CN1197866C - 4,6-dihydrofuran [3,4-d] imidazole-6- ketone derivative and salt and preparation method thereof - Google Patents
4,6-dihydrofuran [3,4-d] imidazole-6- ketone derivative and salt and preparation method thereof Download PDFInfo
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- CN1197866C CN1197866C CN 03115940 CN03115940A CN1197866C CN 1197866 C CN1197866 C CN 1197866C CN 03115940 CN03115940 CN 03115940 CN 03115940 A CN03115940 A CN 03115940A CN 1197866 C CN1197866 C CN 1197866C
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a compound of a general formula (A) disclosed in the specification, acceptable salt in pharmacy and a preparation method of the compound. In the general formula (A), the definition of R#-[1], R#-[2], R#-[3] and R#-[4], the compound of the general formula (A), the acceptable salt in pharmacy and the preparation method of the compound are explained in the specification. The present invention has the first purpose for providing a new 4, 6-dihydrofuran and [3, 4-d]-imidazole-6-ketone derivate (shown in the general formula (A)) and salt thereof, and the second purpose for providing an intermediate body for synthesizing antagonist of angiotensin II receptor (such as olmesartan).
Description
Technical field
The present invention relates to a series ofly 4, the 6-dihydrofuran is the preparation method of [3,4-d] imidazoles-6-ketone derivatives and pharmacy acceptable salt and this compounds also.
Background technology:
4,6-dihydrofuran also [3,4-d] imidazoles-6-ketone derivatives and pharmacy acceptable salt thereof is a class new compound, and it can be used as the important intermediate of angiotensin II receptor antagonists (as: olmesartan medoxomill).Day disclosure special permission JP (31) 27098, European patent EP 503785, CN106563A, CN1381453A, Journal of MedicalChemistry, 1996, Vol.39, all reported the preparation method of olmesartan medoxomill on the No:1323-338, the intermediate that described method adopted is when preparation angiotensin II receptor antagonists (as: olmesartan medoxomill), and by product is many, severe reaction conditions, follow-up separation difficulty, yield is lower.
Summary of the invention
The technical issues that need to address of the present invention provide a class new 4, the 6-dihydrofuran is [3,4-d] imidazoles-6-ketone derivatives (general formula (A)) and salt and preparation method also, to overcome the defective that prior art exists, satisfies the needs of relevant department.
Of the present invention 4, the 6-dihydrofuran also [3,4-d] imidazoles-6-ketone derivatives for having the compound of following general structure (A):
General formula (A)
Wherein:
R
1, R
2, R
3Represent the alkyl of hydrogen atom or 1～6 carbon atom, R
1, R
2, R
3Can be identical also can be different; R
4Represent the substituting group shown in hydrogen atom or the formula (B):
Formula (B)
Wherein: R
5Represent carboxylic acid, tetrazolium-5-base, cyano group, protected carboxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl;
The compounds of this invention must contain the basic nitrogen atom at least one imidazole ring, and thus can with sour salify.This class acid salify example has: with mineral acid, and the salt that example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid are become; With with organic acid, as toxilic acid, fumaric acid, the salt that tartrate and lemon form.
Preferred compound comprises:
Compound (I) compound (II) compound (III)
The preparation method of compound of the present invention comprises the steps:
To have general structure is that the compound shown in the formula (C) carries out condensation reaction with condensing agent in solvent is arranged, then, by formula (D) product of ordinary method collection purifying gained, as recrystallization, column chromatography, preparation thin-layer chromatography.
Formula (C)
Compound shown in the formula (C) adopts document Journal of Medicalchemistry, and 1996, Vol.39, the No:1323-338 disclosed method is prepared.
Reaction is preferentially carried out having under the solvent condition usually, employed solvent property is not particularly limited, as long as reaction or agents useful for same are not had side reaction, solvent for use can dissolve or solubilizing reaction thing to a certain extent, The suitable solvent comprises hydro carbons, as benzene or dimethylbenzene, toluene or alkane, halohydrocarbon; Ethers such as tetrahydrofuran (THF), propyl ether, ether, diox; Ketone such as acetone, methyl ethyl ketone; The sulfoxide class is as methyl-sulphoxide; Amides, as N, dinethylformamide, N, N-diethylformamide, N,N-dimethylacetamide; Pyridine; The cyanogen class.
The character of reacting used condensing agent is inessential, and the condensing agent of acylation reaction all can be used for this reaction on any energy catalytic esterification or the oxygen.Any dewatering agent that uses on esterification also can be used for this reaction.After also can making 5-position carboxyl form active ester or acid anhydrides earlier, again with 4-position 1-hydroxyl-1-methylethyl on hydroxyl be condensed into lactone.Preferred reagent comprises mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; Carbodiimide is as dicyclohexylcarbodiimide; Acid and anhydrides: trifluoracetic acid, trifluoroacetic anhydride (TFAA); And thionyl chloride.
Temperature of reaction can be in the scope of certain width, and precise dose is very unimportant to this reaction.Usually-20 ℃ to 100 ℃, be preferably 0 ℃～50 ℃, the reaction times is preferably 1～56 hour usually because of the solvent reaction temperature is different.
Reaction expression is:
Formula (C) formula (D)
Further, be that the compound shown in the formula (E) reacts with formula (D) product that is obtained with having general structure, then can obtain the compound of another kind of form of the present invention.
Formula (E)
Wherein: X represents halogen, R
5Represent carboxylic acid, tetrazolium-5-base, cyano group, protected carboxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl.
Described formula (E) compound can adopt the commercially available prod.
Reaction expression is:
Formula (D) formula (E)
Reaction is usually preferentially in inert solvent and be preferably under the alkaline condition and carry out.To using solvent property to be not particularly limited, as long as reaction or agents useful for same are not had side reaction.Solvent for use can dissolve or solubilizing reaction thing to a certain extent.The suitable solvent comprises hydro carbons, is preferably aromatic hydrocarbon, as benzene or dimethylbenzene or toluene; Ethers is as tetrahydrofuran (THF), propyl ether, ether Huo diox; Alcohols is as methyl alcohol, ethanol, Virahol or the trimethyl carbinol; Amides, as N, dinethylformamide, N, N-diethylformamide, or N,N-dimethylacetamide; Ketone is as acetone or methyl ethyl ketone; The cyanogen class is as acetonitrile; The sulfoxide class is as methyl-sulphoxide.Wherein be preferably amides, sulfoxide class, ketone or eyeball class.
The character of reacting used alkali is inessential, any can all can be used in this reaction with the alkali of sour H-X reaction.Preferred alkali comprises alkaline carbonate, as: yellow soda ash, salt of wormwood; Alkali metal hydrocarbonate, as sodium bicarbonate, saleratus; Alkalimetal hydride, as sodium hydride, potassium hydride KH, lithium hydride; Alkali metal alcoholates, as sodium methylate, sodium ethylate, potassium tert.-butoxide, lithium methoxide; Alkali metal hydroxide, as sodium hydroxide, potassium hydroxide.Preferably alkaline carbonate, alkali metal hydrocarbonate, alkalimetal hydride or alkali metal alcoholates.
Reaction can be carried out under the temperature of a wide region, and precise dose is very unimportant to this reaction.Usually-20 ℃～100 ℃, being preferably 0～60 ℃, the reaction times is generally 30 minutes～24 hours, preferred 1～16 hour because of the solvent reaction temperature is different.
After reaction is finished, the compound of wanting can from reaction mixture, reclaim with ordinary method and obtain.For example, a suitable recovery method comprises: underpressure distillation removes desolvates, and resistates is with after water mixes, utilize water-insoluble solvent such as ethyl acetate extraction after, dry extraction liquid is as using anhydrous magnesium sulfate drying, by distill except that desolvate product.As needs, obtain product by the ordinary method purifying.This class ordinary method such as recrystallization, column chromatography, preparation thin-layer chromatography.
According to the present invention, above-mentioned preparation method can comprise one or more following reactions steps:
1) removes protecting group on the tetrazyl;
2) transform R in the general formula (A)
5The cyano group of representative is tetrazyl;
3) with R in the general formula (A)
5The formamyl of representative or alkyl-carbamoyl at first are converted into cyano group, change into tetrazyl then.
1) remove protecting group on the tetrazyl:
This step can be finished by making protected compound and acid-respons.Reaction is preferentially carried out in inert solvent usually.But to using solvent property to be not particularly limited, as long as reaction or agents useful for same are not had side reaction.Solvent for use can dissolve or solubilising reagent to a certain extent.The The suitable solvent example has: water; Organic acid is as acetate; Ether is as tetrahydrofuran (THF) Huo diox; Alcohol, as methyl alcohol, the ethanol or the trimethyl carbinol; Ketone is as acetone or methyl ethyl ketone; Or the mixture of any two or more these solvents.Wherein, be preferably water, organic acid, alcohol or their mixture.
The character of the acid of using in the reaction is not particularly limited, as long as have the general function as protonic acid.The preferred example of this class acid comprises: organic acid, and as acetate, formic acid, oxalic acid, methylsulfonic acid.Tosic acid or trifluoroacetic acid; And mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid or phosphoric acid.Wherein, be preferably acetate, formic acid, trifluoroacetic acid or hydrochloric acid.
Reaction can carry out in a wide temperature range and definite temperature of reaction is not critical to the invention.Usually be reflected at-10 ℃～120 ℃, be preferably under 0～100 ℃ the temperature and carry out easily.The reaction required time changes also greatly, and this is subjected to multiple factor affecting, and it is bigger influenced by temperature of reaction and agents useful for same and solvent property.Carry out if be reflected under the above-mentioned optimum condition, reaction only needs 0.5 to 24 hour usually, is preferably 1 to 16 hours.
After reaction was finished, this reaction was wanted product to reclaim from reaction mixture with ordinary method to obtain.For example, after the solvent distillation, in the water-soluble and water-insoluble organic solvents of resistates.Separate and contain the organic layer of wanting product to some extent and use anhydrous magnesium sulfate drying.After boiling off solvent, can obtain the product of wanting.If desired, reaction product can adopt ordinary method to be further purified, and as recrystallization or various chromatographic technique, particularly prepares thin-layer chromatography or column chromatography.
2) transform R in the general formula (A)
5The cyano group of representative is tetrazyl:
To have described compound and an alkali metal azide reaction of cyano group, cyano group will be changed into tetrazyl.
Reaction usually and is preferentially carried out having in the presence of the solvent.The character of solvent for use is not particularly limited, as long as reaction or agents useful for same are free from side effects, and can dissolve, at least to a certain extent can solubilising reagent.The The suitable solvent example has: acid amides, and as N, dinethylformamide, N, N-diethylformamide or N,N-dimethylacetamide; Ether, as diox, or 1, the 2-glycol dimethyl ether; And sulfoxide, as methyl-sulphoxide.
Suitable an alkali metal azide comprises Lithium Azide, and sodiumazide and potassium azide wherein are preferably sodiumazide.The amount of used an alkali metal azide is not particularly limited, but generally whenever the amount cyano compound preferably uses 1～5 equivalent, more preferably is 1～3 equivalent an alkali metal azide.
Reaction is preferably under the halogeno-amine existence to be carried out, and wherein halogeno-amine for example is Neutral ammonium fluoride, ammonium chloride or brometo de amonio, wherein is preferably ammonium chloride.Amount to used ammonium halide is not particularly limited, but generally whenever the amount cyano compound preferably uses 0.5～2 equivalent, more preferably is 1～1.2 equivalent ammonium halide.
Reaction can be carried out in a wide temperature range, and definite temperature of reaction is not critical to the invention.Usually being reflected at 75～150 ℃, more preferably is to carry out easily under 80～120 ℃.The reaction required time changes also greatly, and this is subjected to multiple factor affecting, and it is bigger influenced by temperature of reaction and agents useful for same and solvent property.Carry out if be reflected under the above-mentioned optimum condition, reaction only needs 10 hours to 7 days usually, more preferably is 1 to 5 day.
Perhaps, by making the reaction of prussiate and azide trialkyltin or azide triaryl tin, use acid then, alkali or alkaline metal fluoride cpd are handled formed stannide cyano group are converted to tetrazyl.
The reaction of prussiate and azide trialkyltin or azide triaryl tin usually and is preferentially being carried out having in the presence of the solvent.The character of solvent for use does not have particular restriction, as long as reaction or agents useful for same are not had side reaction, and can dissolve, at least to a certain extent can solubilizing reaction reagent.The The suitable solvent example has: hydrocarbon, can be for aliphatic hydrocarbon or aromatic hydrocarbon, and as benzene, toluene, dimethylbenzene or heptane; Halohydrocarbon, especially halogenated aliphatic hydrocarbon, as 1,2-ethylene dichloride or chloroform; Ether, as diox, or 1, the 2-glycol dimethyl ether; Acid amides, as N, dinethylformamide or N,N-dimethylacetamide; And ester, as ethyl acetate or butylacetate.
Although the character to azide trialkyltin or azide triaryl tin is not particularly limited, and any this compound that is generally used for such reaction all can here be used equally, but we use ordinary priority: wherein each alkyl (can be identical or different, but preferably identical) contain the azide trialkyltin of 1 to 4 carbon atom, as the azide tin trimethyl, azide triethyltin or azide tributyl tin; Or each aryl (can be identical or different, but preferably identical) wherein, be preferably the azide triaryl tin of phenyl or substituted-phenyl, for example azide triphenyltin or azide trimethylphenyl tin.The amount of used azide trialkyltin or azide triaryl tin is not crucial, but is preferably whenever the amount prussiate needs 1 to 3 equivalent stannide, more preferably is the 1-2 equivalent.
The reaction of cyano compound and azide trialkyltin or azide triaryl tin can be carried out in wide temperature range, and accurate temperature of reaction is not crucial to the present invention.Usually, we find to be reflected at 60 to 150 ℃ of temperature, are favourable at 80 to 120 ℃ more preferably.The time of reacting required also changes bigger, depends on many factors, mainly is the temperature of reaction and the character of agents useful for same and solvent.Yet, carry out as long as be reflected under the above-mentioned preferred condition, 8 hours to 7 days, more preferably 1 to 5 day reaction times was normally enough.
The sn-containing compound that this reaction produces is used acid again, and alkali or alkaline metal fluoride cpd are handled, and make it be converted into the tetrazolyl compounds that needs.Be generally used for any acid of this class reaction, alkali or alkaline metal fluoride cpd all can use, and the example of suitable combination thing comprises: acid, especially mineral acid, example hydrochloric acid or sulfuric acid; Alkali, especially mineral alkali are as alkaline carbonate and supercarbonate (for example yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus) or alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide); And alkaline metal fluoride cpd, as lithium fluoride, Sodium Fluoride, Potassium monofluoride.
Reaction is carried out in the presence of solvent usually and preferably.The character of solvent for use does not have particular restriction, as long as its reagent to reaction or use does not have disadvantageous effect, and energy, at least to a certain degree solubilising reagent.The example of suitable solvent comprises those and other solvent of the reaction of listing above that is used for cyano compound and azide trialkyltin or azide triaryl tin, as alcohol (for example methyl alcohol or ethanol), water and aqueous alcohol.Reaction can be carried out in wide temperature range, and accurate temperature of reaction is not crucial to the present invention.Usually, the contriver finds to be reflected at 0 ℃～100 ℃, preferably carries out favourable under about room temperature.The time of reacting required also changes bigger, and this depends on many factors, mainly is the character of stable reaction and reagent and solvent for use.Yet, carry out as long as be reflected under the above-mentioned preferred condition, 30 minutes to 3 days, more preferably 1 hour to 24 hours reaction times was normally enough.
The other method that cyano group is changed into tetrazyl is that cyano compound and halogenation trialkyltin or halogenation triaryl tin are reacted in the presence of an alkali metal azide, and with the tin compound acid that produces, alkali or alkaline metal fluoride cpd are handled then.
Cyano compound and halogenation trialkyltin or halogenation triaryl tin carry out in the presence of solvent usually and preferably in the reaction in the presence of an alkali metal azide.The character of solvent for use does not have particular restriction, as long as it does not have disadvantageous effect to reaction or employed reagent.And at least to a certain extent can solubilising reagent.The example of suitable solvent comprises: hydro carbons, can be for aliphatic hydrocarbon or aromatic hydrocarbon, and as benzene, toluene, dimethylbenzene or heptane; Halohydrocarbon, especially halogenated aliphatic hydrocarbon, as 1,2-ethylene dichloride or chloroform; Ethers, as diox, or 1, the 2-glycol dimethyl ether; Ketone is as acetone or methyl ethyl ketone; Amides, as N, dinethylformamide or N,N-dimethylacetamide; And the ester class, as ethyl acetate or butylacetate.
Although the character to halogenation trialkyltin or halogenation triaryl tin does not have particular restriction, the any compound that is generally used for the reaction of this class all can be equal in this use, ordinary priority is selected for use: wherein each alkyl (can be identical or different, but preferably identical) have a halogenation trialkyltin of 1～4 carbon atom, as trimethyltin chloride, trimethyl tin bromide, triethyltin chloride or tributyltin chloride; Or each aryl (can be identical or different, but be preferably identical) wherein, be preferably the halogenation triaryl tin of phenyl or substituted-phenyl, for example triphenyltin chloride or chlorination trimethylphenyl tin.The amount of used halogenation trialkyltin or halogenation triaryl tin is not crucial, but is preferably whenever amount cyano compound use 1～3 equivalent stannide, and 1～2 equivalent more preferably.
Prussiate does not have particular restriction to employed an alkali metal azide in this reaction.These triazo-compounds include Lithium Azide, and sodiumazide or potassium azide wherein are preferably sodiumazide.The usage quantity of an alkali metal azide is not crucial, but, is preferably whenever the amount prussiate uses 1～3 equivalent an alkali metal azide, and more preferably be 1～2 equivalent.
Cyano compound and halogenation trialkyltin or the reaction of halogenation triaryl tin in the presence of an alkali metal azide can be carried out in wide temperature range, and accurate temperature of reaction is not crucial for the present invention.Usually, we find to be reflected at 60 ℃～150 ℃, are favourable at 80 ℃～120 ℃ more preferably.The time of reacting required also changes bigger, depends on many factors, mainly is the character of temperature of reaction and agents useful for same and solvent.Yet, carry out as long as be reflected under the above-mentioned preferred condition, 8 hours～7 days, more preferably 1～5 day reaction times will be enough.
The sn-containing compound of reaction generation is used acid more thus, and alkali or alkaline metal fluoride cpd are handled, and make it change into required tetrazolyl compounds.This reaction basically with sn-containing compound (producing) and acid by cyano compound and azide trialkyltin or the reaction of azide triaryl tin, the reacting phase of alkali or alkaline metal fluoride cpd together, and available identical solvent and reaction conditions carry out.
3) with R in the general formula (A)
5The formamyl of representative or alkyl-carbamoyl at first are converted into cyano group, change into tetrazyl then.
For alkyl-carbamoyl is changed into cyano group, with the alkyl carbamoyl compound with can be used as halogenating agent, chlorizating agent preferably, oxalic acid chlorine for example, the halide reaction of Phosphorus Oxychloride or SULPHURYL CHLORIDE.Used halid amount does not have particular restriction, but the contriver finds: whenever amount carbamino compound use 1～3 equivalent halogenide, more preferably 1～2 equivalent is favourable.
Reaction is carried out in the presence of solvent usually and preferably.The character of solvent for use does not have particular restriction, as long as it does not have disadvantageous effect to the reagent that reacts or comprise, and can solubilising reagent, at least to a certain degree dissolving.The example of suitable solvent comprises: hydro carbons can be aliphatic hydrocarbon or aromatic hydrocarbon, as benzene, and toluene, dimethylbenzene or heptane; Halogenated hydrocarbon, especially halogenated aliphatic hydrocarbon are as methylene dichloride or chloroform; Ethers, as diox, tetrahydrofuran (THF) or diethyl ether; And the ester class, as ethyl acetate or butylacetate.
Reaction can be carried out in wide temperature range, and accurate temperature of reaction is not crucial for this reaction.Usually, we find to be reflected at-10 ℃ to 100 ℃, are favourable at 0 ℃ to 50 ℃ more preferably.The time of reacting required also changes bigger, depends on many factors, mainly is the character of temperature of reaction and reagent and solvent for use.Yet, carry out as long as be reflected under the aforementioned preferred condition, 10 minutes to 16 hours, more preferably 30 minutes to 6 hours reaction times will be enough.
For making formamyl change into cyano group, with carbamino compound and dehydrated reagent, diacetyl oxide for example, trifluoroacetic anhydride; the methylsulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, oxalyl chloride or SULPHURYL CHLORIDE; at organic amine, for example triethylamine reacts under the existence of pyridine or N-methylmorpholine.
Reaction is carried out in the presence of solvent usually and preferably.The character of solvent for use does not have particular restriction, as long as it does not have disadvantageous effect to the reagent that reacts or comprise, and can solubleness reagent, at least to a certain degree dissolving.The example of suitable solvent comprises: hydro carbons can be aliphatic hydrocarbon or aromatic hydrocarbon, as benzene, and toluene, dimethylbenzene or heptane; Halogenated hydrocarbon, especially halogenated aliphatic hydrocarbon are as methylene dichloride or chloroform; Ethers, as diox, tetrahydrofuran (THF) or ether; And the ester class, as ethyl acetate or butylacetate.
Reaction can be carried out in wide temperature range, and accurate temperature of reaction is not crucial for this reaction.Usually, the contriver finds to be reflected at temperature-10 ℃～100 ℃, and it is favourable more preferably being 0 ℃～50 ℃.The time of reacting required also changes bigger, depends on many factors, mainly is the character of temperature of reaction and reagent and solvent for use.Yet, carry out as long as be reflected under the above-mentioned preferred condition, common 10 minutes to 16 hours, more preferably 30 minutes to 6 hours reaction times will be enough.
The product of these reaction needed can reclaim from reaction mixture with common means.
The cyano compound that obtains like this changes into corresponding tetrazolyl compounds with above-mentioned arbitrary reaction then.
The another kind of preparation method of compound of the present invention comprises the steps:
To have general structure is that compound and the condensing agent shown in the formula (F) reacts, temperature of reaction can be in the scope of certain width, precise dose is very unimportant to this reaction, usually-20 ℃～120 ℃, be preferably 0～100 ℃, reaction times is preferably 4～56 hours usually because of the solvent reaction temperature is different.
After reaction was finished, the compound of can reclaim with ordinary method.As: steaming desolventizes, and adds water, transfers pH, organic solvent extraction, dry this product that gets.If desired, by the product of ordinary method purifying gained, as recrystallization, column chromatography, preparation thin-layer chromatography.
Formula (F)
Reaction expression is:
Formula (F)
Wherein: R
1, R
2, R
3, R
5Ditto described.
Reaction is preferably carried out having under the solvent condition usually, but to using solvent property to be not particularly limited, as long as reaction or agents useful for same are not had side reaction.Solvent for use can dissolve or solubilizing reaction thing to a certain extent.The suitable solvent has: hydro carbons, as: benzene, dimethylbenzene, toluene or alkane, halohydrocarbon; Ethers is as tetrahydrofuran (THF), propyl ether, ether ， diox; Ketone, as: acetone, methyl ethyl ketone; The sulfoxide class, as: methyl-sulphoxide; Amides, as: N, dinethylformamide, N,N-dimethylacetamide; Pyridine; The cyanogen class.
The character of reacting used condensing agent is inessential, and the condensing agent of acylation reaction all can be used for this reaction on any energy catalytic esterification or the oxygen.Any dewatering agent that uses on esterification also can be used for this reaction.After also can making on the imidazole ring 5-position carboxyl form active ester or acid anhydrides earlier, again with 4-position 1-hydroxyl-1-methylethyl on hydroxyl be condensed into lactone.Preferred reagent: mineral acid, as: hydrochloric acid, Hydrogen bromide; Carbodiimide, as: dicyclohexylcarbodiimide; Acid and anhydrides: trifluoracetic acid, trifluoroacetic anhydride (TFAA); And thionyl chloride.
Hydroxyl on 4 (1-hydroxyl-1-methylethyl) and biphenyl part etherificate and cause by product on the imidazole ring when new compound of the present invention can be avoided reacting, the yield height, easy and simple to handle, method is reasonable, be fit to suitability for industrialized production, thereby on preparation angiotensin II receptor antagonists (as: olmesartan medoxomill), have important value.
Embodiment
Below will describe the specific embodiment of the present invention, but embodiment does not limit protection scope of the present invention by embodiment.
Embodiment 1
2-propyl imidazole-4,5-diethyl dicarboxylate's preparation:
One magnetic stirrer is housed, thermometer, reflux condensing tube in the 2L four-hole round-bottomed flask of oil bath heating, adds 80 gram 2-propyl imidazole-4,5 dicarboxylic acid, 1000ml dehydrated alcohol, the vitriol oil of catalytic amount.Be warming up to backflow, react after 16 hours, reaction solution is concentrated into 400ml.After being chilled to room temperature, reaction solution being transferred to mechanical stirring is housed, in the water-bath refrigerative 3L beaker, add ethyl acetate 400ml, water 600ml adds sodium bicarbonate solid in batches and transfers solution to neutral.Divide and to get organic layer, water layer uses ethyl acetate 200ml * 3 to extract again, and organic layer merges after washing once, adds dried over mgso, filters, steam desolventize 81.00 gram title compounds.
1H NMR (CDCl
3, 400MHz): δ 7.5～9.8 (1H, broad peak heavy water exchange back disappears), 4.37 (4H, quartets), 2.75 (2H, triplets), 1.77 (2H, multiplets), 1.36 (6H, triplets), 0.95 (3H, triplet).
EIMS(m/z，％)：254(M
+，7.35)，226(89.67)，180(100)，152(27.60)，110(24.89)
Embodiment 2
4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, ethyl ester
2 (a) prepare CH
3The MgI diethyl ether solution
One mechanical stirrer is housed, thermometer in the 1L four-hole round-bottomed flask of reflux condensing tube, adds magnesium powder 18.88 grams, and the 100ml ether is in the 49ml diethyl ether solution of room temperature dropping 49ml methyl iodide.After finishing, refluxed 15 minutes, promptly get CH
3The MgI diethyl ether solution.
2 (b) prepare 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, ethyl ester:
One mechanical stirrer is housed, thermometer in the 2L four-hole round-bottomed flask of reflux condensing tube, adds 40 gram 2-propyl imidazoles-4, the 5-diethyl dicarboxylate, the 800ml ether, be stirred to molten after, drip CH
3The MgI diethyl ether solution finishes.Again with reaction mixture stirring at room 1 hour.Add ethyl acetate 200ml, drip saturated ammonium chloride solution 350ml, add water 200ml again, divide and get organic layer, anhydrous magnesium sulfate drying, and remove solvent under reduced pressure and get 36.30 gram oily title compounds.
1H NMR (CDCl
3, 400MHz): δ 8.9～10.6 (1H, broad peak heavy water exchange back disappears), 5.99 (1H, unimodal heavy water exchange back disappears), 4.32 (2H, quartet), 2.66 (2H, triplets), 1.73 (2H, singlets), 1.65 (6H, singlet), 1.31 (3H, triplets), 0.93 (3H, triplet).
EIMS(m/z，％)：240(M
+，1.56)，225(92.74)，179(100)，151(15.49)，137(11.78)
Embodiment 3
4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid
One magnetic stirrer is housed, thermometer, reflux condensing tube in the 1L four-hole round-bottomed flask of oil bath heating, adds 73.35 gram 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, ethyl esters, 150ml acetone, 367ml10% sodium hydroxide solution.Be warming up to backflow, reacted 2 hours.Be cooled to 0 ℃ with ice-water bath, add concentrated hydrochloric acid and transfer solution to neutral, restir is after 30 minutes, and suction filtration washs, the dry 33.46 gram title compounds that get.
1H NMR (CDCl
3, 400MHz): δ 2.60 (2H, triplet), 1.65 (2H, sextets), 1.48 (6H, singlets), 0.86 (3H, triplet)
MS(Q-Tofmicro，ESI
+)：195.10，213.12(M+1)，235.10(M+Na)，447.21(2M+Na)
Embodiment 4
4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-ketone also, compound (I)
Magnetic stirrer is being housed, and reflux condensing tube in the 25ml eggplant type bottle of oil bath heating, adds 0.25 gram 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, adds the 10.0ml48% Hydrogen bromide, is warming up to backflow, reacts 14 hours.After being cooled to room temperature, transfer pH greater than 8 with 40% sodium hydroxide solution.Room temperature is continuous stirred 30 minutes, suction filtration, and washing, the dry crude product that gets gets 0.27 gram title compound by silica gel chromatography.
1H NMR (CDCl
3, 400MHz): δ 11.8～12.6 (1H, broad peak), 2.83 (2H, triplets), 1.88 (2H, sextets), 1.70 (6H, singlets), 1.00 (3H, triplets)
MS(Q-Tofmicro，ESI
+)：195.08(M+1)，217.05(M+Na)
13C?NMR(CDCl
3?100MHz)：δ171.91，162.54，161.49，119.04，84.742，31.42，25.59，21.46，13.61
Embodiment 5
4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-ketone also, compound (I)
Magnetic stirrer is being housed, in the water-bath refrigerative 25ml eggplant type bottle, add 0.20 gram 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, add the 10.0ml trifluoroacetic anhydride (TFAA), in room temperature reaction 8 hours, remove solvent under reduced pressure, add ethyl acetate 15ml, after a small amount of washing once, add dried over mgso, steaming desolventizes, and resistates gets 0.11 gram title compound by silica gel chromatography.
The nuclear magnetic resonance spectrum of this product, mass spectrum is consistent with embodiment 4 gained compounds.
Embodiment 6
4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-ketone also, compound (I)
In the 25ml eggplant type bottle of magnetic stirrer is housed, add 0.10 gram 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, 0.11 gram dicyclohexylcarbodiimide, the 10ml pyridine was in 60 ℃ of reactions 4 hours.Suction filtration.The washing, filtrate is concentrated into dried, the post layer separate 0.088 the gram title compound.
1H NMR (CDCl
3, 400MHz): δ 11.4～12.5 (1H, broad peak), 2.85 (2H, triplets), 1.86 (2H, sextets), 1.70 (6H, singlets), 1.02 (3H, triplets)
MS(Q-Tofmicro，ESI
+)：195.08(M+1)，217.05(M+Na)，389.13(2M+1)，411.11(2M+Na)
13CNMR(CDCl
3?100MHz)：δ171.91，162.54，161.49，119.04，84.742，31.42，25.59，21.46，13.61
Embodiment 7
4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-keto hydrochloride also
At magnetic stirring apparatus, in the ice-water bath refrigerative 50ml eggplant type bottle, add 1.0 grams 6,6-dimethyl-2-propyl group-3,6-dihydrofuran be [3,4-d] imidazol-4-one also, and the 20ml dehydrated alcohol is stirred to molten entirely.Drip the 10%HCl/ ethanolic soln, transfer pH to 2～3, finish.Reaction solution is concentrated into dried.Resistates adds a small amount of petroleum ether and stirring, suction filtration, washing, the dry 0.68 gram title compound that gets.
Embodiment 8
4,4-dimethyl-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } methyl-4, the 6-dihydrofuran is [3,4-d] imidazoles-6-ketone also, compound (II)
Magnetic stirring apparatus is being housed, thermometer, in the 50ml four-necked bottle of reflux condensing tube, add 0.3 gram 4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-ketone, 0.86 gram 4-[2-(trityl tetrazole-5-yl) phenyl] bromotoluene, 0.43 gram salt of wormwood, 20mlN, dinethylformamide.In stirring at room 18 hours, reaction solution is transferred in the separating funnel, add ethyl acetate 20ml, water 100ml divides and gets ethyl acetate layer, and water layer uses ethyl acetate 20ml * 3 to extract again, after organic layer merges, washing, anhydrous magnesium sulfate drying.Steaming desolventizes, and resistates is by silica gel chromatography, and eluent is the mixing solutions of 80: 1 methylene dichloride of volume ratio and methyl alcohol.Get 0.75 gram title compound.
1H NMR (CDCl
3400MHz): δ 7.95 (1H, multiplet), 6.8-7.5 (22H, multiplet), 5.11 (2H, singlets), 2.62 (2H, triplets), 1.76 (2H, sextets), 1.70 (6H, singlets) 0.96 (3H, triplet)
MS(Q-Tofmicro，ESI
+)：243.14，693.28(M+Na)，709(M+K)，1363.63(2M+.Na)
13C?NMR(CDCl
3?100MHZ)：δ169.264，163.880，160.184，159.420，141.536，141.345，133.815，130.716，130.228，130.224，129.988，129.906，128.258，127.730，127.621，127.066，126.382，120.658，83.287，82.979，77.202，48.189，29.604，25.834，21.034，13.802。
Embodiment 9
4,4-dimethyl-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } methyl-4, the 6-dihydrofuran is [3,4-d] imidazoles-6-ketone also, compound (II)
Magnetic stirring apparatus is being housed, thermometer, reflux condensing tube, in the 50ml four-necked bottle of ice-water bath, nitrogen atmosphere adds 1.0 grams 6,6-dimethyl-2-propyl group-3,6-dihydrofuran be [3,4-d] imidazol-4-one also, exsiccant 20mlN, dinethylformamide, 0.25 gram NaH (60%), with 2.87 gram 4-[2-(trityl tetrazole-5-yl) phenyl] bromotoluene is dissolved in 28.7ml exsiccant N, in the dinethylformamide, and be transferred in the dropping funnel, in 0 ℃ of dropping, drip and finish, continuous stirring 30 minutes is transferred in the separating funnel, adds the 150ml ethyl acetate, 500ml water, water layer uses ethyl acetate 20ml * 4 to extract again, after the organic layer washing once, and anhydrous magnesium sulfate drying, steaming desolventizes, resistates is by silica gel chromatography, and eluent is the mixing solutions of 80: 1 methylene dichloride of volume ratio and methyl alcohol, gets 2.42 gram title compounds.
The nuclear magnetic resonance spectrum of this product, mass spectrum is consistent with embodiment 7 gained compounds.
Embodiment 10
4,4-dimethyl-2-propyl group-1{4-[2-(tetrazolium-5-yl) phenyl] phenyl } methyl-4, the 6-dihydrofuran is [3,4-d] imidazoles-6-ketone also, compound (III)
Magnetic stirring apparatus is being housed, thermometer, reflux condensing tube, in the 50ml four-necked bottle of oil bath heating, add 0.50 gram 4,4-dimethyl-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } methyl-4,6-dihydrofuran also [3,4-d] imidazoles-6-ketone (compound (II)), 25ml75% (v/v) glacial acetic acid aqueous solution.Be warming up to 60 ℃ of reactions 6 hours.Reaction solution is evaporated to dried, resistates through silica gel chromatography get 0.24 the gram title compound.Fusing point: 171.039 ℃
Ultimate analysis: calculated value: C, 67.27%, H5.65%, N, 19.62%
Measured value: C, 67.07%; H, 5.61%; N, 19.61%
MS(Q-Tof?micro，ESI
+)：429.24(M+1)，857.48(2M+1)
1H NMR (DMSO-d6 400MHz): δ 7.68 (2H, multiplet), 7.62 (2H, multiplets),
(7.22 2H, multiplet), 7.12 (2H, doublets), 5.26 (2H, singlets), 2.68 (2H, triplets),
(1.64 2H, sextet), 1.57 (6H, singlets), 0.88 (3H, triplet)
13C?NMR(DMSO-d6?100MHZ)：δ169.037，159.606，159.405，140.980，
139.036，135.372，131.018，130.583，129.362，127.886，127.100，123.648，
119.857，82.635，47.144，28.560，
Claims (29)
1. a class 4, the 6-dihydrofuran is [3,4-d] imidazoles-6-ketone derivatives or its pharmacy acceptable salt also, it is characterized by the compound with following general structure (A):
General formula (A)
Wherein:
R
1, R
2, R
3Represent the alkyl of hydrogen atom or 1～6 carbon atom, R
1, R
2, R
3Can be identical also can be different; R
4Represent the substituting group shown in hydrogen atom or the formula (B):
Formula (B)
Wherein: R
5Represent carboxylic acid, tetrazolium-5-base, cyano group, protected carboxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl.
2. derivative according to claim 1 is characterized by compound or its pharmacy acceptable salt with one of following general structure:
Compound (I) compound (II) compound (III)
3. according to the preparation method of the described derivative of claim 1, it is characterized in that comprising the steps:
To have general structure is that the compound shown in the formula (C) carries out condensation reaction with condensing agent in solvent, then, collects the product of purifying gained formula (D) by ordinary method;
Formula (C) formula (D)
R
1, R
2, R
3Represent the alkyl of hydrogen atom or 1～6 carbon atom, R
1, R
2, R
3Can be identical also can be different.
4. according to the preparation method of the described derivative of claim 3, it is characterized in that the condensing agent of being addressed is the condensing agent of acylation reaction or the dewatering agent that uses on energy catalytic esterification or the oxygen on esterification.
5. according to the preparation method of the described derivative of claim 3, it is characterized in that temperature of reaction is-20 ℃～100 ℃, the reaction times is 1～56 hour.
6. according to the preparation method of the described derivative of claim 3, its feature comprises that also the product with institute's acquisition formula (D) is that the compound shown in the formula (E) reacts with having general structure under inert solvent and alkaline condition;
Formula (E)
Wherein: X represents halogen, R
5Represent carboxylic acid, tetrazolium-5-base, cyano group, protected carboxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl.
7. method according to claim 6 is characterized in that temperature of reaction is-20 ℃～100 ℃, and the reaction times is 30 minutes～24 hours.
8. method according to claim 6 is characterized in that, works as R
5During for protected tetrazolium-5-base, also comprise the step of protected compound and acid-respons being sloughed protecting group, be reflected in the inert solvent and carry out that the acid of being addressed is the acid that has as the general function of protonic acid.
9. method according to claim 8 is characterized in that, temperature of reaction is-10 ℃～120 ℃, and the reaction times is 0.5 to 24 hour.
10. method according to claim 6 is characterized in that, R in formula (B)
5During for cyano group, will have the described compound of cyano group and an alkali metal azide, cyano group will be changed into tetrazyl in that reaction in the presence of solvent and the halogeno-amine is arranged.
11. method according to claim 10 is characterized in that, an alkali metal azide of being addressed is a Lithium Azide, sodiumazide or potassium azide.
12. method according to claim 10 is characterized in that, temperature of reaction is at 75～150 ℃, 10 hours to 7 days reaction times.
13. method according to claim 6 is characterized in that, R in formula (B)
5During for cyano group, will have the described compound of cyano group and azide trialkyltin or azide triaryl tin in that reaction in the presence of the solvent is arranged, and use acid then, alkali or alkaline metal fluoride cpd are handled formed stannide cyano group are converted to tetrazyl.
14. method according to claim 13 is characterized in that, the azide trialkyltin of being addressed contains the azide trialkyltin of 1 to 4 carbon atom for each alkyl wherein; Azide triaryl tin is the azide triaryl tin of phenyl or substituted-phenyl.
15. method according to claim 13 is characterized in that, temperature of reaction is 60 to 150 ℃, and the reaction times is 8 hours to 7 days.
16. method according to claim 13 is characterized in that, the acid of being addressed is mineral acid, and alkali is mineral alkali.
17. method according to claim 6 is characterized in that, R in formula (B)
5During for cyano group, cyano compound and halogenation trialkyltin or halogenation triaryl tin are reacted in the presence of an alkali metal azide and solvent, with the tin compound acid that produces, alkali or alkaline metal fluoride cpd are handled then.
18. method according to claim 17 is characterized in that, the halogenation trialkyltin of being addressed has the halogenation trialkyltin of 1～4 carbon atom for each alkyl, and halogenation triaryl tin is the halogenation triaryl tin of phenyl or substituted-phenyl.
19. method according to claim 17 is characterized in that, an alkali metal azide is Lithium Azide, sodiumazide or potassium azide.
20. method according to claim 17 is characterized in that, temperature of reaction is at 60 ℃～150 ℃, and the reaction times is 8 hours～7 days.
21. method according to claim 17 is characterized in that, the acid of being addressed is mineral acid, and alkali is mineral alkali.
22. method according to claim 6 is characterized in that, when R5 represents alkyl-carbamoyl, alkyl carbamoyl compound and halogenating agent is reacted in the presence of solvent, at first is converted into cyano group, changes into tetrazyl then.
23. method according to claim 22 is characterized in that, halogenating agent is oxalic acid chlorine, Phosphorus Oxychloride or SULPHURYL CHLORIDE.
24. method according to claim 22 is characterized in that, temperature of reaction is-10 ℃ to 100 ℃, and the reaction times is 10 minutes to 16 hours.
25. method according to claim 6 is characterized in that, works as R
5When representing formamyl, carbamino compound and dehydrated reagent are reacted in the presence of solvent and organic amine, at first be converted into cyano group, change into tetrazyl then.
26. method according to claim 25 is characterized in that, dehydrated reagent is a diacetyl oxide, trifluoroacetic anhydride, methylsulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, oxalyl chloride or SULPHURYL CHLORIDE.
27. method according to claim 25 is characterized in that, organic amine is triethylamine, pyridine or N-methylmorpholine.
28. method according to claim 25 is characterized in that, temperature of reaction is a temperature-10 ℃～100 ℃, and the reaction times is 10 minutes to 16 hours.
29., it is characterized in that comprising the steps: according to the preparation method of the described derivative of claim 1
To have structure and be compound shown in the formula (F) and condensing agent and react having under the solvent condition, temperature of reaction is-20 ℃～120 ℃, and the reaction times is 4～56 hours;
Formula (F)
R
1, R
2, R
3Represent the alkyl of hydrogen atom or 1～6 carbon atom, R
1, R
2, R
3Can be identical also can be different; R
5Represent carboxylic acid, tetrazolium-5-base, cyano group, protected carboxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl;
Described condensing agent for can catalytic esterification or oxygen on the dewatering agent that uses on the condensing agent of acylation reaction or the esterification.
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| CN 03115940 CN1197866C (en) | 2003-03-21 | 2003-03-21 | 4,6-dihydrofuran [3,4-d] imidazole-6- ketone derivative and salt and preparation method thereof |
| PCT/CN2004/000199 WO2004083213A1 (en) | 2003-03-21 | 2004-03-12 | 4,6-dihydrofuro[3,4-d]imidazole-6-one derivatives and their salts and process for the preparation of the same |
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|---|---|---|---|
| CN 03115940 CN1197866C (en) | 2003-03-21 | 2003-03-21 | 4,6-dihydrofuran [3,4-d] imidazole-6- ketone derivative and salt and preparation method thereof |
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| CN1271068C (en) * | 2003-03-25 | 2006-08-23 | 上海医药工业研究院 | Novel method for preparing olmesartan |
| EP1910343B1 (en) | 2005-07-29 | 2014-10-29 | Krka | Process for the preparation of olmesartan medoxomil |
| CN101311168B (en) * | 2007-05-21 | 2010-12-08 | 上海医药工业研究院 | Method for preparing 4-(1-hydroxyl-1-methyl ethyl)-2-propyl glyoxaline-5-carboxylic ether |
| WO2010054515A1 (en) * | 2008-11-17 | 2010-05-20 | 上海医药工业研究院 | Process for the preparation of 4-(1-hydroxy-1-methylethyl)- 2-propyl-imidazole-5-carboxylates |
| CN102079747B (en) * | 2010-12-10 | 2012-07-18 | 江苏江神药物化学有限公司 | Olmesartan medoxomil key intermediate, synthesis method thereof and method for synthesizing olmesartan medoxomil from same |
| CN104402873A (en) * | 2014-12-02 | 2015-03-11 | 千辉药业（安徽）有限责任公司 | Preparation method of olmesartan medoxomil intermediate |
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| ATE199548T1 (en) * | 1992-06-02 | 2001-03-15 | Sankyo Co | 4-CARBOXYIMIDAZOLE DERIVATIVES AS ANGIOTENSIN II ANTAGONISTS AND THEIR THERAPEUTIC USE |
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