CN102766099A - Compound with xanthine oxidase inhibitory activity as well as salt, preparation methods and application thereof - Google Patents
Compound with xanthine oxidase inhibitory activity as well as salt, preparation methods and application thereof Download PDFInfo
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- CN102766099A CN102766099A CN2012102795112A CN201210279511A CN102766099A CN 102766099 A CN102766099 A CN 102766099A CN 2012102795112 A CN2012102795112 A CN 2012102795112A CN 201210279511 A CN201210279511 A CN 201210279511A CN 102766099 A CN102766099 A CN 102766099A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Abstract
The invention relates to a compound with xanthine oxidase inhibitory activity as well as salt, a preparation method and an application of the compound. The compound has a structure shown as formulas I, II and III, wherein R can be methyl or ethyl or n-propyl or isopropyl or n-butyl or iso-butyl or sec-butyl or isoamyl or n-hexyl or n-heptyl or n-octy or 4-methyl-benzyl. The preparation method of the compound is simple and easy to implement and the prepared product can be used as an xanthine oxidase inhibitor for treating and/or preventing hyperuricemia and gout.
Description
Technical field
The invention belongs to medical technical field, be specifically related to have compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity.
Background technology
Gout (Gout) is one group of heterogeneity, the metabolism class disease that causes urate deposition to form with soft tissue in the joint owing to long-term hyperuricemia (Hyperuricemia).The normal male blood uric acid is 150-380 μ mol/L, and Women was 100-300 μ mol/L in the past, and its value is near the male sex after climacterium.The saturation concentration of serum uric acid is about 416 μ mol/L in the time of 37 ℃, is higher than this value and is hyperuricemia.Hyperuricemia is the biochemical basis of goat.
The sickness rate of gout in the general population is 1%-2%, and the sickness rate of developed country is higher, and Britain reaches 1.4% with the sickness rate of Germany.According to relevant bibliographical information gout become the second largest metabolism class disease that is only second to mellitus in the world (Clin.2003,25:1593-1610).China still was the rarely found country of goat in the time of 1980; In recent years along with the raising of living standards of the people; The change of dietary structure; The sickness rate of gout increases year by year, reaches 1.1% (The Journal of Foot and Ankle Surgery 48 (1): 70-73.), brought huge pressure and heavy economical load to society to China's gout morbidity in 2008 general crowd.
XOD in the purine metabolism process (Xanthine oxidase; XO) be the key enzyme of uricogenesis; In the final stage of purine metabolism, xanthine generates uric acid under the effect of XOD, and the activity that therefore suppresses XOD can effectively reduce the generation of uric acid.In the treatment of hyperuricemia and gout; Xanthine oxidase inhibitor occupies important status; Thereby the mechanism of action of such medicine mainly is the activity that suppresses XOD can effectively reduce the generation of uric acid, thereby plays the effect of treatment hyperuricemia and gout.
Very limited in view of gout treatment drug kinds in the market, the anti-gout drugs of development high-efficiency low-toxicity is significant.
Summary of the invention
The purpose of this invention is to provide compound and salt, preparation method and purposes with xanthine oxidase inhibitory activity.
The invention provides compound or pharmacy acceptable salt with xanthine oxidase inhibitory activity; Such structural general formula is as shown in Figure 1, and wherein: R is methyl or ethyl or n-propyl or sec.-propyl or normal-butyl or isobutyl-or sec.-butyl or isopentyl or n-hexyl or n-heptyl or n-octyl or 4-methyl-benzyl.
Compound or pharmacy acceptable salt with xanthine oxidase inhibitory activity provided by the invention, this compounds are any in following compound (1) ~ (29):
(1) 2-(3-cyanic acid-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-1),
(2) 2-(3-cyanic acid-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-2),
(3) 2-(3-cyanic acid-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-3),
(4) 2-(3-cyanic acid-4-n-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-4),
(5) 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-5),
(6) 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-6),
(7) 2-(3-cyanic acid-4-isopentyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-7),
(8) 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-8),
(9) 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-9),
(10) 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-10),
(11) 2-(3-cyanic acid-4-is to the methyl benzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-11),
(12) 2-(3-cyanic acid-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-1),
(13) 2-(3-cyanic acid-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-2),
(14) 2-(3-cyanic acid-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-3),
(15) 2-(3-cyanic acid-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-4),
(16) 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-5),
(17) 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-6),
(18) 2-(3-cyanic acid-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-7),
(19) 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-8),
(20) 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-9),
(21) 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-10),
(22) 2-(3-cyanic acid-4-methyl-benzyl) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-11),
(23) 2-(3-cyanic acid-4-n-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-1),
(24) 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-2),
(25) 2-(3-cyanic acid-4-sec.-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-3),
(26) 2-(3-cyanic acid-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-4),
(27) 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-5),
(28) 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-6),
(29) 2-(3-cyanic acid-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-7).
The present invention also provides a kind of prepare described the have compound of xanthine oxidase inhibitory activity or the midbody of pharmacy acceptable salt, and this midbody comprises 2-(3-cyanic acid-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyanic acid-4-alkoxyl group) phenyl-1-hydroxyl base-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyanic acid-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-manthanoate; Wherein, said ester is methyl esters or ethyl ester or propyl ester or the tert-butyl ester or benzyl ester or to methyl benzyl ester.
The present invention also provides a kind of described miaow to have the preparation method of the compound or the pharmacy acceptable salt of xanthine oxidase inhibitory activity, and step is following:
1) be starting raw material with the 4-hydroxy benzaldehyde; Obtain 3-bromo-4-hydroxy benzaldehyde through bromo; Carry out alkylation reaction with hydrobromic ether and obtain 3-bromine 4--oxyl phenyl aldehyde; Obtain 3-cyanic acid-4--oxyl phenyl aldehyde with cuprous cyanide reaction again, and then with 2-(hydroxyl imide base)-3-oxobutanoic acid esters ring with, obtain 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate;
2) 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate makes the series compound shown in the formula I through hydrolysis reaction;
3) 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate methylates with methyl-sulfate; Make 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate; Through hydrolysis reaction, make the series compound shown in the general formula II;
4) 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate makes 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-4-methyl isophthalic acid H-imidazoles-5-manthanoate with trimethylammonium halosilanes and iodized salt dehydroxylation; Through hydrolysis reaction, make the series compound shown in the general formula III.
The invention provides a kind of pharmaceutical composition; It includes described compound or pharmacy acceptable salt with xanthine oxidase inhibitory activity; With and verivate, analogue, tautomer, polymorphic form, pharmaceutically useful solvate as activeconstituents, and pharmaceutically useful auxiliary material, carrier, thinner etc.
The pharmaceutical composition that contains The compounds of this invention can be through ordinary method preparation, and for example at Remington:the Science and Practice of Pharmacy, 19th Ed. describes in 1995.Said composition can be conventional formulation such as capsule, tablet, powder, solution, suspension, syrup, aerosol or topical form.They can contain suitable solid or liquid vehicle, or in suitable sterile media, form injection solution or suspension.Said composition can contain the active compound of 5-20%, preferred 0.5-10% weight, and surplus is pharmaceutically useful carrier, excipient, thinner, solvent etc.
Typical compsn contains the formula I, II, the compound shown in the III or its solvolyte; And pharmaceutically useful excipient, it can be carrier or thinner, or the suppressed by vector dilution; Or be wrapped in the carrier, it can be the form of capsule, pouch, paper or other container.When carrier was used as thinner, it can be solid, semisolid or liquid substance, and it can be as carrier, excipient or the medium of active compound.This active compound can with container for example the form of the particulate solid in the pouch be absorbed.Some carriers that are fit to are water; Salts solution; Alcohol; Polyoxyethylene glycol; Gather the hydroxyl-oxethyl Viscotrol C; Peanut oil; Coconut palm pulls oil; Gelatin; Lactose; Terra alba; Sucrose; Schardinger dextrins; Amylose starch; Magnesium Stearate (magnesium sterate); Talcum; Gelatin; Agar; Pectin; Gum arabic; Triple Pressed Stearic Acid or cellulosic lower alkyl ether; Silicic acid; Lipid acid; Fatty acid amine; Fatty mono glyceride and triglyceride; Season becomes the tetrol fatty ester; T 46155; Hydroxy-methyl cellulose and Vinylpyrrolidone polymer.Likewise, carrier or thinner can comprise any slow-release material known in the art, and like glyceryl monostearate or distearin, it uses separately or mixes with wax.Can also comprise wetting agent in the preparation, emulsifying agent, suspensoid, sanitas, sweeting agent or sweetener.Method that can oneself knows through this area prepared preparation of the present invention, with provide behind the delivery of active ingredients patient fast, continue or postpone to discharge.
This pharmaceutical composition can be aseptic, and if desired can with assistant agent, emulsifying agent, buffer reagent and (or) tinting material etc. mixes, as long as it does not react with active compound.
Can need only it and effectively active medicine is sent to suitable or required reactive site with any administration, for example oral; Nasal cavity; Through skin, lung, or administered parenterally; For example in rectum, storage storehouse, subcutaneous, intravenously, the urethra, in the intramuscular, nose, ophthalmic solution or ointment, preferred by oral route administration.
If solid carrier is used for oral administration, said preparation can be pressed into tablet, or in incapsulating with powder or bead form, perhaps processes lozenge or lozenge.If use liquid vehicle, said preparation can be syrup, emulsion, soft gelatin capsule or aseptic parenteral solution, like water-based or non-aqueous liquid suspension or solution.
For intranasal administration, said preparation can contain dissolving or be suspended in the formula I compound in liquid vehicle, the especially aqueous carrier, as the aerosol administration.This carrier can contain additive, comprises solubilizing agent such as Ucar 35, tensio-active agent, absorption enhancer such as Yelkin TTS (phosphatide phenol choline) or Schardinger dextrins, or sanitas such as parabens.
For administered parenterally, particularly suitable is injection solution or suspension, the preferred aqueous solution of active compound solvent in polyhydroxylated Viscotrol C.
Have talcum with (or) tablet, drageeing or the capsule of carbohydrate carrier or tackiness agent etc. be particularly suitable for oral administration.Preferably, tablet, drageeing or capsular carrier comprise lactose, W-Gum and (or) yam starch.When using when adding sugar carrier, can use the syrup or the agent of indulging in.
The invention provides a kind of treatment with (or) prevention hyperuricemia and goat medicine, it includes described compound or pharmacy acceptable salt with xanthine oxidase inhibitory activity.
Description of drawings
The general structure figure of Fig. 1 The compounds of this invention;
The preparation flow figure of Fig. 2 The compounds of this invention.
Embodiment
Following embodiment will further explain the present invention, but therefore not limit the present invention.
According to flow preparation as shown in Figure 1.
The preparation of embodiment 1.3-bromo-4-hydroxy benzaldehyde (CSL-1)
In the 2000mL three-necked bottle, and the adding PARA HYDROXY BENZALDEHYDE (100g, 0.820mol), iodine (5g, 0.0192mol) with methylene dichloride 600mL ,-5 ℃ of following mechanical stirring 10min.With bromine (143.4g, 0.902mol) and methylene dichloride (200mL) mixing solutions slowly splash in the above-mentioned reaction solution, drip to finish room temperature reaction 24h.Reaction is finished, and above-mentioned reaction solution is slowly poured in 1000mL (16%) aqueous solution of sodium bisulfite, stir 30min after, suction filtration, washing, drying, bullion 120.0g, productive rate: 72.7%, the thick product of gained is not purified directly to be used for next step reaction.
The preparation of embodiment 2.3-bromo-4-alkoxy benzene formaldehyde (CSL-2)
2.1 the preparation of 3-bromo-4-isobutoxy phenyl aldehyde (CSL-2-7)
With 3-bromo-4-hydroxy benzaldehyde (10.0g, 0.05mol), isobutane bromide (10.275g, 0.075mol); Anhydrous potassium carbonate (8.97g, 0.065mol), potassiumiodide (0.166g, 0.001mol); Add in the 100ml single port bottle, stirring reaction is 8 hours under 50 ℃ of nitrogen protections, and reaction is finished, suction filtration; Filter cake is washed 2 times with DMF, and about 3/4 DMF is revolved in decompression, and residue is used acetic acid ethyl dissolution, washing; Saturated common salt washing, anhydrous sodium sulfate drying spends the night, and revolves ETHYLE ACETATE, and the thick product of gained is not purified directly to be used for next step reaction.
2.2 the preparation of 3-bromo-4-methyl methoxybenzaldehyde (CSL-2-1)
With 3-bromo-4-hydroxy benzaldehyde (10g, 0.05mol), Anhydrous potassium carbonate (13.8g, 0.00mol) and DMF (40ml) add in the 100ml reaction flask; Ice bath drips methyl-sulfate down, and (6.6g 0.035mol), drips and finishes stirring reaction 2h under the room temperature; The completeness of TLC detection reaction, reaction is finished, and reaction solution is poured in the 100ml water into stirring at room 20min; Suction filtration, bullion 9.7g, productive rate: 90.6%, the thick product of gained is not purified directly to be used for next step reaction.
2.3 the preparation of 3-bromo-4-ethyl methoxybenzaldehyde (CSL-2-2)
With the monobromethane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.4 the preparation of 3-bromo-4-positive propoxy phenyl aldehyde (CSL-2-3)
With the n-propyl bromide is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.5 the preparation of 3-bromo-4-isopropoxide benzaldehyde (CSL-2-4)
With the bromo propane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.6 the preparation of 3-bromo-4-n-butoxy phenyl aldehyde (CSL-2-5)
With the bromination of n-butane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.7 the preparation of 3-bromo-4-sec.-butoxy phenyl aldehyde (CSL-2-6)
With the chung-bromo butane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.8 the preparation of 3-bromo-4-isopentyloxy phenyl aldehyde (CSL-2-8)
With the bromo iso-pentane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.9 the preparation of 3-bromo-4-positive hexyl phenenyl formaldehyde (CSL-2-9)
With the bromo normal hexane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.10 the preparation of 3-bromo-4-oxygen benzaldehyde in positive heptan (CSL-2-10)
With the bromo heptane is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.11 the preparation of 3-bromo-4-n-octyloxy phenyl aldehyde (CSL-2-11)
With the n-octane bromide is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
2.12 3-bromo-4-is to the preparation of methyl benzyloxy phenyl aldehyde (CSL-2-12)
With 4-methyl benzyl chloride is raw material, and the preparation method is with (CSL-2-7), and the thick product of gained is not purified directly to be used for next step.
The preparation of embodiment 3.3-cyanic acid-4-alkoxy benzene formaldehyde (CSL-3)
3.1 the preparation of 3-cyano-4-isobutoxy phenyl aldehyde (CSL-3-7)
With 3-bromo-4-isobutoxy phenyl aldehyde (25.7g, 0.1mol), cuprous cyanide (9.9g, 0.11mol) and DMF (100ml) add in the 250ml reaction flask; Stirring reaction 6h under 150 ℃ of nitrogen protections, the completeness of TLC detection reaction, reaction is finished, and reaction solution is put and is chilled to room temperature; Methylene dichloride is added in the reaction solution, suction filtration, filter cake is washed 2 times with methylene dichloride, gets filtrating; Use ammoniacal liquor successively, water, saturated common salt washing; Anhydrous sodium sulfate drying spends the night, and methylene dichloride is removed in decompression, and the thick product of gained is not purified directly to be used for next step.
3.2 the preparation of 3-cyanic acid-4-methyl methoxybenzaldehyde (CSL-3-1)
With CSL-3-1 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.3 the preparation of 3-cyanic acid-4-ethyl methoxybenzaldehyde (CSL-3-2)
With CSL-3-2 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.4 the preparation of 3-cyanic acid-4-positive propoxy phenyl aldehyde (CSL-3-3)
With CSL-3-3 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.5 the preparation of 3-cyanic acid-4-isopropoxide benzaldehyde (CSL-3-4)
With CSL-3-4 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.6 the preparation of 3-cyanic acid-4-n-butoxy phenyl aldehyde (CSL-3-5)
With CSL-3-5 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.7 the preparation of 3-cyanic acid-4-sec.-butoxy phenyl aldehyde (CSL-3-6)
With CSL-3-6 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.8 the preparation of 3-cyanic acid-4-isopentyloxy phenyl aldehyde (CSL-3-8)
With CSL-3-8 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.9 the preparation of 3-cyanic acid-4-positive hexyl phenenyl formaldehyde (CSL-3-9)
With CSL-3-9 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.10 the preparation of 3-cyanic acid-4-oxygen benzaldehyde in positive heptan (CSL-3-10)
With CSL-3-10 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.11 the preparation of 3-cyanic acid-4-n-octyloxy phenyl aldehyde (CSL-3-11)
With CSL-3-11 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
3.12 3-cyanic acid-4-is to the preparation of methyl benzyloxy phenyl aldehyde (CSL-3-12)
With CSL-3-12 is raw material, and the preparation method is with (CSL-3-7), and the thick product of gained is not purified directly to be used for next step.
The preparation of embodiment 4.2-(3-cyanic acid-4-alkoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4)
4.1 the preparation of 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-7)
With 3-cyano-4-isobutoxy phenyl aldehyde (8.8g, 0.0432mol), 2-hydroxyl imide-ethyl 3-oxobutanoate (8.3g; 0.0520mol), ammonium acetate (33.3g, 0.4320mol) and acetic acid (176ml) add in the 500ml reaction flask; Stirring reaction is 24 hours under 50 ℃ of nitrogen protections, and reaction is finished, and adds reaction solution and pours (500ml) in the water into; Stir 30min under the room temperature, suction filtration, filter cake is used re-crystallizing in ethyl acetate; Get white solid powder 10.3g, yield: 69.4%, mp:147.4-148.3 ℃.MS(ESI):m/z?344.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:12.12（s,1H,NO-H），8.30d,1H,J=2.2Hz,Ar-H）,8.28(dd,1H,J=2.2&9.6Hz,Ar-H),7.39(d,1H,J=9.6Hz,Ar-H),4.29(q,2H,J=7.1Hz,CH
2),4.00(t,2H,J=6.5Hz,CH
2),2.38(s,3H,CH
3),2.08(m,1H,CH),1.32(t,3H,J=7.1H?z,CH
3),1.02(d,6H,J=6.7Hz,CH
3)。
4.2 the preparation of 2-(3-cyanic acid-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-1)
With (CSL-3-1) is raw material, and the preparation method gets white solid powder 12.3g, yield with (CSL-4-7): 65.8%, and mp:173.2-175.1 ℃.
MS(ESI):m/z?302.3[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.32（d,1H,J=2.1Hz,Ar-H）,8.21(dd,1H,J=2.1&9.0Hz,Ar-H),7.14(d,1H,J=8.1H?z,Ar-H),4.41(q,2H,J=6.9H?z,CH
2),3.94(s,3H,CH
3),2.19(s,3H,CH
3),1.26(d,6H,J=6.9Hz,CH
3)。
4.3 the preparation of 2-(3-cyanic acid-4-oxyethyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-2)
With (CSL-3-2) is raw material, and the preparation method gets white solid powder 9.9g with (CSL-4-7), yield: 55.0%, and mp:153.5-155.8 ℃.
MS(ESI):m/z?316.3[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.28（d,1H,J=2.1Hz,Ar-H）,8.23(dd,1H,J=2.4&9.0Hz,Ar-H),7.26(d,1H,J=9.0Hz,Ar-H),4.26(q,2H,J=7.2Hz,CH
2),4.21(q,2H,J=7.2Hz,CH
2),2.29(s,3H,CH
3),1.40(t,3H,J=6.9Hz,CH
3),1.28(t,3H,J=7.2Hz，CH
3)。
4.4 the preparation of 2-(3-cyanic acid-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-3)
With (CSL-3-3) is raw material, and the preparation method gets white solid powder 10.8g with (CSL-4-7), yield: 62.1%, and mp:152.2-154.1 ℃.
MS(ESI):m/z?330.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.29（dd,1H,J=8.9Hz&2.1Hz,Ar-H）,8.26(s,1H,Ar-H),7.40(d,1H,J=9.0Hz,Ar-H),4.38(q,2H,J=7.2H?z,CH
2),4.22(t,2H,J=6.6Hz,CH
2),2.25(s,3H,CH
3),1.84(m,2H,CH
2),1.35(t,3H,J=7.3Hz,CH
3),1.03(t,3H,J=7.1H?z,CH
3)。
4.5 the preparation of 2-(3-cyanic acid-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-4)
With (CSL-3-4) is raw material, and the preparation method gets white solid powder 12.2g with (CSL-4-7), yield: 70.1%, and mp:150.2-151.9 ℃.
MS(ESI):m/z?330.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.26（dd,1H,J=8.8Hz&2.1Hz,Ar-H）,8.23(d,1H,J=2.1Hz,Ar-H),7.40(d,1H,J=8.9H?z,Ar-H),4.88(m,1H,CH),4.35(q,2H,J=7.2Hz,CH
2),2.42(s,3H,CH
3),1.38(d,6H,J=6.3Hz,CH
3),1.35(t,3H,J=7.0Hz,CH
3)。
4.6 the preparation of 2-(3-cyanic acid-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-5)
With (CSL-3-5) is raw material, and the preparation method gets white solid powder 12.0g with (CSL-4-7), yield: 71.0%, and mp:149.8-150.5 ℃.
MS(ESI):m/z344.4[M+H]
+；
1H-MNR(300MH?z,DMSO-d
6)δppm:12.16（s,1H,NO-H），8.28（dd,1H,J=2.1&8.7Hz,Ar-H）,8.26(d,1H,J=2.4Hz,Ar-H),7.39(d,1H,J=9.6Hz,Ar-H),4.30(q,2H,J=7.2Hz,CH
2),4.21(t,2H,J=6.3Hz,CH
2),2.37(s,3H,CH
3),1.77(m,2H,CH
2),1.48(m,2H,CH
3),1.32(t,3H,J=6.9Hz,CH
3),0.96(t,3H,J=7.5Hz,CH
3)。
4.7 the preparation of 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-6)
With (CSL-3-6) is raw material, and the preparation method gets white solid powder 11.8g with (CSL-4-7), yield: 69.8%, and mp:159.8-162.3 ℃.
MS(ESI):m/z?344.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:12.11（s,1H,NO-H），8.28（s,1H,Ar-H）,8.24(d,1H,J=9.1Hz,Ar-H),7.41(d,1H,J=9.0Hz,A-H),4.67(m,1H,CH),4.29(q,2H,J=9.1Hz,CH
2),2.38(s,3H,CH
3),1.77(m,2H,CH
2),1.7(m,2H,CH
3),1.30(m,6H,2CH
3),0.96((t,3H,J=7.4Hz,CH
3)。
The preparation of (4.82-3-cyanic acid-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-8)
With (CSL-3-8) is raw material, and the preparation method gets white solid powder 11.5g with (CSL-4-7), yield: 69.7%, and mp:148.8-150.1 ℃.
MS(ESI):m/z?358.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.41（s,1H,Ar-H）,8.25(dd,1H,J=2.1&8.7Hz,Ar-H),7.21(d,1H,J=9.0Hz,Ar-H),4.20(q,2H,J=6.9Hz,CH
2),4.18(t,2H,J=6.3Hz,CH
2),2.24(s,3H,CH
3),1.85(m,1H,CH),1.68(q,2H,J=6.6Hz,CH
2),1.27(t,3H,J=6.9Hz,CH
3),0.98((d,6H,J=6.6Hz,CH
3)。
4.9 the preparation of 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-9)
With (CSL-3-9) is raw material, and the preparation method gets white solid powder 10.3g with (CSL-4-7), yield: 64.1%, and mp:109.3-112.8 ℃.
MS(ESI):m/z372.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:12.14（s,1H,NO-H），8.29（s,1H,Ar-H）,8.27(s,1H,Ar-H),7.38(d,1H,J=8.6Hz,A-H),4.29(q,2H,J=7.1Hz,CH
2),4.20(t,2H,J=6.4Hz,CH
2),2.50(s,3H,CH
3),1.77(m,2H,CH
2),1.46(m,2H,CH
3),1.35-1.29(m,7H,CH
2&CH
3),0.87(t,3H,J=6.9H?z,CH
3)。
4.10 the preparation of 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-10)
With (CSL-3-10) is raw material, and the preparation method gets white solid powder 10.5g with (CSL-4-7), yield: 66.8%, and mp:139.5-142.2 ℃.
MS(ESI):m/z?386.5[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.27（d,1H,J=2.0Hz,Ar-H）,8.24(dd,1H,J=2.2&8.6Hz,Ar-H),7.39(d,1H,J=8.9Hz,Ar-H),4.24(q,2H,J=7.1Hz,CH
2),4.18(t,2H,J=6.4Hz,CH
2),2.31(s,3H,CH
3),1.75(m,2H,CH),1.48-1.28(m,11H,CH2&CH
3),0.88(t,3H,J=6.7Hz,CH
3)。
4.11 the preparation of 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-11)
With (CSL-3-11) is raw material, and the preparation method gets white solid powder 11.1g with (CSL-4-7), yield: 72.1%, and mp:143.2-145.1 ℃.
MS(ESI):m/z400.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：8.35（d,1H,J=1.8Hz,Ar-H）,8.19(dd,1H,J=2.1&9.0Hz,Ar-H),7.39(d,1H,J=8.1Hz,Ar-H),7.26(d,2H,J=8.9Hz,Ar-H),7.24(d,2H,J=8.4Hz,Ar-H),5.24(s,2H,CH
2),4.14(q,2H,J=7.2Hz,CH
2),2.33(s,3H,CH
3)2.20(s,3H,CH
3),125((t,3H,J=6.9Hz,CH
3)。
4.12 the preparation of 2-(3-cyanic acid-4-is to the methyl benzyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-12)
With (CSL-3-12) is raw material, and the preparation method gets white solid powder 10.9g, yield with (CSL-4-7): 70.0%, and mp:150.3-151.5 ℃.
MS(ESI):m/z?392.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：8.27（dd,1H,J=2.1&7.2Hz,Ar-H）,8.26(s,1H,Ar-H),7.51(d,1H,J=7.2Hz,Ar-H),7.39(d,2H,J=8.1Hz,Ar-H),7.24(d,2H，j=7.8Hz,Ar-H),5.32(s,2H,CH
2),4.31(q,2H,J=7.2Hz,CH
2),3.96(s,3H,CH
3),2.40(s,3H,CH
3),2.32(s,3H,CH
3),1.33((t,3H,J=7.2Hz,CH
3)。
Embodiment 5.2-(3-cyanic acid-4-alkoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid
(5.12-3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-6)
With 2-(3-cyano-4-isobutoxy phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (1.0g, 2.9mmol), sodium hydroxide water liquid (1moL, 11.0ml) and THF: the mixed solvent (10ml) of absolute ethyl alcohol (1:1) adds in the 25ml reaction flask; 50 ℃ of following stirring reactions 8 hours, the completeness of TLC detection reaction, reaction is finished; Remove the part organic solvent under reduced pressure, using 5% Hydrogen chloride to transfer pH value of solution then is 1, leaves standstill 30min; Suction filtration, the filter cake seasoning is used methyl alcohol: ETHYLE ACETATE (2:1) mixed solvent recrystallization; Get white solid powder 0.60g, yield: 65.2%, mp:191.6-192.2 ℃.
MS(ESI):m/z?316.1291[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.55（s,1H,Ar-H）,8.47(d,1H,J=8.8Hz,Ar-H),7.46(d,1H,J=9.0Hz,Ar-H),4.00(d,2H,J=6.4Hz,CH
2),2.51(s,3H,CH
3),2.10(m,1H,CH),1.03(d,6H,J=6.7Hz,CH
3)。
5.2 the preparation of 2-(3-cyanic acid-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-1)
With (CSL-4-1) is raw material, and the preparation method gets white solid powder 0.50g, yield with (CSL-HI-6): 52.5%, and mp:214.1-214.5 ℃.
MS(ESI):m/z?296.0642[M+Na]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.60(d,1H,J=2.0Hz,Ar-H),8.44(dd,1H,J=8.8Hz?and?2.2Hz,Ar-H),7.27(d,1H,8.9Hz,Ar-H),3.88(s,3H,CH
3),2.42(s,3H,CH
3)。
5.3 the preparation of 2-(3-cyanic acid-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-2)
With (CSL-4-3) is raw material, and the preparation method gets white solid powder 0.60g, yield with (CSL-HI-6): 62.5%, and mp:191.9-193.0 ℃.
MS(ESI):m/z?302.1135[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.69(s,1H,COOH),8.54(s,1H,Ar-H),8.46(d,1H,J=8.7Hz,Ar-H),7.45(d,1H,J=8.8Hz,Ar-H),4.18(t,2H,J=6.3Hz,CH
2),2.50(s,3H,CH
3),1.80(m,2H,CH
2),1.03(t,3H,J=7.4Hz,CH
3)。
5.4 the preparation of 2-(3-cyanic acid-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-3)
With (CSL-4-4) is raw material, and the preparation method gets white solid powder 0.62g, yield with (CSL-HI-6): 64.6%, and mp:190.8-191.2 ℃.
MS(ESI):m/z?302.1135[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.65(s,1H,COOH),8.54(s,1H,Ar-H),8.48(d,1H,J=8.7Hz,Ar-H),7.52(d,1H,J=8.8Hz,Ar-H),4.91(m,1H,CH),2.51(s,3H,CH
3),1.37(d,6H,J=5.9Hz,CH
3)。
5.5 the preparation of 2-(3-cyanic acid-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-4)
With (CSL-4-5) is raw material, and the preparation method gets white solid powder 0.66g, yield with (CSL-HI-6): 68.7%, and mp:193.7-195.3 ℃.
MS(ESI):m/z?316.1292[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.56（s,1H,Ar-H）,8.49(d,1H,J=7.0Hz,Ar-H),7.45(d,1H,J=8.9Hz,Ar-H),4.22(t,2H,J=6.2Hz,CH
2),2.51(s,3H,CH
3),1.77(m,2H,CH
2),1.48(m,2H,CH
2),0.97(t,3H,J=7.3Hz,CH
3)。
5.6 the preparation of 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-5)
With (CSL-4-6) is raw material, and the preparation method gets white solid powder 0.63g, yield with (CSL-HI-6): 65.6%, and mp:190.9-191.5 ℃.
MS(ESI):m/z316.1292[M+H]
+；1H-MNR(300MHz,DMSO-d6)δppm:8.55（s,1H,Ar-H）,8.48(d,1H,J=8.8Hz,Ar-H),7.52(d,1H,J=9.1Hz,Ar-H),4.72(m,1H,CH),2.51(s,3H,CH
3),1.71(m,2H,CH
2),1.33(d,3H,J=5.9Hz,CH
3),0.97(t,3H,J=7.3Hz,CH
3)。
5.7 the preparation of 2-(3-cyanic acid-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-7)
With (CSL-4-8) is raw material, and the preparation method gets white solid powder 0.62g, yield with (CSL-HI-6): 64.6%, and mp:194.7-194.9 ℃.
MS(ESI):m/z?330.1448[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.54(s,1H,Ar-H),8.48(s,1H,Ar-H),7.50(s,1H,Ar-H),4.25(s,2H,CH
2),2.51(s,3H,CH
3),1.82(s,1H,CH
2),1.70(s,2H,CH
2),0.97(s,6H,CH
3)。
5.8 the preparation of 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-8)
With (CSL-4-9) is raw material, and the preparation method gets white solid powder 0.72g, yield with (CSL-HI-6): 75.0%, and mp:190.8-191.1 ℃.
MS(ESI):m/z?344.1605[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.53（s,1H,Ar-H）,8.45(d,1H,J=8.7Hz,Ar-H),7.45(d,1H,J=8.9Hz,Ar-H),4.21(t,2H,J=5.9Hz,CH
2),2.50(s,3H,CH
3),1.78(m,2H,CH
2),1.46(m,2H,CH
2),1.34(m,4H,CH
2),0.89(s,3H,CH
3)。
5.9 the preparation of 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-9)
With (CSL-4-10) is raw material, and the preparation method gets white solid powder 0.68g, yield with (CSL-HI-6): 70.8%, and mp:194.3-194.9 ℃.
MS(ESI):m/z?358.1761[M+H]
+；
1H-MNR(600MHz,DMSO-d
6)δppm:17.31（s,1H,Ar-NOH）,13.75(s,1H,COOH),8.55(s,1H,Ar-H),8.48(d,1H,J=8.9Hz,Ar-H),7.47(d,1H,J=9.1Hz，Ar-H),4.22(t,2H,J=6.4H?z,CH
2),2.51(s,3H,CH
3),1.78(m,2H,CH
2),1.45(m,2H,CH
2),1.35(m，2H,CH
2),1.29(m,4H,CH
2),0.88(t,3H,J=6.6Hz,C?H
3)。
5.10 the preparation of 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-10)
With (CSL-4-11) is raw material, and the preparation method gets white solid powder 0.68g, yield with (CSL-HI-6): 70.8%, and mp:186.5-187.5 ℃.
MS(ESI):m/z372.1918[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.76（s,1H,COOH）,8.57(s,1H,Ar-H),8.51(d,1H,J=9.2Hz,Ar-H),7.50(d,1H,J=9.1Hz,Ar-H),4.23(t,2H,J=6.4Hz,CH
2),2.52(s,3H,CH
3),1.78(m,2H,CH
2),1.44(m,2H,CH
2),1.41-1.27(m,8H,CH
2),0.86(t,3H,J=6.4Hz,CH
3)。
5.11 the preparation of 2-(3-cyanic acid-4-is to the methyl benzyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-11)
With (CSL-4-12) is raw material, and the preparation method gets white solid powder 0.69g, yield with (CSL-HI-6): 71.9%, and mp:199.2-199.8 ℃.
MS(ESI):m/z?364.1292[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.81（s,1H,COOH）,8.58(s,1H,Ar-H),8.51(d,1H,J=8.9Hz，Ar-H),7.60(d,1H,J=9.1Hz,Ar-H),7.39(d,2H,J=8.0Hz,Ar-H),7.24(d,2H,J=7.9Hz,Ar-H),5.33(s,2H,CH
2),2.51(s,3H,CH
2),2.32(s,3H,CH
3)。
The preparation of embodiment 6.2-(3-cyanic acid-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5)
6.1 the preparation of 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group-4-base-1H-imidazoles-5-ethyl formate (CSL-5-6)
With 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (1.5g, 4.37mmol), Anhydrous potassium carbonate (1.2g, 8.74mmol) and DMF (6ml) add in the 25ml reaction flask; Finish, ice bath drips methyl-sulfate down, drips and finishes stirring reaction 1.5h under the room temperature; The completeness of TLC detection reaction, reaction is finished, and reaction solution is poured in the 50ml water; Stir 20min under the room temperature, suction filtration, re-crystallizing in ethyl acetate; Get pale solid 1.45g, productive rate: 92.9%, mp:123.8-124.9 ℃.
MS(ESI):m/z?358.4[M+H]
+。
6.2 the preparation of 2-(3-cyanic acid-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-1)
With (CSL-4-2) is raw material, and the preparation method gets white solid 1.33g, productive rate: 84.7% with (csl-5-6).mp:145.1-147.4℃。
MS(ESI):m/z?330.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.27（dd,1H,J=2.3Hz&8.8Hz,Ar-H）,8.24(d,1H,J=1.9Hz,Ar-H),7.41(d,1H,J=8.9Hz，Ar-H),4.31(m,4H,CH
2),3.96(s,3H,CH
3),2.40(s,3H,CH
3),1.41(t,3H,J=6.9Hz,CH
3),1.33(t,3H,J=7.2Hz，CH
3)。
6.3 the preparation of 2-(3-cyanic acid-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-2)
With (CSL-4-3) is raw material, and the preparation method gets white solid 1.23g, productive rate: 78.8% with (CSL-5-6).mp:143.2-144.5℃。
MS(ESI):m/z?344.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.27（dd,1H,J=8.7Hz&2.3Hz，Ar-H）,8.24(s,1H,Ar-H),7.42(d,1H,J=8.8Hz,Ar-H),4.33(q,2H,J=7.2Hz,CH
2),4.19(t,2H,J=6.4Hz,CH
2),3.96(s,3H,CH
3),2.40(s,3H,CH
3),1.80(m,2H,CH
2),1.33(t,3H,J=7.1Hz,CH
3),1.03(t,3H,J=7.3Hz，CH
3)。
6.4 the preparation of 2-(3-cyanic acid-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-3)
With (CSL-4-4) is raw material, and the preparation method gets white solid 1.26g, productive rate with (csl-5-6): 80.8%, and mp:170.4-172.8 ℃.
MS(ESI):m/z?344.4[M+H]
+；
1H-MNR(300MH?z,DMSO-d
6)δppm:8.27（dd,1H,J=8.5Hz&2.3Hz,Ar-H）,8.24(d,1H,J=2.3Hz,Ar-H),7.45(d,1H,J=8.6H?z,Ar-H),4.90(m,1H,CH),4.32(q,2H,J=7.1Hz,CH
2),3.96(s,3H,CH
3),2.40(s,3H,CH
3),1.36(d,6H,J=5.9Hz,CH
3),1.31(t,3H,J=7.1H?z,CH
3)。
The preparation of (6.52-3-cyanic acid-4-n-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-4)
With (CSL-4-5) is raw material, and the preparation method gets white solid 1.35g, productive rate with (CSL-5-6): 86.5%, and mp:135.4-136.2 ℃.
MS(ESI):m/z?358.4[M+H]
+；
1H-MNR(300MH?z,DMSO-d
6)δppm:8.26（dd,1H,J=8.8Hz&2.3Hz,Ar-H）,8.24(d,1H,J=1.9Hz,Ar-H),7.42(d,1H,J=8.9H?z,Ar-H),4.32(q,2H,J=7.1Hz,CH
2),4.23(t,2H,J=6.4Hz,CH
2),3.96(s,3H,CH3),2.34(s,3H,CH
3),1.77(m,2H,CH
2),1.48(m,2H,CH
2),1.33(t,3H,J=7.1Hz,CH3),0.96(t,3H,J=7.3H?z,CH3)。
6.6 the preparation of 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-5)
With (CSL-4-6) is raw material, and the preparation method gets white solid 1.38g, productive rate with (CSL-5-6): 88.5%, and mp:122.9-123.1 ℃.
MS(ESI):m/z358.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.26（dd,1H,J=8.8Hz&2.1Hz,Ar-H）,8.24(s,1H,Ar-H),7.51(d,1H,J=9.0Hz,Ar-H),4.69(m,1H,CH),4..31(q,2H,J=6.9Hz,CH
2),3.96(s,3H,CH3),2.40(s,3H,CH
3),1.70(m,2H,CH
2),134(t,3H,J=6.9Hz,CH
3),1.31(d,3H,J=6.0Hz,CH
3),0.96(t,3H,J=7.2Hz,CH
3)
6.7 the preparation of 2-(3-cyanic acid-4-isopentyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-7)
With (CSL-4-8) is raw material, and the preparation method gets white solid 1.15g, productive rate with (CSL-5-6): 73.7%, and mp:138.1-139.6 ℃.
MS(ESI):m/z?372.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.27（dd,1H,J=8.8Hz&2.0Hz,Ar-H）,8.24(d,1H,J=2.0Hz,Ar-H),7.45(d,1H,J=8.9Hz,Ar-H),4.33(t,2H,J=7.1Hz,CH
2),4.26(t,2H,J=6.6Hz,CH
2),3.96(s,3H,CH
3),2.40(s,3H,CH
3),1.82(m,1H,CH),1.69(m,2H,CH
2),1.33(t,3H,J=7.1Hz,CH
3),0.96(d,6H,J=6.6Hz,CH
3)。
6.8 the preparation of 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-8)
With (CSL-4-9) is raw material, and the preparation method gets white solid 1.12g, productive rate with (CSL-5-6): 71.8%, and mp:118.7-120.6 ℃.
MS(ESI):m/z?386.5[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.26（dd,1H,J=8.7Hz&2.3Hz，Ar-H）,8.24(d,1H,J=2.0Hz，Ar-H),7.42(d,1H,J=8.9Hz,Ar-H),4.32(q,2H,J=7.1Hz,CH
2),4.22(t,2H,J=6.4Hz，CH
3),3.96(s,3H,CH
3),2.40(s,3H,CH
3),1.78(m,2H,CH
2),1.49-1.31(m,9H,CH
2&CH
3),0.89(t,3H,J=6.8Hz,CH
3)。
6.9 the preparation of 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-9)
With (CSL-4-10) is raw material, and the preparation method gets white solid 1.19g, productive rate with (cCSL-5-6): 76.8%, and mp:166.2-166.6 ℃.
MS(ESI):m/z400.5[M+H]
+；
1H-MNR(300MHz，DMSO-d
6)δppm:8.26（dd,1H,J=8.7Hz&2.3Hz，Ar-H）,8.24(d,1H,J=2.0Hz，Ar-H),7.42(d,1H,J=8.8Hz，Ar-H),4.32(q,2H,J=7.1Hz,CH2),4.22(t,2H,J=6.4Hz，CH
2),3.96(s,3H,CH
3),2.34(s,3H,CH
3),1.78(m,2H,CH
2),1.48-1.28(m,11H,CH
2&?CH
3),0.87(t,3H,J=6.7Hz，CH
3).
6.10 the preparation of 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-10)
With (CSL-4-11) is raw material, and the preparation method gets white solid 1.21g, productive rate with (CSL-5-6): 78.1%, and mp:165.8-167.3 ℃.
MS(ESI):m/z?414.5[M+H]
+。
6.11 the preparation of 2-(3-cyanic acid-4-is to the methyl benzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-11)
With (CSL-4-12) is raw material, and the preparation method gets white solid 1.10g, productive rate with (CSL-5-6): 70.1%, and mp:147.5-149.5 ℃.
MS(ESI):m/z405.5[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：8.27（dd,1H,J=2.1&7.2Hz，Ar-H）,8.26(s,1H,Ar-H),7.51(d,1H,J=7.2Hz，Ar-H),7.39(d,2H,J=8.1Hz,Ar-H),7.24(d,2H，j=7.8Hz，Ar-H),5.32(s,2H,CH
2),4.31(q,2H,J=7.2Hz，CH
2),3.96(s,3H,CH
3),2.40(s,3H,CH
3),2.32(s,3H,CH
3),1.33((t,3H,J=7.2Hz,CH
3)
The preparation of embodiment 7.2-(3-cyanic acid-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid
7.1 the preparation of 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-5)
With 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group base-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (1.0g, 2.8mmol), sodium hydroxide water liquid (1mol/L, 7.0ml) and THF: the mixed solvent (10ml) of absolute ethyl alcohol (1:1) adds in the 25ml reaction flask; 50 ℃ of following stirring reactions 2 hours, the completeness of TLC detection reaction, reaction is finished; Remove the part organic solvent under reduced pressure, using 5% Hydrogen chloride to transfer pH value of solution then is 1, leaves standstill 30min; Suction filtration, the filter cake seasoning is used methyl alcohol: ETHYLE ACETATE (1:2) mixed solvent recrystallization; Get white solid powder 0.64g, yield: 69.56%, mp:190.8-191.3 ℃.
MS(ESI):m/z?330.1448[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.0（s,1H,-COOH）,8.27(d,1H,J=2.2Hz,Ar-H),8.24（s,1H,Ar-H）,7.41(d,1H,J=8.8Hz,Ar-H),4.01(d,2H,J=6.4Hz,CH
2),3.96(s,3H,CH
3),2.39(s,3H,CH
3),2.10(m,1H,CH),1.03(d,6H,J=6.7Hz,CH
3)。
7.2 the preparation of 2-(3-cyanic acid-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-1)
With (CSL-5-1) is raw material, and the preparation method gets white solid powder 0.55g, yield with (CSL-MI-5): 60.4%, and mp:195.4-196.3 ℃.
MS(ESI):m/z?302.1135[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.01（s,1H,COOH）,8.26(dd,1H,J=2.0Hz?and?9.0Hz,Ar-H),8.24(s,1H,Ar-H),7.40(d,1H,J=8.9Hz,Ar-H),4.29(q,2H,J=7.0H?z,CH
2),3.95(s,3H,CH
3),2.40(s,3H,CH
3),1.41(t,3H,J=6.9H?z,CH
3)。
7.3 the preparation of 2-(3-cyanic acid-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-2)
With (CSL-5-2) is raw material, and the preparation method gets white solid powder 0.58g, yield with (CSL-MI-5): 63.0%, and mp:193.1-194.0 ℃.
MS(ESI):m/z?316.1292[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.06(s,1H,COOH),8.28(d,1H,J=2.1Hz,Ar-H),8.24(s,1H,Ar-H),7.41(d,1H,J=8.9Hz,Ar-H),4.19(t,2H,J=6.4Hz,CH
2),3.95(s,3H,CH
3),2.39(s,3H,CH
3),1.79(m,2H,CH
3),1.03(t,3H,J=7.3Hz,CH
3)。
7.4 the preparation of 2-(3-cyanic acid-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-3)
With (CSL-5-3) is raw material, and the preparation method gets white solid powder 0.60g, yield with (CSL-MI-5): 65.2%, and mp:189.0-189.3 ℃.
MS(ESI):m/z?316.1292[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.06（s,1H,Ar-H）,8.27(d,1H,J=2.2Hz,Ar-H),8.24(s,1H,Ar-H),7.40(d,1H,J=9Hz,Ar-H),4.86(m,1H,CH),3.93(s,3H,CH
3),2.39(s,3H,CH
3),1.37(d,6H,J=6.0Hz,CH
3)。
The preparation of (7.52-3-cyanic acid-4-n-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-4)
With (CSL-5-4) is raw material, and the preparation method gets white solid powder 0.67g, yield with (CSL-MI-5): 72.8%, and mp:193.1-194.0 ℃.
MS(ESI):m/z330.1448[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：8.28(s,1H,Ar-H),8.24(s,1H,Ar-H),7.41(d,1H,J=8.9Hz,Ar-H),4.23(t,2H,J=6.3Hz,CH
2),3.95(s,3H,CH
3),2.39(s,3H,CH
3),1.78(m,2H,CH
2),1.50(m,2H,CH
2),0.96(t,3H,J=7.3Hz,CH
3)。
7.6 the preparation of 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-6)
With (CSL-5-5) is raw material, and the preparation method gets white solid powder 0.62g, yield with (CSL-MI-5): 67.4%, and mp:181.5-182.3 ℃.
MS(ESI):m/z?330.1448[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.06（s,1H,COOH）,8.27(s,1H,,Ar-H),8.24(s,1H,Ar-H),7.44(d,1H,J=8.8Hz,Ar-H),4.69(m,1H,CH
2),3.97(s,3H,CH
3),2.39(s,3H,CH
3),1.33(d,3H,J=5.9Hz,CH
3),0.97(t,3H,J=7.3Hz,CH
3)。The preparation of (7.72-3-cyanic acid-4-isopentyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-7)
With (CSL-5-7) is raw material, and the preparation method gets white solid powder 0.58g, yield with (CSL-MI-5): 63.0%, and mp:191.3-191.9 ℃.
MS(ESI):m/z?344.1605[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.06(s,1H,COOH),8.27(dd,1H,J=8.9Hz?and2.2Hz,Ar-H),8.24(d,1H,J=2.0Hz,Ar-H),7.44(d,1H,J=8.9Hz,Ar-H),4.25(t,3H,J=6.5H?z,CH
2),3.95(s,3H,CH
3),2.40(s,3H,CH
3),1.86(m,1H,CH),1.70(m,2H,CH
2),0.96(d,6H,J=6.6Hz,CH
3)。
The preparation of (7.82-the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-8)
With (CSL-5-8) is raw material, and the preparation method gets white solid powder 0.60g, yield with (CSL-MI-5): 64.5%, and mp:192.8-193.9 ℃.
MS(ESI):m/z?358.1761[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:13.02(s,1H,COOH),8.26(dd,1H.J=2.2Hz?and?9.0Hz,Ar-H),8.23(d,1H,J=2.0Hz,Ar-H),7.41(d,1H,J=8.9H?z,Ar-H),4.22(t,2H,J=6.4Hz,CH
2),3.95(s,3H,CH
3),2.39(s,3H,CH
3),1.78(m,2H,CH
2),1.46(m,2H,CH
2),1.32(m,4H,CH
2),0.89(t,3H,J=6.8Hz,CH
3)。
7.9 the preparation of 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-9)
With (CSL-5-9) is raw material, and the preparation method gets white solid powder 0.59g, yield with (CSL-MI-5): 63.4%, and mp:193.9-194.2 ℃.
MS(ESI):m/z372.1918[M+H]
+；
1H-MNR(600MHz,DMSO-d
6)δppm:13.05（s,1H,COOH）,8.26(dd,1H,J=2.2Hz?and?9.0Hz,Ar-H),8.23(d,1H,J=2.2Hz,Ar-H),7.41(d,1H,J=9.0Hz,Ar-H),4.21(t,2H,J=6.4Hz,CH
2),3.95(s,3H,CH
3),2.40(s,3H,CH
3),1.79(m,2H,CH
2),1.45(m,2H,CH
2),1.36(m,2H,CH2),1.28(m,4H,CH
2),0.87(t,3H,J=6.7Hz,CH
3)。
7.10 the preparation of 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-10)
With (CSL-5-10) is raw material, and the preparation method gets white solid powder 0.62g, yield with (CSL-MI-5): 66.7%, and mp:188.6-189.8 ℃.
MS(ESI):m/z?386.2074[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δpp?m:13.06（s,1H,COOH）,8.26(dd,1H,J=2.2Hz?and?8.9Hz,Ar-H),8.23(d,1H,J=2.0Hz,Ar-H),7.41(d,1H,J=8.9Hz,Ar-H),4.21(t,3H,J=6.4Hz,CH
2),3.95(s,3H,CH
3),2.39(s,3H,CH
3),1.78(m,2H,CH
3),1.45-1.27(m,10H,CH
3),0.86(t,3H,J=6.3Hz,CH
3)。
7.11 the preparation of 2-(3-cyanic acid-4-is to the methyl benzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-11)
With (CSL-5-11) is raw material, and the preparation method gets white solid powder 0.54g, yield with (CSL-MI-5): 58.1%, and mp:189.0-190.1 ℃.
MS(ESI):m/z?378.1148[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.31（s,1H,Ar-H）,8.30(dd,1H,J=2.2Hz?and?8.1Hz,Ar-H),7.55(d,1H,J=9.8Hz，Ar-H),7.40(d,2H,J=8.0Hz,Ar-H),7.25(d,2H,J=7.9Hz,Ar-H),5.34(s,2H,CH
2),3.98(s,3H,CH
3),2.50(s,3H,CH
3),2.32(s,3H,CH
3)。
The preparation of embodiment 8.2-(3-cyanic acid-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6)
8.1 the preparation of 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-2)
With 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (2.0g, 5.824mol), trimethylchlorosilane (2.5g, 23.298mmol); Soiodin (3.5g, 23.298mmol) and anhydrous acetonitrile (12ml) add in the 50ml reaction flask nitrogen protection refluxed reaction 6h, the completeness of TLC detection reaction; Reaction is finished, and reaction solution is put and is chilled to room temperature, suction filtration, and filter cake is washed 2-3 time with methyl alcohol; Get filtrate decompression and be concentrated into driedly, add under 20% sodium hydroxide water liquid (10ml) room temperature and stir 1h, suction filtration, re-crystallizing in ethyl acetate; Get white solid powder 1.68g, yield: 70.6%, mp:219.2-220.9 ℃
+
MS(ESI):m/z?328.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：8.53（d,1H,J=2.1Hz,Ar-H）,8.43(dd,1H,J=2.2&8.9Hz，Ar-H),7.48(d,1H,J=9.0Hz,Ar-H),4.35(q,2H,J=7.1Hz,CH
2),4.03(d,2H,J=6.5Hz,CH
2),2.56(s,3H,CH3),2.10(m,1H,CH),1.34(t,3H,J=7.1Hz,CH
3),1.02(d,6H,J=6.7Hz，CH
3)。
8.2 the preparation of 2-(3-cyanic acid-4-n-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-1)
With (CSL-4-5) is raw material, and the preparation method gets white solid powder 1.72g, yield with (CSL-6-2): 72.3%, and 198.7-200.6 ℃.
MS(ESI):m/z?328.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：8.23（s,1H,Ar-H）,8.20(s,1H,Ar-H),7.31(d,1H,J=8.6Hz，Ar-H),4.22(q,2H,J=7.1Hz,CH
2),4.18(t,2H,J=6.6Hz,CH
2),2.44(s,3H,CH
3),1.75(m,2H,CH
2),1.52(m,2H,CH
3),1.29(t,3H,J=7.1Hz,CH
3),0.96((t,3H,J=7.3Hz,CH
3)。
8.3 the preparation of 2-(3-cyanic acid-4-sec.-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-3)
With (CSL-4-6) is raw material, and the preparation method gets white solid powder 1.69g, yield with (CSL-6-2): 71.0%, and mp:192.4-194.3 ℃.
MS(ESI):m/z?328.2[M+H]
+。
8.4 the preparation of 2-(3-cyanic acid-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-4)
With (CSL-4-8) is raw material, and the preparation method gets white solid powder 1.74g, yield with (CSL-6-2): 72.8%, and mp:148.8-149.3 ℃.
MS(ESI):m/z?342.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:12.88(s,1H,NH),8.25（s,1H,Ar-H），8.22(s,1H,Ar-H),7.39(d,1H,J=8.9Hz,Ar-H),4.27(q,2H,J=6.9Hz,CH
2),4.22(t,2H,J=6.9Hz,CH
2),2.47(s,3H,CH
3),1.81(m,1H,CH),1.68(q,2H,J=6.4Hz,CH
2),1.30(t,3H,J=7.1Hz,CH
3),0.95((d,6H,J=6.6Hz,2CH
3)。
8.5 the preparation of 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-5)
With (CSL-4-9) is raw material, and the preparation method gets white solid powder 1.69g, yield with (CSL-6-2): 70.7%, and mp:151.2-152.0 ℃.
MS(ESI):m/z?356.4[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm：10.51(s,1H,NH)8.15（s,1H,Ar-H），8.12(d,1H,J=7.0Hz,Ar-H),7.64(d,1H,J=8.3Hz,Ar-H),4.38(q,2H,J=7.1Hz,CH
2),4.11(t,2H,J=6.3Hz,CH
2),2.56(s,3H,CH
3),1.87(m,2H,CH),1.48(m,2H,CH
2),1.45-1.34(m,7H,CH
2&CH
3),0.91(t,3H,J=6.9Hz,CH
3)。
8.6 the preparation of 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-6)
With (CSL4-10) is raw material, and the preparation method gets white solid powder 1.65g, yield with (CSL-6-2): 68.7%, and mp:166.3-167.2 ℃.
MS(ESI):m/z?370.5[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.28（s,1H,Ar-H）,8.24(dd,1H,J=2.1&8.8Hz,Ar-H),7.64(d,1H,J=8.9Hz,Ar-H),4.27(q,2H,J=7.1Hz,CH
2),4.19(d,2H,J=6.4H?z,CH
2),2.47(s,3H,CH
3),1.77(m,2H,CH
2),1.47-1.28(d,11H,CH
2&CH
3),0.87(t,3H,J=6.7Hz,CH
3)。
8.7 the preparation of 2-(3-cyanic acid-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-7)
With (CSL-4-11) is raw material, and the preparation method gets white solid powder 1.56g, yield with (CSL-6-2): 65.0%, and mp:162.1-163.7 ℃.
MS(ESI):m/z?384.5[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:12.81(s,1H,NH)，8.34（d,1H,J=8.8Hz,Ar-H）,8.16(d,1H,J=1.9Hz,Ar-H),7.37(d,1H,J=9.3Hz,Ar-H),4.25(q,2H,J=6.9Hz,CH
2),4.19(t,2H,J=6.4Hz,CH
2),2.50(s,3H,CH
3),1.77(m,2H,CH),1.45(m,2H,CH
2),1.31-1.26(m,11H,CH
2&CH
3),0.86(t,3H,J=6.8Hz,CH
3)。
The preparation of embodiment 9.2-(3-cyanic acid-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid
9.1 the preparation of 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-2)
With 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (1.0g, 3.1mmol), sodium hydroxide water liquid (1mol/L; 4.6ml) and THF: the mixed solvent (10ml) of absolute ethyl alcohol (1:1) adds in the 25ml reaction flask, and stirring reaction is 36 hours under refluxing, and removes the part organic solvent under reduced pressure; Using 5% Hydrogen chloride to transfer pH value of solution then is 3, leaves standstill 30min, suction filtration; The filter cake seasoning, use methyl alcohol: ETHYLE ACETATE (1:2) mixed solvent recrystallization gets white solid powder 0.27g; Yield: mp:29.7%, 234.6-235.4 ℃.
MS(ESI):m/z?300.1314[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.45(d,1H,J=1.9Hz,Ar-H),8.36(dd,1H,J=2.0Hz?and?8.9Hz,Ar-H),7.44(d,J=9.0Hz,Ar-H),4.01(d,2H,J=6.5Hz,CH
2),2.50(s,3H,CH
3),2.09(m,1H,CH),1.02(d,6H,J=6.7Hz,CH
3)
9.2 the preparation of 2-(3-cyanic acid-4-n-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-1)
With (CSL-8-1) is raw material, and the preparation method gets white solid powder 0.22g, yield with (CSL-I-2): 24.2%, and mp:218.1-218.8 ℃.
MS(ESI):m/z?300.1314[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.47(d,1H,J=2.1Hz,Ar-H),8.38(dd,1H,J=2.1Hz?and?8.9Hz,Ar-H),7.46(d,1H,J=9.0Hz,Ar-H),4.24(t,2H,J=6.4Hz,CH
2),2.51(s,3H,CH
3),1.77(m,2H,CH
2),1.47(m,2H,CH
2),0.96(t,3H,J=7.4Hz,CH
3)。
9.3 the preparation of 2-(3-cyanic acid-4-sec.-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-3)
With (CSL-8-3) is raw material, and the preparation method gets white solid powder 0.26g, yield with (CSL-I-2): 28.6%, and mp:218.1-218.5 ℃.
MS(ESI):m/z?300.1314[M+H]
+；
1H-MNR(600MHz,DMSO-d
6)δppm:12.88（s,1H,Ar-H）,12.49(s,1H,-COOH),8.29(s,1H,Ar-H),8.24(d,1H,J=7.9Hz,Ar-H),7.39(d,1H,J=9.1Hz,Ar-H),4.66(m,1H,C?H),2.45(s,3H,CH
3),1.69(m,2H,CH
2),1.31(d,3H,J=6.1Hz,CH
3),0.96(t,3H,J=7.4Hz,CH
3)。
9.4 the preparation of 2-(3-cyanic acid-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-4)
With (CSL-8-4) is raw material, and the preparation method gets white solid powder 0.24g, yield with (CSL-I-2): 26.1%, and mp:207.1-207.7 ℃.
MS(ESI):m/z?314.1499[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:8.46(d,1H,J=2.0Hz,Ar-H),8.38(dd,1H,J=2.0Hz?and?8.9Hz,Ar-H),7.45(d,1H,J=9.0Hz,Ar-H),4.25(t,2H,J=6.5Hz,CH
2),2.51(s,3H,CH
3),1.81(m,1H,CH
3),1.68(q,2H,J=6.4Hz,CH
2),0.96(d,6H,J=6.5Hz,CH
3)。
9.5 the preparation of 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-5)
With (CSL-8-5) is raw material, and the preparation method gets white solid powder 0.26g, yield with (CSL-I-2): 28.3%, and mp:216.3-216.5 ℃.
MS(ESI):m/z?328.1656[M+H]
+；
1H-MNR(600MH?z,DMSO-d
6)δpp?m:13.08（s,1H,-COOH）,8.38(d,1H,J=1.4Hz,Ar-H),8.31(dd,1H,J=1.8Hz?and?8.9Hz,Ar-H),7.40(d,1H,J=8.9Hz,Ar-H),4.21(t,2H,J=6.4Hz,CH
2),2.48(s,3H,CH
3),1.77(m,2H,CH
2),1.45(m,2H,CH
2),1.35-1.30(m,4H,CH
2),0.89(t,3H,J=7.0Hz,CH
3)。
9.6 the preparation of 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-6)
With (CSL-8-6) is raw material, and the preparation method gets white solid powder 0.28g, yield with (CSL-I-2): 30.0%, and mp:217.1-217.7 ℃.
MS(ESI):m/z?342.1812[M+H]
+；
1H-MNR(600MHz,DMSO-d
6)δpp?m:13.5（s,1H,-COOH）,8.46(s,1H,Ar-H),8.37(d,1H,J=8.9H?z,Ar-H),7.45(d,1H,J=8.9Hz,Ar-H),4.22(t,2H,J=6.4Hz,CH
2),2.51(s,3H,CH
3),1.78(m,2H,CH
2),1.45(m,2H,CH
2),1.35(m,2H,CH
2),1.32-1.29(m,4H,CH
2)0.87(t,3H,J=6.9Hz,CH
3)。
9.7 the preparation of 2-(3-cyanic acid-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-7)
With (CSL-8-7) is raw material, and the preparation method gets white solid powder .023g, yield with (CSL-I-2): 24.7%, and mp:216.5-217.3 ℃.
MS(ESI):m/z?356.1969[M+H]
+；
1H-MNR(300MHz,DMSO-d
6)δppm:12.76（s,1H,-COOH）,8.31(s,1H,Ar-H),8.26(d,1H,J=8.9Hz,Ar-H),7.31(d,1H,J=8.9Hz,Ar-H),4.18(t,2H,J=6.3Hz,CH
2),2.45(s,3H,CH
3),1.76(m,2H,CH
2),1.43(m,2H,CH
2),1.39-1.26(s,8H,CH
2),0.85(t,3H,J=6.7Hz,CH
3)。
The preparation of embodiment 10. Compound C SL-HI-6 tablets
Prescription is formed and content
Coating fluid prescription:
Opadry (03B28796) 21g
95% ethanol is an amount of
Process about 430ml
Technology
The auxiliary material of crossing 100 mesh sieves is crossed 60 mesh sieves with main ingredient mix, with 95% ethanol system softwood, granulate with 18 mesh sieves, 60 ℃ of air seasonings mix with Magnesium Stearate with the whole grain of 16 mesh sieves back, charge and attack sheet with Φ 6mm scrobicula.
The preparation of dressing solution: in appropriate vessel, add 95% an amount of ethanol, start stirrer, join Opadry (03B28796) pressed powder of recipe quantity in the vortex uniformly; Avoided powder to swim in fluid surface simultaneously as far as possible, in case of necessity, can improve rotating speed to keep suitable vortex; After treating that all Opadries (03B28796) all add, reduce stirring velocity, vortex is disappeared; Continue to stir 45min, promptly get.
The preparation of thin membrane coated tablet: label is put in the coating pan, kept 60 ℃ ± 5 ℃ of temperature, carry out dressing, promptly get.
The xanthine oxidase inhibitory activity research of embodiment 11. target compounds
1. test materials
1.1 reagent: XOD, xanthine, trisodium phosphate, EDTA Disodium.
1.2 instrument: electronic analytical balance (AR1140 type), electric-heated thermostatic water bath (DK-98-1 type), desk centrifuge (TDL80-2B type), ultraviolet-visible pectrophotometer (WFZ UV-2000 type)
1.3 given the test agent (code name): positive drug FBST, WSJ-00545 ~ WSJ-00573
2. experimental technique:
2.1 medicine collocation method
Compound is dissolved into the 10mM mother liquor with 10%KOH solution, faces the time spent with the reaction diluted, joins existing usefulness at present.The enzyme activity detection method
Preparation reaction diluent: 0.1mol/L trisodium phosphate 0.3mmol/L EDTA disodium, pH value 8.3.
XOD is purchased to sigma, faces the time spent with reaction diluted, XOD 25U/L in the reaction system, xanthine 200 μ mol/L.Add XOD during reaction successively, receive the reagent thing (positive drug adopts Febuxostat FBST-00), 25 ℃ hatch and add xanthine, 25 ℃ behind the 15min and hatch behind the 2h and 295nm place detection absorbancy, blank control group adopts corresponding drug solvent as contrast.
2.2 statistical method
All data adopt the analysis of testing of SPSS (17.0) statistical packages.The result representes that with MV ± standard error mean relatively carries out the homoscedasticity analysis between group, and carry out Dunnett ' s test analytical procedure organize between relatively
3. experimental result:
Experimental result shows that 29 target compound major parts of institute's synthetic demonstrate stronger xanthine oxidase inhibitory activity (experimental data is seen table 1).
Table 129 kind of sample 10 μ g/ml are to the influence (M+SE) of xanthine oxidase activity
*, compare P＜0.05 with solvent control group; * compares P＜0.01 with solvent control group; * * compares P＜0.001 with solvent control group.
Claims (8)
1. have the compound or the pharmacy acceptable salt of xanthine oxidase inhibitory activity, it is characterized in that: such structural general formula is suc as formula shown in I, II, the III:
Wherein: R is methyl or ethyl or n-propyl or sec.-propyl or normal-butyl or isobutyl-or sec.-butyl or isopentyl or n-hexyl or n-heptyl or n-octyl or 4-methyl-benzyl.
2. according to described compound or the pharmacy acceptable salt with xanthine oxidase inhibitory activity of claim 1, it is characterized in that: this compounds is any in following compound (1) ~ (29):
(1) 2-(3-cyanic acid-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-1),
(2) 2-(3-cyanic acid-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-2),
(3) 2-(3-cyanic acid-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-3),
(4) 2-(3-cyanic acid-4-n-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-4),
(5) 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-5),
(6) 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-6),
(7) 2-(3-cyanic acid-4-isopentyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-7),
(8) 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-8),
(9) 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-9),
(10) 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-10),
(11) 2-(3-cyanic acid-4-is to the methyl benzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-11),
(12) 2-(3-cyanic acid-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-1),
(13) 2-(3-cyanic acid-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-2),
(14) 2-(3-cyanic acid-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-3),
(15) 2-(3-cyanic acid-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-4),
(16) 2-(3-cyanic acid-4-sec.-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-5),
(17) 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-6),
(18) 2-(3-cyanic acid-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-7),
(19) 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-8),
(20) 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-9),
(21) 2-(3-cyanic acid-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-10),
(22) 2-(3-cyanic acid-4-methyl-benzyl) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-11),
(23) 2-(3-cyanic acid-4-n-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-1),
(24) 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-2),
(25) 2-(3-cyanic acid-4-sec.-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-3),
(26) 2-(3-cyanic acid-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-4),
(27) 2-(the positive hexyloxy of 3-cyanic acid-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-5),
(28) 2-(3-cyanic acid-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-6),
(29) 2-(3-cyanic acid-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-7).
3. one kind prepares claim 1 or 2 and describedly has the compound of xanthine oxidase inhibitory activity or a midbody of pharmacy acceptable salt, and this midbody comprises 2-(3-cyanic acid-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyanic acid-4-alkoxyl group) phenyl-1-hydroxyl base-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyanic acid-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-manthanoate.
4. according to the described midbody of claim 3, it is characterized in that: said ester is methyl esters or ethyl ester or propyl ester or the tert-butyl ester or benzyl ester or to methyl benzyl ester.
5. claim 1 or 2 described miaows have the preparation method of the compound or the pharmacy acceptable salt of xanthine oxidase inhibitory activity, it is characterized in that:
1) be starting raw material with the 4-hydroxy benzaldehyde; Obtain 3-bromo-4-hydroxy benzaldehyde through bromo; Carry out alkylation reaction with hydrobromic ether and obtain 3-bromine 4--oxyl phenyl aldehyde; Obtain 3-cyanic acid-4--oxyl phenyl aldehyde with cuprous cyanide reaction again, and then with 2-(hydroxyl imide base)-3-oxobutanoic acid esters ring with, obtain 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate;
2) 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate makes the series compound shown in the formula I through hydrolysis reaction;
3) 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate methylates with methyl-sulfate; Make 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate; Through hydrolysis reaction, make the series compound shown in the general formula II;
4) 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate makes 2-(3-cyanic acid-4-hydrocarbon oxygen phenyl)-4-methyl isophthalic acid H-imidazoles-5-manthanoate with trimethylammonium halosilanes and iodized salt dehydroxylation; Through hydrolysis reaction, make the series compound shown in the general formula III.
6. pharmaceutical composition, it includes the compound with xanthine oxidase inhibitory activity or pharmacy acceptable salt and acceptable accessories, thinner and carrier described in claim 1 or 2.
7. according to the described pharmaceutical composition of claim 6; It is characterized in that: having the compound of xanthine oxidase inhibitory activity or the weight percent of pharmacy acceptable salt in the said composition is 5%-20%, and acceptable auxiliary, thinner and carrier are surplus.
A treatment with (or) prevention hyperuricemia and goat medicine, it includes compound with xanthine oxidase inhibitory activity or pharmacy acceptable salt described in claim 1 or 2.
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| PCT/CN2013/073327 WO2014023104A1 (en) | 2012-08-07 | 2013-03-28 | Compound with xanthine oxidase inhibitory activity and salt thereof, preparation method and usage for the same |
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| WO2014023104A1 (en) * | 2012-08-07 | 2014-02-13 | 沈阳药科大学 | Compound with xanthine oxidase inhibitory activity and salt thereof, preparation method and usage for the same |
| CN106282136A (en) * | 2015-06-01 | 2017-01-04 | 中国药科大学 | Xanthine oxidase B cell epi-position and the antigenic peptides comprising this epi-position and application thereof |
| CN106674098A (en) * | 2016-12-23 | 2017-05-17 | 中国医科大学 | N-(3-cyano-4-alkoxyphenyl) pyridine carboxamide compound and application thereof |
| CN106892871A (en) * | 2015-12-18 | 2017-06-27 | 中国科学院上海药物研究所 | One class 4,5- disubstituted imidazole derivatives and its production and use |
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| CN106892871A (en) * | 2015-12-18 | 2017-06-27 | 中国科学院上海药物研究所 | One class 4,5- disubstituted imidazole derivatives and its production and use |
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| CN106674098A (en) * | 2016-12-23 | 2017-05-17 | 中国医科大学 | N-(3-cyano-4-alkoxyphenyl) pyridine carboxamide compound and application thereof |
| CN108072712A (en) * | 2017-01-22 | 2018-05-25 | 中国医科大学附属第医院 | The blood concentration quantitative analysis method of noval chemical compound WSJ-557 in a kind of SD rat plasmas |
| CN108689948A (en) * | 2018-06-04 | 2018-10-23 | 沈阳药科大学 | 6- (3,4- substituted-phenyls) -2- mercaptopyrimidine -4- formic acid compounds and its preparation method and application |
| CN108689948B (en) * | 2018-06-04 | 2021-08-24 | 沈阳药科大学 | 6- (3, 4-substituted phenyl) -2-mercaptopyrimidine-4-formic acid compound and preparation method and application thereof |
| CN108929275A (en) * | 2018-06-14 | 2018-12-04 | 沈阳药科大学 | 6- (3,4- substituted-phenyl) -3- oxo -2,3- dihydrogen dazin -4- hydrazide kind compound and application thereof |
| CN108929275B (en) * | 2018-06-14 | 2021-08-24 | 沈阳药科大学 | 6- (3, 4-substituted phenyl) -3-oxo-2, 3-dihydropyridazine-4-hydrazide compound and application thereof |
| CN108484494A (en) * | 2018-06-15 | 2018-09-04 | 沈阳药科大学 | 2- oxo -1,2- dihydropyridine -4- formic acid compounds |
| CN108484494B (en) * | 2018-06-15 | 2021-07-30 | 沈阳药科大学 | 2-oxo-1, 2-dihydropyridine-4-carboxylic acid compounds |
| CN110204494A (en) * | 2019-07-01 | 2019-09-06 | 华南理工大学 | Oxygen substituted-phenyl imidazoles XOR/URAT1 double inhibitor and preparation and application |
| CN110204494B (en) * | 2019-07-01 | 2023-03-24 | 华南理工大学 | Oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitor and preparation and application thereof |
| CN114105881A (en) * | 2020-08-31 | 2022-03-01 | 沈阳海诺威医药科技有限公司 | Platelet aggregation inhibitor and preparation method and application thereof |
| CN114105881B (en) * | 2020-08-31 | 2024-01-26 | 沈阳海诺威医药科技有限公司 | Platelet aggregation inhibitor, and preparation method and application thereof |
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| Publication number | Publication date |
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| WO2014023104A1 (en) | 2014-02-13 |
| CN102766099B (en) | 2015-09-23 |
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