drying the extract, such as drying over anhydrous magnesium sulfate, and removing the solvent by distillation to obtain the product . If necessary, purified by conventional methods To product. Such conventional methods such as recrystallization, column chromatography, and preparative thin-layer chromatography.

According to the present invention, the above-mentioned preparation method may include one or more of the following reaction steps:

1) removing the protecting group on the tetrazolyl group;

2) converting the cyano group represented by ₁₅ in the general formula (A) to a tetrazolyl group;

3) The carbamoyl or alkylcarbamoyl represented by the general formula (A) is first converted into a cyano group, and then into a tetrazolyl group.

1) Remove the protecting group on the tetrazolyl group:

This step can be accomplished by reacting the protected compound with an acid. The reaction is usually preferably carried out in an inert solvent. However, there are no particular restrictions on the nature of the solvent used, as long as there are no side reactions to the reaction or reagents used. The solvent used is capable of dissolving or to some extent the reagents. Examples of suitable solvents are: zK; organic acids such as acetic acid; ethers such as tetrahydrofuran or dioxane; alcohols such as methanol, ethanol or tert-butanol; ketones such as acetone or methyl ethyl ketone; or any two or A mixture of many of these solvents. Among them, water, organic acid, alcohol or a mixture thereof is preferred. The nature of the acid used in the reaction is not particularly limited as long as it has a general function as a proton acid. Preferred examples of such acids include: organic acids such as acetic acid, formic acid, oxalic acid, and methanesulfonic acid. P-toluenesulfonic acid or trifluoroacetic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Among them, acetic acid, formic acid, trifluoroacetic acid or hydrochloric acid is preferred.

The reaction can take place over a wide range of temperatures and the exact reaction temperature is not critical to the invention. The reaction is usually carried out at a temperature of -10 ° C to 120 ° C, preferably 0 to 100 ° C. The time required for the reaction also varies greatly, which is affected by many factors, especially by the reaction temperature and the nature of the reagents and solvents used. If the reaction is carried out under the preferred conditions described above, Normal reaction only requires 0.5 to 24 hours, preferably 1 to 16 hours.

After completion of the reaction, the desired product of the reaction can be recovered from the reaction mixture by a conventional method. For example, after distilling the solvent, the residue is dissolved in water and a water-insoluble organic solvent. The organic layer containing the desired product was separated and dried over anhydrous magnesium sulfate. After distilling off the solvent, the desired product can be obtained. If necessary, the reaction product can be further purified by conventional methods, such as recrystallization or various chromatography techniques, especially preparative thin-layer chromatography or column chromatography.

2) Convert the cyano group represented by ^ in the general formula (A) to a tetrazolyl group:

The compound having a cyano group is reacted with an alkali metal azide to convert the cyano group into a tetrazolyl group.

The reaction is usually and preferably carried out in the presence of a solvent. The nature of the solvent used is not particularly limited, as long as there are no side effects on the reaction or the reagent used, and it can dissolve the reagent, at least to some extent. Examples of suitable solvents are: amides such as N, N-dimethylformamide, N, N-diethylformamide or ^ -dimethylacetamide; ethers such as dioxin, or 1,2 -Dimethoxyethane; and sulfoxides, such as dimethylsulfoxide.

Suitable alkali metal azides include lithium azide, sodium azide, and potassium azide, with sodium azide being preferred. The amount of the alkali metal azide used is not particularly limited, but generally 1 to 5 equivalents are preferably used per equivalent of the cyano compound, and more preferably 1 to 3 equivalents of the alkali metal azide.

The reaction is preferably performed in the presence of an amine halide, wherein the amine halide is, for example, ammonium fluoride, ammonium chloride, or ammonium bromide, and ammonium chloride is preferred. There is no particular limitation on the amount of ammonium halide used, but in general it is best to use 0.5 to 2 equivalents per equivalent of cyano compound, more preferably 1 to 1.2 equivalents of ammonium halide. The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. The reaction is usually easy at 75 ~ 150 ° (, more preferably 80 ~ 120 ° C. The time required for the reaction also varies greatly, which is affected by many factors, especially the reaction temperature and the nature of the reagents and solvents used. If the reaction is performed under the above-mentioned preferred conditions, the reaction usually takes only 10 hours to 7 days, and more preferably 1 to 5 days.

Alternatively, the cyanide group is converted to a tetrazolyl group by reacting a cyanide with a trialkyltin azide or a triaryltin azide, and then treating the resulting tin compound with an acid, an alkali, or an alkali metal fluoride.

The reaction of cyanide with trisammonium azide or triaryltin azide is usually and preferably performed in the presence of a solvent. The nature of the solvent used is not particularly limited, as long as there is no side reaction to the reaction or the reagent used, and it can dissolve, at least to a certain extent, it can dissolve the reaction reagent. Examples of suitable solvents are: hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as 1,2-dichloroacetamidine or chloroform; Ethers, such as dioxane, or 1,2-dimethoxyethane; amides, such as N, N-dimethylformamide or N, N-dimethylacetamide; and esters, such as ethyl acetate or Butyl acetate.

Although there are no particular restrictions on the properties of trisammonium azide or triaryltin azide, and any such compounds commonly used in this type of reaction can be used here as well, we generally prefer to use: Alkyl (may be the same or different but is preferably the same) Trialkyltin azide containing 1 to 4 carbon atoms, such as trimethyltin azide, triethyltin azide or azide Tributyltin; or each aryl group (which may be the same or different, but preferably the same), preferably phenyl or substituted phenyl triarylazide, Examples are triphenyltin azide or tricresyltin azide. The amount of trialkyltin azide or triaryltin azide used is not critical, but it is preferably 1 to 3 equivalents of tin compound per equivalent of cyanide, and more preferably 1 to 2 equivalents.

The reaction of the cyano compound with trialkyltin azide or triaryltin azide can be performed over a wide temperature range, and the precise reaction temperature is not critical to the present invention. In general, we find it advantageous to carry out the reaction at a temperature of 60 to 150 ° C, more preferably 80 to 120 ° C. The time required for a reaction can also vary widely, depending on many factors, mainly the temperature of the reaction and the nature of the reagents and solvents used. However, as long as the reaction is performed under the above-mentioned preferred conditions, a reaction time of 8 hours to 7 days, more preferably 1 to 5 days is usually sufficient.

The tin-containing compound produced by this reaction is then treated with an acid, an alkali or an alkali metal fluoride to convert it into the desired tetrazolyl compound. Any acid, base or alkali metal fluoride commonly used in this type of reaction can be used. Examples of suitable compounds include: acids, especially inorganic acids, such as hydrochloric acid or sulfuric acid; bases, especially inorganic bases, such as alkali metal carbonate Salts and bicarbonates (such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate) or alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide); and alkali metal fluorides, such as lithium fluoride, fluorine Sodium chloride, potassium fluoride.

The reaction is usually and preferably performed in the presence of a solvent. The nature of the solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagents used, and is capable of dissolving the reagents to at least some extent. Examples of suitable solvents include those listed above for the reaction of cyano compounds with trialkyltin azide or triaryltin azide and other solvents such as alcohols (e.g. methanol or ethanol), water and aqueous alcohol. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. Generally, the inventors have found that it is advantageous to carry out the reaction at 0 ° C to 100 ° C, preferably at about room temperature. The time required for the reaction also varies greatly, depending on Many factors are mainly the stability of the reaction and the nature of the reagents and solvents used. However, as long as the reaction is performed under the above-mentioned preferred conditions, a reaction time of 30 minutes to 3 days, more preferably 1 hour to 24 hours is usually sufficient.

Another method for converting cyano to tetrazolyl is to react a cyano compound with a trialkyltin halide or a triaryltin halide in the presence of an alkali metal azide, and then use the resulting tin compound with an acid, base or base Metal fluoride treatment.

The reaction of a cyano compound with a trialkyltin halide or a triaryltin halide in the presence of an alkali metal azide is usually and preferably performed in the presence of a solvent. The nature of the solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagents used. And at least to a certain extent can dissolve reagents. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as 1,2-dichloroethane or chloroform ; Ethers, such as dioxane, or 1,2-dimethoxyethane; ketones, such as acetone or methyl ethyl ketone; amides, N ₅ N-dimethylformamide or N, N- Dimethylacetamide; and esters such as ethyl acetate or butyl acetate.

Although there is no particular restriction on the nature of the trihalide tin trihalide or triaryl tin halide, any compound commonly used in this type of reaction can be equally used here, and it is generally preferred: each of the alkyl groups (which may be the same or different, However, it is preferably the same) a trimethyltin halide having 1 to 4 carbon atoms, such as trimethyltin chloride, trimethyltin bromide, triethyltin chloride or tributyltin chloride; or each of An aryl group (may be the same or different, but preferably the same), preferably a phenyl or substituted phenyl halotriaryltin halide, such as triphenyltin chloride or tricresyltin chloride. The amount of trialkyltin halide or triaryltin halide used is not critical, but it is preferred to use 1 to 3 equivalents of tin compound per equivalent of cyano compound, and 1 to 2 equivalents is more preferred. The cyanide is not particularly limited to the alkali metal azide used in the reaction. These azide compounds include lithium azide, sodium azide, or potassium azide, with sodium azide being preferred. The amount of the alkali metal azide used is not critical, however, it is preferred to use 1 to 3 equivalents of the alkali metal azide per equivalent of cyanide, and more preferably 1 to 2 equivalents.

The reaction of a cyano compound with a trialkyltin halide or a triaryltin halide in the presence of an alkali metal azide can be performed over a wide temperature range, and the precise reaction temperature is not critical to the present invention. In general, we find it advantageous to carry out the reaction at 60 ° C to 150 ° C, more preferably at 80 ° C to 120 ° C. The time required for the reaction also varies widely, depending on many factors, mainly the reaction temperature and the nature of the reagents and solvents used. However, as long as the reaction is performed under the above-mentioned preferred conditions, a reaction time of 8 hours to 7 days, more preferably 1 to 5 days will be sufficient.

The tin-containing compound produced by this reaction is then treated with an acid, an alkali or an alkali metal fluoride to convert it into the desired tetrazolyl compound. This reaction is basically the same as the reaction of tin-containing compounds (produced by the reaction of 'cyano compounds with trialkyltin azide or triaryltin azide) with acids, alkalis or alkali metal fluorides, and the same solvents can be used. And reaction conditions.

3) The carbamoyl or fluorenylcarbamoyl represented by R _{5 in} the general formula (A) is first converted into a cyano group, and then into a tetrazolyl group.

In order to convert a fluorenylcarbamoyl group to a cyano group, an alkylcarbamoyl compound is reacted with a halide which can be used as a halogenating agent, preferably a chlorinating agent such as chlorine oxalate, phosphorus oxychloride or sulfonyl chloride. The amount of halide used is not particularly limited, but the inventors have found that 1 to 3 equivalents of halide are used per amount of carbamoyl compound, and more preferably 1 to 2 equivalents is advantageous.

The reaction is usually and preferably performed in the presence of a solvent. The nature of the solvent used is not particularly limited, as long as it does not adversely affect the reaction or the reagents contained, and can dissolve the reagents, to Less soluble to some extent. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as dichloromethane or chloroform; ethers, Such as dioxane, tetrahydrofuran or diethyl ether; and esters such as ethyl acetate or butyl acetate.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the reaction. In general, we find it advantageous to carry out the reaction at -10 ° C to 100 ° C, more preferably at 0 ° C to 50 ° C. The time required for the reaction also varies widely, depending on many factors, mainly the reaction temperature and the nature of the reagents and solvents used. However, as long as the reaction is performed under the aforementioned preferable conditions, a reaction time of 10 minutes to 16 hours, more preferably 30 minutes to 6 hours will be sufficient.

To convert a carbamoyl group to a cyano group, a carbamoyl compound and a dehydrating agent such as acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, oxalyl chloride or sulfonyl chloride, Reaction in the presence of ethylamine, pyridine or N-methylmorpholine.

The reaction is usually and preferably performed in the presence of a solvent. The nature of the solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagents contained, and it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as dichloromethane or chloroform; ethers, Such as dioxane, tetrahydrofuran or ether; and esters such as ethyl acetate or butyl acetate.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the reaction. Generally, the inventors have found that it is advantageous to carry out the reaction at a temperature of -10 ° C to 100 ° C, more preferably 0 ° C to 50 ° C. The time required for the reaction also varies greatly, depending on many factors, the main It depends on the reaction temperature and the nature of the reagents and solvents used. However, as long as the reaction is performed under the above-mentioned preferred conditions, a reaction time of usually 10 minutes to 16 hours, more preferably 30 minutes to 6 hours will be sufficient.

The products required for these reactions can be recovered from the reaction mixture by conventional means.

The cyano compound thus obtained is then converted into the corresponding tetrazolyl compound by any of the reactions described above.

Another method for preparing the compound of the present invention includes the following steps:

The compound having the general structural formula (F) is reacted with a condensing agent, and the reaction temperature can be in a certain range. The precise temperature is not very important for the reaction, usually -20 ° C ~ 120 ° C. The reaction time is preferably 0 to 100 ° C, and the reaction time varies depending on the reaction temperature of the solvent. Usually, it is preferably 4 to 56 hours.

After completion of the reaction, the desired compound can be recovered by a conventional method. Such as: evaporating the solvent, adding water, adjusting the pH, extracting with an organic solvent, and drying to obtain the product. If necessary, the resulting product is purified by conventional methods, such as recrystallization, column chromatography, and preparative thin-layer chromatography.

Formula (F)

The reaction formula is:

Formula (F)

Among them: RR ₂ , R ₃ , and R _{5 are the} same as described above.

The reaction is usually preferably carried out in the presence of a solvent, but the nature of the solvent used is not particularly limited as long as there is no side reaction on the reaction or the reagents used. The solvent used is capable of dissolving or to some extent the reactants. Suitable solvents are: hydrocarbons, such as: benzene, xylene, toluene or alkane, halogenated hydrocarbons; ethers such as: tetrahydrofuran, propyl ether, ether, dioxane; ketones, such as: acetone, methyl ethyl ketone Sulfoxides such as: dimethyl sulfoxide; amides such as: Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide; pyridine; cyanides.

The nature of the condensing agent used in the reaction is not important, and any condensing agent that can catalyze the esterification reaction or the acylation reaction on oxygen can be used for the reaction. Any dehydrating agent used in the esterification reaction can also be used for the reaction. The carboxyl group at the 5-position on the imidazole ring can also be used to form an active ester or anhydride before condensing with the 1-hydroxy-1-methylethyl group at the 4-position to form a lactone. Preferred reagents: inorganic acids, such as: hydrochloric acid, hydrobromic acid; carbodiimides, such as: dicyclohexylcarbodiimide; acids and anhydrides: trifluoroacetic acid, trifluoroacetic anhydride; and dichlorosulfoxide.

The novel compound of the present invention can avoid by-products caused by partial etherification of the hydroxyl group on the 4-position (1-hydroxy-1-methylethyl) on the imidazole ring with biphenyl during the reaction. The yield is high, the operation is simple, and the method is reasonable. Suitable for industrial production, it is of great value in the preparation of angiotensin II receptor antagonists (eg olmesartan medoxomil). detailed description

Specific embodiments of the present invention will be described below through examples, but the examples do not limit the protection scope of the present invention.

Example 1

Preparation of 2-propylimidazole-4,5-dicarboxylic acid diethyl ester:

In a 2L four-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer, a reflux condenser, and an oil bath, add 80 g of 2-propylimidazole-4,5 dicarboxylic acid, 1000 ml of absolute ethanol, and a catalytic amount of concentrated sulfuric acid. The temperature was raised to reflux, and after 16 hours of reaction, the reaction solution was concentrated to 400 ml. After cooling to room temperature, the reaction solution was transferred to a 3L beaker equipped with a mechanical stirrer and cooled in a water bath. 400 mL of ethyl acetate and 6001111 water were added in ₃ portions to adjust the solution to neutrality. The organic layer was separated, and the aqueous layer was extracted with 200 ml of ethyl acetate. The organic layers were combined and washed once with water, dried over magnesium sulfate, filtered, and the solvent was distilled off to obtain 81.00 g of the title compound.

Ή NMR (CDC1 ₃ , 400MHz): δ 7.5 ~ 9.8 (1Η, disappears after heavy water exchange with broad peak), 4.37 (4H, quartet), 2.75 (2H, triplet), 1.77 (2H, multiplet) , 1.36 (6H, triplet), 0.95 (3H, triplet).

EIMS (m / z ₅ %): 254 (M ⁺ , 7.35), 226 (89.67), 180 (100), 152 (27.60), 110 (24.89)

Example 2

4- (1-hydroxy-1-methylethyl:)-2-propylimidazole-5-carboxylic acid ethyl ester

2 (a) Preparation of CH ₃ MgI ether solution

In a 1 L four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, and a reflux condenser, 18.88 g of magnesium powder, 100 ml of ether were added, and 49 ml of a solution of 49 ml of methyl iodide was added dropwise at room temperature. After the addition was completed, the mixture was refluxed for 15 minutes to obtain a CH ₃ MgI ether solution. 2 (b) Preparation of 4- (l-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid ethyl ester:

In a 2 L four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, and a reflux condenser, add 40 g of 2-propylimidazole-4,5-dicarboxylic acid diethyl ester, 800 ml of ether, and stir until dissolved. Add CH ₃ MgI ether solution dropwise. The reaction mixture was stirred for an additional hour at room temperature. 200 ml of ethyl acetate was added, 350 ml of a saturated ammonium chloride solution was added dropwise, and 200 ml of water was added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 36.30 g of the title compound as an oil.

¾ NMR (CDC1 ₃ , 400MHz): δ 8.9 ~ 10.6 (1Η, disappears after heavy water exchange with broad peak), 5.99 (1Η, disappears after heavy water exchange with single peak), 4.32 (2H, quadruple), 2.66 (2H, triple Peak, 1.73 (2H, singlet), 1.65 (6H, singlet), 1.31 (3H, triplet), 0.93 (3H, triplet)

EIMS (nVz,%): 240 (M ⁺ ₃ 1.56) ₅ 225 (92.74) ₃ 179 (100), 151 (15.49) ₃ 137 (11.78)

Example 3

4- (1-hydroxy-1 -methylethyl) -2-propylimidazole-5-carboxylic acid

In a 1 L four-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer, a reflux condenser, and an oil bath, 73.35 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5 was added. -Ethyl carboxylate, 150 ml of acetone, 367 ml of a 0% sodium hydroxide solution. The temperature was raised to reflux, and the reaction was carried out for 2 hours. The solution was cooled to 0 ° C in an ice water bath, and the solution was adjusted to neutrality by adding concentrated hydrochloric acid. After stirring for another 30 minutes, suction filtration, washing and drying were performed to obtain 33.46 g of the title compound.

¾ NMR (CDC1 ₃ , 400MHz): δ 2.60 (2Η, triplet), 1.65 (2Η, hexaplex), 1.48 (6Η, singlet), 0.86 (3Η, triplet)

MS (Q-Tofmicro ₅ ESI ⁺ ): 195.10,213.12 (M + 1), 235.10 (M + Na), 447.21 (2M + Na) Example 4 4,4-dimethyl-2-propyl-4,6-dihydrofuro [3,4-d] imidazole-6-one, compound (I) is equipped with a magnetic stirrer, a reflux condenser, and an oil bath In a heated 25ml eggplant-shaped bottle, 0.25 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid was added, and 10.0 ml of 48% hydrobromic acid was heated up to reflux. The reaction took 14 hours. After cooling to room temperature, adjust the pH to greater than 8 with a 40% sodium hydroxide solution. Stirring was continued at room temperature for 30 minutes, suction filtration, washing, drying were performed to obtain a crude product, which was purified by silica gel column chromatography to obtain 0.27 g of the title compound.

¾ NMR (CDCl ₃₃ 400MHz): δ 11 · 8 ~ 12 · 6 (1Η, broad peak), 2.83 (2Η, triplet), 1.88 (2Η: hexaplex), 1.70 (6Η, singlet), 1 · 00 (3Η, triplet)

MS (Q-Tofmicro, ESI ⁺ ): 195.08 (M + 1), 217.05 (M + Na)

¹³ C NMR (CDC1 ₃ 100MHz): δ 171.91,162.54,161.49,119.04,84.742,31.42,

25.59,21.46,13.61

Example 5

4,4-dimethyl-2-propyl-4,6-dihydrofuro [3,4-d] imidazol-6-one, compound (I)

In a 25 ml eggplant-shaped bottle equipped with a magnetic stirrer and cooled in a water bath, 0.20 g of 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid was added, and 10.0 ml of trifluoro Acetic anhydride was reacted at room temperature for 8 hours. The solvent was distilled off under reduced pressure. 15 ml of ethyl acetate was added. After washing with a small amount of water, it was dried with magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography to obtain 0.11 g of the title compound.

The NMR spectrum and the mass spectrum of the product were consistent with the compound obtained in Example 4.

Example 6

4,4-dimethyl-2-propyl-4,6-dihydrofuro [3,4-d] imidazole-6-one, compound (I)

In a 25 ml eggplant bottle equipped with a magnetic stirrer, add 0.10 g of 4- (1-hydroxy-1-form Ethyl) -2-propylimidazole-5-carboxylic acid, 0.11 g of dicyclohexylcarbodiimide, 10 ml of pyridine at 60

° C reaction for 4 hours. Suction. After washing, the filtrate was concentrated to dryness, and 0.088 g of the title compound was separated from the column layer.

¾ NMR (CDCl ₃ , 400 MHz): δ 11.4 to 12.5 (1Η, broad peak), 2.85 (2Η, triplet), 1.86 (2Η: hexaplex), 1.70 (6Η, singlet), 1.02 ( 3Η, triplet)

MS (Q-Tofmicro, ESI ⁺ ): 195.08 (M + l), 217.05 (M + Na), 389.13 (2M + l), 411.11 (2M + Na)

¹³ C NMR (CDC1 ₃ 100MHz): δ 171.91,162.54,161.49,119.04,84.742,31.42, 25.59,21.46,13.61

Example 7

4,4-dimethyl-2-propyl-4,6-dihydrofuro [3,4-d] imidazole-6-one hydrochloride

In a 50 ml eggplant-shaped bottle cooled with a magnetic stirrer and ice-water bath, add 1.0 g of 6,6-dimethyl-2-propyl-3,6-dihydrofuro [3,4-d] imidazole-4- Ketone, 20ml absolute ethanol, stir until completely dissolved. Add 10% HC1 / ethanol solution dropwise, adjust the pH to 2 ~ 3, and add. The reaction was concentrated to dryness. The residue was stirred with a small amount of petroleum ether, suction filtered, washed, and dried to obtain 0.68 g of the title compound.

Example 8

4,4-dimethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methyl-4,6-dihydrofuro [3,4-d] imidazole-6-one, compound (II)

In a 50 ml four-necked flask equipped with a magnetic stirrer, a thermometer, and a reflux condenser, add 0.3 g of 4,4-dimethyl-2-propyl-4,6-dihydrofuro [3,4-d] Imidazole-6-one, 0.86 g of 4- [2- (trityltetrazol-5-yl) phenyl] benzyl bromide, 0.43 g of potassium carbonate, 20 ml of N, N-dimethyl Formamide. Stir at room temperature for 18 hours, transfer the reaction solution to a separatory funnel, add 20 ml of ethyl acetate and 100 ml of water, separate the ethyl acetate layer, and extract the aqueous layer with 20 ml of ethyl acetate X 3. The organic layers are combined and washed with water. Dry over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The eluent was a mixed solution of methylene chloride and methanol in a volume ratio of 80: 1. 0.75 g of the title compound were obtained.

¾ NMR (CDC1 ₃ 400MHz): δ 7.95 (1Η, multiplet), 6.8—7.5 (22Η, multiplet), 5.11 (2Η, singlet), 2.62 (2Η, triplet), 1.76 (2Η, hexaplex Peak), 1.70 (6Η, singlet) 0.96 (3Η, triplet)

MS (Q-Tof micro ₃ ESI ⁺ ): 243.14, 693.28 (M + Na), 709 (M + K), 1363.63 (2M + .Na)

¹³ C NMP, (CDC1 ₃ 100MHZ): δ 169.264, 163.880, 160.184, 159.420, 141.536, 141.345, 133.815, 130.716, 130.228, 130.224, 129.988, 129.906, 128.258, 127.730, 127.621, 127.066, 126.382.382. 120. , 77.202, 48.189, 29.604, 25.834, 21.034, 13.802.

Example 9

4,4-dimethyl-2-propyl-1- {4- [2- (trityltetrazol-5-yl) phenyl] phenyl} methyl-4,6-dihydrofuro [3,4-d] imidazole-6-one, compound (Π)

In a 50-ml four-necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser, and an ice-water bath, add 1.0 g of 6,6-dimethyl-2-propyl-3,6-dihydrofuro [ 3,4-d] imidazol-4-one, dry 20ml N, N-dimethylformamide, 0.25 g NaH (60%), 2.87 g 4- [2- (trityltetrazol-5- (Phenyl) phenyl] benzyl bromide was dissolved in 28.7 ml of dry N, N-dimethylformamide and transferred to a dropping funnel, added dropwise at 0 ° C, and then stirred for 30 minutes. After 15 minutes, transfer to a separatory funnel, add 150ml of ethyl acetate, 500ml of water, and extract the aqueous layer with 20ml of ethyl acetate X4. After the organic layer was washed once with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was passed through silica gel. Purified by column chromatography. The eluent was a mixed solution of methylene chloride and methanol with a volume ratio of 80: 1 to obtain 2.42 g of the title compound.

The NMR spectrum and mass spectrum of the product were consistent with the compound obtained in Example 7.

Example 10

4,4-dimethyl-2-propyl-1- {4- [2- (tetrazol-5-yl) phenyl] phenyl} methyl-4,6-dihydrofuro [ ₃ , 4_ _d ] imidazole-6-one, compound (II)

In a 50 ml four-necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser, and an oil bath, add 0.50 g of 4,4-dimethyl-2-propyl-1- {4- [2- (triphenylbenzene) Methyltetrazole-5-yl) phenyl] phenyl} methyl-4,6-dihydrofuro [3,4-d] imidazol-6-one (compound (11)), 25ml75% (v / v) Aqueous glacial acetic acid. The temperature was raised to 60 ° C for 6 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.24 g of the title compound. Melting point: 171.039 ° C

Elemental analysis: Calculated values: C, 67.27%, H5.65%, N, 19.62%

Found: C ₅ 67.07%; H, 5.61%; N, 19.61%.

MS (Q-Tofmicro, ESI ⁺ ): 429.24 (Μ + 1), 857.48 (2Μ + 1)

¾ NMR (DMSO-d6 400MHz): δ 7.68 (2H, multiplet), 7.62 (2H, multiplet), 7.22 (2Η, multiplet), 7.12 (2Η, doublet), 5.26 (2Η , Singlet), 2.68 (2Η, triplet), 1.64 (2Η, hexaplex), 1.57 (6Η, singlet), 0 · 88 (3Η, triplet)

1 ³ C NMR (DMSO-d6 100MHZ): δ 169.037, 159.606, 159.405, 140.980, 139.036, 135.372, 131.018, 130.583, 129.362, 127.886, 127.100, 123.648, 119.857, 82.635, 47.144, 28.560, 25.714, 20.

Claims

Claim

1. Class 4,6-dihydrofuro [3,4-d] imidazole-6-one derivatives and pharmaceutically acceptable salts thereof, which are characterized by compounds having the following general formula (A):

General formula (A)

among them:

Equation (B)

• Where: R ₅ represents carboxylic acid, tetrazol-5-yl, cyano, protected carboxyl, protected tetrazol-5-yl, carbamoyl or alkylcarbamoyl.

2. The derivative according to claim 1, characterized in that the compound has one of the following general formulae and a pharmaceutically acceptable salt thereof:

Compound (I) Compound (II) Compound (III)

3. The method for preparing a derivative according to claim 1, further comprising the following steps:

Subjecting the compound having the general formula (C) to a condensation reaction with a condensing agent in a solvent, and then collecting and purifying the product of the formula (D) by a conventional method;

Formula (C) Formula (D)

4. The method for preparing a derivative according to claim 3, wherein the condensing agent comprises a condensing agent capable of catalyzing an esterification reaction or an acylation reaction on oxygen or a dehydrating agent used for the esterification reaction.

5. The method for preparing a derivative according to claim 3, wherein the reaction temperature is -20 ° C to 100 ° C, and the reaction time is 1 to 56 hours.

6. The method for preparing a derivative according to claim 3, further comprising performing the obtained product of formula (D) and a compound having the general formula (E) under an inert solvent and a basic condition. Carry out a reaction

Formula (E)

Where: X represents halogen, R ₅ represents carboxylic acid, tetrazol-5-yl, cyano, protected carboxyl group, Protected tetrazol-5-yl, carbamoyl or alkylcarbamoyl.

7. The method according to claim 6, characterized in that the reaction temperature is -20 ° C to 100 V, and the reaction time is 30 minutes to 24 hours.

8. The method according to any one of claims 3 to 7, characterized in that when ^ is a protected tetrazol-5-yl, further comprising the step of removing the protecting group by reacting the protected compound with an acid, The reaction is performed in an inert solvent, and the acid mentioned is an acid having a general function as a protic acid.

9. The method according to claim 8, characterized in that the reaction temperature is -10 ° C to 120 V, and the reaction time is 0.5 to 24 hours.

The method according to any one of claims 3 to 7, characterized in that when R ₅ in the formula (B) is a cyano group, the compound having a cyano group and an alkali metal azide are mixed in a solvent It reacts with a halogenated amine to convert cyano to tetrazolyl.

11. The method according to claim 10, wherein the alkali metal azide comprises lithium azide, sodium azide, or potassium azide.

12. The method according to claim 10, wherein the reaction temperature is 75 to 150 ° C, and the reaction time is 10 hours to 7 days.

13. The method according to any one of claims 3 to 10, wherein when R ₅ in the formula (B) is a cyano group, the compound having a cyano group is mixed with trifluorenyl tin azide or Triaryltin azide is reacted in the presence of a solvent, and then the resulting tin compound is treated with an acid, an alkali or an alkali metal fluoride to convert the cyano group to a tetrazolyl group.

14. The method according to claim 13, wherein the said trialkyltin azide or triaryltin azide includes a compound in which each alkyl group contains 1 to 4 carbon atoms. Trialkyltin azide or phenyl or substituted phenyl triaryltin.

The method according to claim 13, wherein the reaction temperature is 60 to 150 ° C., and the reaction time is 8 hours to 7 days.

16. The method according to claim 13, wherein the acid, alkali or alkali metal fluoride includes an inorganic acid, an inorganic base, or an alkali metal fluoride.

17. The method according to any one of claims 3 to 10, wherein when R ₅ in the formula (B) is a cyano group, a cyano compound and a trialkyltin halide or a triaryltin halide are placed in a base The metal azide is reacted in the presence of a solvent, and the resulting tin compound is then treated with an acid, an alkali or an alkali metal fluoride.

18. The method according to claim 17, wherein said trialkyltin halide or triaryltin halide includes trialkyltin or phenyl halide having 4 carbon atoms per fluorenyl group or Triaryltin halide substituted phenyl.

19. The method according to claim 17, wherein the alkali metal azide comprises lithium azide, sodium azide or potassium azide.

20. The method according to claim 17, wherein the reaction temperature is 60 ° C to 150 ° C, and the reaction time is 8 hours to 7 days.

21. The method according to claim 17, wherein the acid, alkali or alkali metal fluoride includes an inorganic acid, an inorganic base, or an alkali metal fluoride.

22. The method according to any one of claims 3 to 10, wherein, when representing an alkylcarbamoyl group, the alkylcarbamoyl compound is reacted with a halogenating agent in the presence of a solvent, and firstly converted into a cyano group And then converted to tetrazolyl.

23. The method according to claim 21, wherein the halogenating agent is chlorine oxalate, Oxochlorine or sulfonyl chloride.

24. The method according to claim 21, wherein the reaction temperature is -10 ° C to 100 ° (:, the reaction time is 10 minutes to 16 hours.

25. The method according to any one of claims 3 to 10, wherein when the carbamoyl group is represented, the carbamoyl compound and a dehydrating reagent are reacted in the presence of a solvent and an organic amine. First to cyano, then to tetrazolyl,

26. The method according to claim 25, wherein the dehydrating reagent comprises acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, oxalyl chloride or sulfonyl chloride.

27. The method according to claim 25, wherein the organic amine comprises triethylamine, pyridine or N-methylmorpholine.

28. The method according to claim 25, wherein the reaction temperature is from a temperature of-10 ° C to 100 ° C, and the reaction time is from 10 minutes to 16 hours.

29. The method for preparing a derivative according to claim 1, comprising the steps of: reacting a compound represented by the formula (F) with a condensing agent under a solvent condition, and the reaction temperature is -20 ° C ~ 120 ° C, reaction time is 4 ~ 56 hours.

Formula (F)

The condensation agent includes a condensation agent capable of catalyzing an esterification reaction or an acylation reaction on oxygen or a dehydrating agent used in the esterification reaction.