CN102766099B - There is compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity - Google Patents

There is compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity Download PDF

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CN102766099B
CN102766099B CN201210279511.2A CN201210279511A CN102766099B CN 102766099 B CN102766099 B CN 102766099B CN 201210279511 A CN201210279511 A CN 201210279511A CN 102766099 B CN102766099 B CN 102766099B
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csl
phenyl
imidazoles
cyano group
methyl
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CN102766099A (en
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王绍杰
苑振亭
张廷剑
陈绍磊
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Shenyang Pharmaceutical University
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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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

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Abstract

The present invention relates to the compound and salt, preparation method and purposes with xanthine oxidase inhibitory activity, this compounds has such as formula the structure shown in I, II, III:

Description

There is compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity
Technical field
The invention belongs to medical art, be specifically related to compound and salt, preparation method and the purposes with xanthine oxidase inhibitory activity.
Background technology
Gout (Gout) is one group of heterogeneous, metabolism class disease because long-term hyperuricemia (Hyperuricemia) causes urate deposition to be formed in joint and soft tissue.Normal male blood uric acid is 150-380 μm of ol/L, and Menopause was 100-300 μm of ol/L in the past, and after climacterium, its value is close to the male sex.When 37 DEG C, the saturation concentration of serum uric acid is about 416 μm of ol/L, is hyperuricemia higher than this value.Hyperuricemia is the biochemical basis of goat.
The sickness rate of gout in general population is 1%-2%, and the sickness rate of developed country is higher, and the sickness rate of Britain and Germany reaches 1.4%.Second largest metabolism class disease (Clin.2003,25:1593-1610) being only second to diabetes in the world has been become according to related documents report gout.China is 1980 time or the rarely found country of goat, 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, 1.1%(The Journal of Foot and Ankle Surgery 48 (1): 70-73. is reached at population to China's prevalence of gout in 2008), bring huge pressure and heavy economical load to society.
XOD (Xanthine oxidase in purine metabolism process, XO) be the key enzyme of uricogenesis, in the final stage of purine metabolism, xanthine generates uric acid under the effect of XOD, therefore suppresses the activity of XOD effectively can reduce the generation of uric acid.In the treatment of hyperuricemia and gout, xanthine oxidase inhibitor occupies very important status, the mechanism of action of such medicine mainly suppresses the activity of XOD thus effectively can reduce the generation of uric acid, thus plays treatment hyperuricemia and pain wind action.
In view of gout treatment medicament categories is in the market very limited, the anti-gout drugs of development high-efficiency low-toxicity is significant.
Summary of the invention
The object of this invention is to provide the compound and salt, preparation method and purposes with xanthine oxidase inhibitory activity.
The invention provides the compound or pharmacy acceptable salt with xanthine oxidase inhibitory activity, the general structure of this compounds as shown in Figure 1, 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 the pharmacy acceptable salt with xanthine oxidase inhibitory activity provided by the invention, this compounds is any one in following compound (1) ~ (29):
(1) 2-(3-cyano group-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-1),
(2) 2-(3-cyano group-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-2),
(3) 2-(3-cyano group-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-3),
(4) 2-(3-cyano group-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-cyano group-4-sec-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-6),
(7) 2-(3-cyano group-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-cyano group-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-8),
(9) 2-(3-cyano group-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-cyano group-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-10),
(11) 2-(3-cyano group-4-is to methylbenzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-11),
(12) 2-(3-cyano group-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-1),
(13) 2-(3-cyano group-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-2),
(14) 2-(3-cyano group-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-3),
(15) 2-(3-cyano group-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-4),
(16) 2-(3-cyano group-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-cyano group-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-7),
(19) 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-8),
(20) 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-9),
(21) 2-(3-cyano group-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-10),
(22) 2-(3-cyano group-4-methyl-benzyl) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-11),
(23) 2-(3-cyano group-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-cyano group-4-sec-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-3),
(26) 2-(3-cyano group-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-4),
(27) 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-5),
(28) 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-6),
(29) 2-(3-cyano group-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-7).
Present invention also offers and described have the compound of xanthine oxidase inhibitory activity or the intermediate of pharmacy acceptable salt a kind of preparation, this intermediate comprises 2-(3-cyano group-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyano group-4-alkoxyl group) phenyl-1-hydroxyl base-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyano group-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-manthanoate; Wherein, described ester is methyl esters or ethyl ester or propyl ester or the tert-butyl ester or benzyl ester or to methyl benzyl ester.
Present invention also offers a kind of described miaow and have the compound of xanthine oxidase inhibitory activity or the preparation method of pharmacy acceptable salt, step is as follows:
1) with 4-hydroxy benzaldehyde for starting raw material, the bromo-4-hydroxy benzaldehyde of 3-is obtained through bromo, carry out alkylation reaction with hydrobromic ether and obtain 3-bromine 4--oxyl phenyl aldehyde, 3-cyano group-4--oxyl phenyl aldehyde is obtained by reacting again with cuprous cyanide, and then with 2-(hydroxyl imide base)-3-oxobutanoic acid esters ring and, obtain 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate;
2) 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate is through hydrolysis reaction, obtained series compound shown in formula I;
3) 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate dimethyl sulfate methylation of ester, obtained 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate, through hydrolysis reaction, obtained series compound shown in general formula II;
4) 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate trimethylammonium halosilanes and iodized salt dehydroxylation obtain 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-4-methyl isophthalic acid H-imidazoles-5-manthanoate, through hydrolysis reaction, obtained series compound shown in general formula III.
The invention provides a kind of pharmaceutical composition, it includes the described compound with xanthine oxidase inhibitory activity or pharmacy acceptable salt, and its derivative, analogue, tautomer, polymorphic form, pharmaceutically useful solvate as activeconstituents, and pharmaceutically useful auxiliary material, carrier, thinner etc.
Pharmaceutical composition containing the compounds of this invention can be prepared by ordinary method, such as, at Remington:theScience and Practice of Pharmacy, 19th Ed., describes in 1995.Said composition can be that the formulation of routine is as capsule, tablet, powder, solution, suspension, syrup, aerosol or Topical application forme.They can contain suitable solid or liquid vehicle, or form injection solution or suspension in suitable sterile media.Said composition can contain the active compound of 5-20%, preferably 0.5-10% weight, and surplus is pharmaceutically useful carrier, excipient, thinner, solvent etc.
Typical composition contains formula I, and II, the compound shown in III or its solvate, and pharmaceutically useful excipient, it can be carrier or thinner, or loaded body dilution, or being wrapped in carrier, it can be the form of capsule, pouch, paper or other container.When the carrier serves as a diluent, it can be solid, semisolid or liquid substance, and it can as the carrier of active compound, excipient or medium.This active compound can be absorbed with the form of the particulate solid in container such as pouch.Some carriers be applicable to are water, salts solution, alcohol, polyoxyethylene glycol, poly-hydroxyl-oxethyl Viscotrol C, peanut oil, coconut palm pulls oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose starch, Magnesium Stearate (magnesium sterate), talcum, gelatin, agar, pectin, gum arabic, stearic acid or cellulosic lower alkyl ether, silicic acid, lipid acid, fatty acid amine, fatty mono glyceride and triglyceride, Ji Chengsi alcohol fatty acid ester, polyoxyethylene, hydroxy-methyl cellulose and polyvinylpyrrolidone.Similarly, carrier or thinner can comprise any slow-release material known in the art, and as glyceryl monostearate or distearin, it is used alone or mixes with wax.Wetting agent can also be comprised, emulsifying agent, suspensoid, sanitas, sweeting agent or sweetener in preparation.Oneself knows by this area method can prepare preparation of the present invention, with provide after delivery of active ingredients patient quick, continue or delayed release.
This pharmaceutical composition can be aseptic, and if need to mix, as long as it does not react with active compound with assistant agent, emulsifying agent, buffer reagent and (or) tinting material etc.
Can with any administration, as long as active medicine is sent to suitable or required reactive site by effectively, such as oral, nasal cavity, through skin, lung, or administered parenterally, such as, in rectum, reservoir, subcutaneous, intravenously, urethra, in intramuscular, nose, ophthalmic solution or ointment, preferably by oral administration.
If solid carrier is used for oral administration, said preparation can be pressed into tablet, or in incapsulating with powder or pellet form, or make lozenge or lozenge.If use liquid vehicle, said preparation can be syrup, emulsion, soft gelatin capsule or aseptic parenteral solution, as water-based or non-aqueous liquid suspension or solution.
For intranasal administration, said preparation can containing dissolving or being suspended in liquid vehicle, and the type I compound especially in aqueous carrier, as Aerosol administration.This carrier can contain additive, comprises solubilizing agent as propylene glycol, tensio-active agent, and absorption enhancer is as Yelkin TTS (phosphatide phenol choline) or cyclodextrin, or sanitas is as parabens.
For administered parenterally, it is particularly suitable that injection solution or suspension, the aqueous solution of preferred active compound solvent in polyhydroxylated Viscotrol C.
There is the tablet of talcum and (or) carbohydrate carrier or tackiness agent etc., drageeing or capsule and be particularly suitable for oral administration.Preferably, the carrier of tablet, drageeing or capsule comprises lactose, W-Gum and (or) yam starch.When sweetened vehicle can be used, syrup or agent of indulging in can be used.
The invention provides a kind for the treatment of and (or) prevent hyperuricemia and goat medicine, it includes the described compound with xanthine oxidase inhibitory activity or pharmacy acceptable salt.
Accompanying drawing explanation
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
The following examples will be further described the present invention, but not thereby limiting the invention.
According to flow process preparation as shown in Figure 1.
The preparation of the bromo-4-hydroxy benzaldehyde (CSL-1) of embodiment 1.3-
In 2000mL three-necked bottle, add p-Hydroxybenzaldehyde (100g, 0.820mol), iodine (5g, 0.0192mol) and methylene dichloride 600mL, mechanical stirring 10min at-5 DEG C.Bromine (143.4g, 0.902mol) and methylene dichloride (200mL) mixing solutions are slowly instilled in above-mentioned reaction solution, drips and finish, room temperature reaction 24h.Reaction is finished, and is slowly poured into by above-mentioned reaction solution in 1000mL (16%) aqueous solution of sodium bisulfite, and after stirring 30min, suction filtration, washing, dry, obtain crude product 120.0g, productive rate: 72.7%, the thick product of gained is not purified is directly used in next step reaction.
The preparation of the bromo-4-alkyloxybenzaldehydes (CSL-2) of embodiment 2.3-
The preparation of 2.1 3-bromo-4-isobutoxy phenyl aldehyde (CSL-2-7)
By bromo-for 3-4-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 100ml single port bottle; 50 DEG C of stirred under nitrogen atmosphere react 8 hours, and reaction is finished, suction filtration; filter cake DMF washes 2 times; the DMF of about 3/4 is revolved in decompression, and residue with Ethyl acetate dissolves, washing; saturated common salt is washed; anhydrous sodium sulfate drying spends the night, and revolves ethyl acetate, and the thick product of gained is not purified is directly used in next step reaction.
The preparation of 2.2 3-bromo-4-methyl methoxybenzaldehyde (CSL-2-1)
By bromo-for 3-4-hydroxy benzaldehyde (10g, 0.05mol), Anhydrous potassium carbonate (13.8g, 0.00mol) and DMF(40ml) add in 100ml reaction flask, drip methyl-sulfate (6.6g, 0.035mol) under ice bath, drip and finish, the completeness of stirred at ambient temperature reaction 2h, TLC detection reaction, reaction is finished, and is poured into by reaction solution in 100ml water, stirring at room temperature 20min, suction filtration, obtain crude product 9.7g, productive rate: 90.6%, the thick product of gained is not purified is directly used in next step reaction.
The preparation of 2.3 3-bromo-4-ethyl methoxybenzaldehyde (CSL-2-2)
Take monobromethane as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 2.4 3-bromo-4-positive propoxy phenyl aldehyde (CSL-2-3)
Take n-propyl bromide as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of the bromo-4-isopropoxide benzaldehyde (CSL-2-4) of 2.5 3-
Take bromo propane as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 2.6 3-bromo-4-n-butoxy phenyl aldehyde (CSL-2-5)
Take bromination of n-butane as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 2.7 3-bromo-4-sec-butoxy phenyl aldehyde (CSL-2-6)
Take chung-bromo butane as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 2.8 3-bromo-4-isopentyloxy phenyl aldehyde (CSL-2-8)
With bromo iso-pentane for raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 2.9 3-bromo-4-positive hexyl phenenyl formaldehyde (CSL-2-9)
With bromo normal hexane for raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of the positive heptyloxybenzaldehyde of the bromo-4-of 2.10 3-(CSL-2-10)
Take bromo heptane as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 2.11 3-bromo-4-n-octyloxy phenyl aldehyde (CSL-2-11)
Take n-octane bromide as raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The bromo-4-of 2.12 3-is to the preparation of methylbenzyloxy phenyl aldehyde (CSL-2-12)
With 4-methyl benzyl chloride for raw material, preparation method is with (CSL-2-7), and the thick product of gained is not purified is directly used in next step.
The preparation of embodiment 3.3-cyano group-4-alkyloxybenzaldehydes (CSL-3)
The preparation of 3.1 3-cyano-4-isobutoxy phenyl aldehydes (CSL-3-7)
By bromo-for 3-4-isobutoxy phenyl aldehyde (25.7g; 0.1mol); cuprous cyanide (9.9g; 0.11mol) add in 250ml reaction flask with DMF (100ml), the completeness of 150 DEG C of stirred under nitrogen atmosphere reaction 6h, TLC detection reaction; reaction is finished; reaction solution lets cool to room temperature, is added by methylene dichloride in reaction solution, suction filtration; filter cake methylene dichloride washes 2 times; get filtrate, use ammoniacal liquor successively, water; saturated common salt is washed; anhydrous sodium sulfate drying spends the night, and decompression removing methylene dichloride, the thick product of gained is not purified is directly used in next step.
The preparation of 3.2 3-cyano group-4-methyl methoxybenzaldehyde (CSL-3-1)
Take CSL-3-1 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.3 3-cyano group-4-ethyl methoxybenzaldehyde (CSL-3-2)
Take CSL-3-2 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.4 3-cyano group-4-positive propoxy phenyl aldehyde (CSL-3-3)
Take CSL-3-3 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.5 3-cyano group-4-isopropoxide benzaldehyde (CSL-3-4)
Take CSL-3-4 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.6 3-cyano group-4-n-butoxy phenyl aldehyde (CSL-3-5)
Take CSL-3-5 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.7 3-cyano group-4-sec-butoxy phenyl aldehyde (CSL-3-6)
Take CSL-3-6 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.8 3-cyano group-4-isopentyloxy phenyl aldehyde (CSL-3-8)
Take CSL-3-8 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.9 3-cyano group-4-positive hexyl phenenyl formaldehyde (CSL-3-9)
Take CSL-3-9 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of the 3.10 positive heptyloxybenzaldehyde of 3-cyano group-4-(CSL-3-10)
Take CSL-3-10 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of 3.11 3-cyano group-4-n-octyloxy phenyl aldehyde (CSL-3-11)
Take CSL-3-11 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
3.12 3-cyano group-4-are to the preparation of methylbenzyloxy phenyl aldehyde (CSL-3-12)
Take CSL-3-12 as raw material, preparation method is with (CSL-3-7), and the thick product of gained is not purified is directly used in next step.
The preparation of embodiment 4.2-(3-cyano group-4-alkoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4)
The preparation of 4.1 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-7)
By 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) add in 500ml reaction flask with acetic acid (176ml); 50 DEG C of stirred under nitrogen atmosphere react 24 hours, and reaction is finished, and adds reaction solution and is poured into water (500ml); stirred at ambient temperature 30min; suction filtration, filter cake re-crystallizing in ethyl acetate, obtains white solid powder 10.3g; yield: 69.4%, mp:147.4-148.3 DEG C.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)。
The preparation of 4.2 2-(3-cyano group-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-1)
With (CSL-3-1) for raw material, preparation method, with (CSL-4-7), obtains white solid powder 12.3g, yield: 65.8%, mp:173.2-175.1 DEG C.
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)。
The preparation of 4.3 2-(3-cyano group-4-oxyethyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-2)
With (CSL-3-2) for raw material, preparation method obtains white solid powder 9.9g with (CSL-4-7), yield: 55.0%, mp:153.5-155.8 DEG C.
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)。
The preparation of 4.4 2-(3-cyano group-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-3)
With (CSL-3-3) for raw material, preparation method obtains white solid powder 10.8g with (CSL-4-7), yield: 62.1%, mp:152.2-154.1 DEG C.
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)。
The preparation of 4.5 2-(3-cyano group-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-4)
With (CSL-3-4) for raw material, preparation method obtains white solid powder 12.2g with (CSL-4-7), yield: 70.1%, mp:150.2-151.9 DEG C.
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)。
The preparation of 4.6 2-(3-cyano group-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-5)
With (CSL-3-5) for raw material, preparation method obtains white solid powder 12.0g with (CSL-4-7), yield: 71.0%, mp:149.8-150.5 DEG C.
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)。
The preparation of 4.7 2-(3-cyano group-4-sec-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-6)
With (CSL-3-6) for raw material, preparation method obtains white solid powder 11.8g with (CSL-4-7), yield: 69.8%, mp:159.8-162.3 DEG C.
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-cyano group-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-8)
With (CSL-3-8) for raw material, preparation method obtains white solid powder 11.5g with (CSL-4-7), yield: 69.7%, mp:148.8-150.1 DEG C.
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)。
The preparation of 4.9 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-9)
With (CSL-3-9) for raw material, preparation method obtains white solid powder 10.3g with (CSL-4-7), yield: 64.1%, mp:109.3-112.8 DEG C.
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)。
The preparation of 4.10 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-10)
With (CSL-3-10) for raw material, preparation method obtains white solid powder 10.5g with (CSL-4-7), yield: 66.8%, mp:139.5-142.2 DEG C.
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)。
The preparation of 4.11 2-(3-cyano group-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-11)
With (CSL-3-11) for raw material, preparation method obtains white solid powder 11.1g with (CSL-4-7), yield: 72.1%, mp:143.2-145.1 DEG C.
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)。
The preparation of 4.12 2-(3-cyano group-4-is to methylbenzyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (CSL-4-12)
With (CSL-3-12) for raw material, preparation method, with (CSL-4-7), obtains white solid powder 10.9g, yield: 70.0%, mp:150.3-151.5 DEG C.
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-cyano group-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)
By 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 tetrahydrofuran (THF): the mixed solvent (10ml) of dehydrated alcohol (1:1) adds in 25ml reaction flask, stirring reaction 8 hours at 50 DEG C, the completeness of TLC detection reaction, reaction is finished, remove part organic solvent under reduced pressure, then pH value of solution is adjusted to be 1 with the dilute hydrochloric acid of 5%, leave standstill 30min, suction filtration, filter cake seasoning, with methyl alcohol: ethyl acetate (2:1) mixed solvent recrystallization, obtain white solid powder 0.60g, yield: 65.2%, mp:191.6-192.2 DEG C.
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)。
The preparation of 5.2 2-(3-cyano group-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-1)
With (CSL-4-1) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.50g, yield: 52.5%, mp:214.1-214.5 DEG C.
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)。
The preparation of 5.3 2-(3-cyano group-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-2)
With (CSL-4-3) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.60g, yield: 62.5%, mp:191.9-193.0 DEG C.
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)。
The preparation of 5.4 2-(3-cyano group-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-3)
With (CSL-4-4) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.62g, yield: 64.6%, mp:190.8-191.2 DEG C.
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)。
The preparation of 5.5 2-(3-cyano group-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-4)
With (CSL-4-5) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.66g, yield: 68.7%, mp:193.7-195.3 DEG C.
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)。
The preparation of 5.6 2-(3-cyano group-4-sec-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-5)
With (CSL-4-6) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.63g, yield: 65.6%, mp:190.9-191.5 DEG C.
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)。
The preparation of 5.7 2-(3-cyano group-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-7)
With (CSL-4-8) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.62g, yield: 64.6%, mp:194.7-194.9 DEG C.
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)。
The preparation of 5.8 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-8)
With (CSL-4-9) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.72g, yield: 75.0%, mp:190.8-191.1 DEG C.
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)。
The preparation of 5.9 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-9)
With (CSL-4-10) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.68g, yield: 70.8%, mp:194.3-194.9 DEG C.
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)。
The preparation of 5.10 2-(3-cyano group-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-10)
With (CSL-4-11) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.68g, yield: 70.8%, mp:186.5-187.5 DEG C.
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)。
The preparation of 5.11 2-(3-cyano group-4-is to methylbenzyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-11)
With (CSL-4-12) for raw material, preparation method, with (CSL-HI-6), obtains white solid powder 0.69g, yield: 71.9%, mp:199.2-199.8 DEG C.
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-cyano group-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5)
The preparation of 6.1 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group-4-base-1H-imidazoles-5-ethyl formate (CSL-5-6)
By 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 25ml reaction flask, finish, under ice bath, drip methyl-sulfate, drip and finish, stirred at ambient temperature reaction 1.5h, the completeness of TLC detection reaction, reaction is finished, and is poured into by reaction solution in 50ml water, stirred at ambient temperature 20min, suction filtration, re-crystallizing in ethyl acetate, obtains pale solid 1.45g, productive rate: 92.9%, mp:123.8-124.9 DEG C.
MS(ESI):m/z 358.4[M+H] +。
The preparation of 6.2 2-(3-cyano group-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-1)
With (CSL-4-2) for raw material, preparation method, with (csl-5-6), obtains white solid 1.33g, productive rate: 84.7%.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)。
The preparation of 6.3 2-(3-cyano group-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-2)
With (CSL-4-3) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.23g, productive rate: 78.8%.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)。
The preparation of 6.4 2-(3-cyano group-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-3)
With (CSL-4-4) for raw material, preparation method, with (csl-5-6), obtains white solid 1.26g, productive rate: 80.8%, mp:170.4-172.8 DEG C.
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-cyano group-4-n-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-4)
With (CSL-4-5) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.35g, productive rate: 86.5%, mp:135.4-136.2 DEG C.
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)。
The preparation of 6.6 2-(3-cyano group-4-sec-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-5)
With (CSL-4-6) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.38g, productive rate: 88.5%, mp:122.9-123.1 DEG C.
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)
The preparation of 6.7 2-(3-cyano group-4-isopentyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-7)
With (CSL-4-8) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.15g, productive rate: 73.7%, mp:138.1-139.6 DEG C.
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)。
The preparation of 6.8 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-8)
With (CSL-4-9) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.12g, productive rate: 71.8%, mp:118.7-120.6 DEG C.
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)。
The preparation of 6.9 2-(3-cyano group-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) for raw material, preparation method, with (cCSL-5-6), obtains white solid 1.19g, productive rate: 76.8%, mp:166.2-166.6 DEG C.
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).
The preparation of 6.10 2-(3-cyano group-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-10)
With (CSL-4-11) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.21g, productive rate: 78.1%, mp:165.8-167.3 DEG C.
MS(ESI):m/z 414.5[M+H] +。
The preparation of 6.11 2-(3-cyano group-4-is to methylbenzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-5-11)
With (CSL-4-12) for raw material, preparation method, with (CSL-5-6), obtains white solid 1.10g, productive rate: 70.1%, mp:147.5-149.5 DEG C.
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-cyano group-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid
The preparation of 7.1 2-(3-cyano-4-isobutoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-5)
By 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 tetrahydrofuran (THF): the mixed solvent (10ml) of dehydrated alcohol (1:1) adds in 25ml reaction flask, stirring reaction 2 hours at 50 DEG C, the completeness of TLC detection reaction, reaction is finished, remove part organic solvent under reduced pressure, then pH value of solution is adjusted to be 1 with the dilute hydrochloric acid of 5%, leave standstill 30min, suction filtration, filter cake seasoning, with methyl alcohol: ethyl acetate (1:2) mixed solvent recrystallization, obtain white solid powder 0.64g, yield: 69.56%, mp:190.8-191.3 DEG C.
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)。
The preparation of 7.2 2-(3-cyano group-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-1)
With (CSL-5-1) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.55g, yield: 60.4%, mp:195.4-196.3 DEG C.
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)。
The preparation of 7.3 2-(3-cyano group-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-2)
With (CSL-5-2) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.58g, yield: 63.0%, mp:193.1-194.0 DEG C.
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)。
The preparation of 7.4 2-(3-cyano group-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-3)
With (CSL-5-3) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.60g, yield: 65.2%, mp:189.0-189.3 DEG C.
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-cyano group-4-n-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-4)
With (CSL-5-4) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.67g, yield: 72.8%, mp:193.1-194.0 DEG C.
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)。
The preparation of 7.6 2-(3-cyano group-4-sec-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-6)
With (CSL-5-5) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.62g, yield: 67.4%, mp:181.5-182.3 DEG C.
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-cyano group-4-isopentyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-7)
With (CSL-5-7) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.58g, yield: 63.0%, mp:191.3-191.9 DEG C.
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-cyano group-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-8)
With (CSL-5-8) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.60g, yield: 64.5%, mp:192.8-193.9 DEG C.
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)。
The preparation of 7.9 2-(3-cyano group-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) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.59g, yield: 63.4%, mp:193.9-194.2 DEG C.
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)。
The preparation of 7.10 2-(3-cyano group-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-10)
With (CSL-5-10) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.62g, yield: 66.7%, mp:188.6-189.8 DEG C.
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)。
The preparation of 7.11 2-(3-cyano group-4-is to methylbenzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-11)
With (CSL-5-11) for raw material, preparation method, with (CSL-MI-5), obtains white solid powder 0.54g, yield: 58.1%, mp:189.0-190.1 DEG C.
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-cyano group-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6)
The preparation of 8.1 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-2)
By 2-(3-cyano-4-isobutoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-ethyl formate (2.0g, 5.824mol), trimethylchlorosilane (2.5g, 23.298mmol), sodium iodide (3.5g, 23.298mmol) add in 50ml reaction flask with anhydrous acetonitrile (12ml), back flow reaction 6h under nitrogen protection, the completeness of TLC detection reaction, reaction is finished, reaction solution lets cool to room temperature, suction filtration, filter cake methanol wash column 2-3 time, get filtrate reduced in volume to dry, add 20% sodium hydroxide water liquid (10ml) stirred at ambient temperature 1h, suction filtration, re-crystallizing in ethyl acetate, obtain white solid powder 1.68g, yield: 70.6%, mp:219.2-220.9 DEG C +.
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)。
The preparation of 8.2 2-(3-cyano group-4-n-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-1)
With (CSL-4-5) for raw material, preparation method, with (CSL-6-2), obtains white solid powder 1.72g, yield: 72.3%, 198.7-200.6 DEG C.
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)。
The preparation of 8.3 2-(3-cyano group-4-sec-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-3)
With (CSL-4-6) for raw material, preparation method, with (CSL-6-2), obtains white solid powder 1.69g, yield: 71.0%, mp:192.4-194.3 DEG C.
MS(ESI):m/z 328.2[M+H] +。
The preparation of 8.4 2-(3-cyano group-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-4)
With (CSL-4-8) for raw material, preparation method, with (CSL-6-2), obtains white solid powder 1.74g, yield: 72.8%, mp:148.8-149.3 DEG C.
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)。
The preparation of 8.5 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-5)
With (CSL-4-9) for raw material, preparation method, with (CSL-6-2), obtains white solid powder 1.69g, yield: 70.7%, mp:151.2-152.0 DEG C.
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)。
The preparation of 8.6 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-6)
With (CSL4-10) for raw material, preparation method, with (CSL-6-2), obtains white solid powder 1.65g, yield: 68.7%, mp:166.3-167.2 DEG C.
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)。
The preparation of 8.7 2-(3-cyano group-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-ethyl formate (CSL-6-7)
With (CSL-4-11) for raw material, preparation method, with (CSL-6-2), obtains white solid powder 1.56g, yield: 65.0%, mp:162.1-163.7 DEG C.
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-cyano group-4-alkoxyl group) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid
The preparation of 9.1 2-(3-cyano-4-isobutoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-2)
By 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 tetrahydrofuran (THF): the mixed solvent (10ml) of dehydrated alcohol (1:1) adds in 25ml reaction flask, stirred at reflux reacts 36 hours, remove part organic solvent under reduced pressure, then pH value of solution is adjusted to be 3 with the dilute hydrochloric acid of 5%, leave standstill 30min, suction filtration, filter cake seasoning, with methyl alcohol: ethyl acetate (1:2) mixed solvent recrystallization, obtain white solid powder 0.27g, yield: mp:29.7%, 234.6-235.4 DEG C.
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)
The preparation of 9.2 2-(3-cyano group-4-n-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-1)
With (CSL-8-1) for raw material, preparation method, with (CSL-I-2), obtains white solid powder 0.22g, yield: 24.2%, mp:218.1-218.8 DEG C.
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)。
The preparation of 9.3 2-(3-cyano group-4-sec-butoxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-3)
With (CSL-8-3) for raw material, preparation method, with (CSL-I-2), obtains white solid powder 0.26g, yield: 28.6%, mp:218.1-218.5 DEG C.
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)。
The preparation of 9.4 2-(3-cyano group-4-isopentyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-4)
With (CSL-8-4) for raw material, preparation method, with (CSL-I-2), obtains white solid powder 0.24g, yield: 26.1%, mp:207.1-207.7 DEG C.
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)。
The preparation of 9.5 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-5)
With (CSL-8-5) for raw material, preparation method, with (CSL-I-2), obtains white solid powder 0.26g, yield: 28.3%, mp:216.3-216.5 DEG C.
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)。
The preparation of 9.6 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-6)
With (CSL-8-6) for raw material, preparation method, with (CSL-I-2), obtains white solid powder 0.28g, yield: 30.0%, mp:217.1-217.7 DEG C.
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)。
The preparation of 9.7 2-(3-cyano group-4-n-octyloxy) phenyl-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-I-7)
With (CSL-8-7) for raw material, preparation method, with (CSL-I-2), obtains white solid powder .023g, yield: 24.7%, mp:216.5-217.3 DEG C.
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 tablet
Prescription composition and content
Coating fluid prescription:
Opadry (03B28796) 21g
95% appropriate amount of ethanol
Make about 430ml
Technique
The auxiliary material crossing 100 mesh sieves is crossed 60 mesh sieves with main ingredient mix, with 95% ethanol softwood, granulate with 18 mesh sieves, 60 DEG C of air seasonings, to mix with Magnesium Stearate after the whole grain of 16 mesh sieve, charge and attack sheet with Φ 6mm scrobicula.
The preparation of Coating Solution: add 95% appropriate ethanol in appropriate vessel, start stirrer, Opadry (03B28796) pressed powder of recipe quantity is joined in vortex uniformly, has avoided powder floats at fluid surface, if desired simultaneously as far as possible, rotating speed can be improved to keep suitable vortex, after all Opadries (03B28796) all add, reduce stirring velocity, vortex is disappeared, continue to stir 45min, to obtain final product.
The preparation of thin membrane coated tablet: put by label in coating pan, keeps temperature 60 C ± 5 DEG C, carries out dressing, to obtain final product.
The xanthine oxidase inhibitory activity research of embodiment 11. target compound
1. test materials
1.1 reagent: XOD, xanthine, trisodium phosphate, disodium ethylene diamine tetraacetate.
1.2 instruments: 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 ordinance methods
Compound 10%KOH solubilize becomes 10mM mother liquor, faces the used time to react diluted, now with the current.Enzyme activity detection method
Preparation reaction diluent: 0.1mol/L trisodium phosphate 0.3mmol/L EDETATE SODIUM, pH value 8.3.
XOD is purchased to sigma, faces the used time with reacting diluted, XOD 25U/L in reaction system, xanthine 200 μm of ol/L.Add successively during reaction XOD, test medicine (positive drug adopt Febuxostat FBST-00), 25 DEG C hatch 15min after add xanthine, 25 DEG C hatch 2h after detects absorbancy with 295nm place, the blank corresponding drug solvent of employing of organizing is as contrast.
2.2 statistical method
Whole data adopts SPSS(17.0) statistical package tests analysis.Result mean value ± standard error represents, between group, mean compares and carries out homoscedasticity analysis, and carries out comparing between Dunnett ' s test analytical procedure group
3. experimental result:
Experimental result shows, 29 synthesized target compound major parts demonstrate stronger xanthine oxidase inhibitory activity (experimental data is in table 1).
Table 129 kind of sample 10 μ g/ml is on the impact (M+SE) of xanthine oxidase activity
*, compare with solvent control group, P < 0.05; *, compares with solvent control group, P < 0.01; * *, compares with solvent control group, P < 0.001.

Claims (7)

1. there is compound or the pharmacy acceptable salt of xanthine oxidase inhibitory activity, it is characterized in that: this compounds is any one in following compound (1) ~ (22):
(1) 2-(3-cyano group-4-oxyethyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-1),
(2) 2-(3-cyano group-4-positive propoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-2),
(3) 2-(3-cyano group-4-isopropoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-3),
(4) 2-(3-cyano group-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-cyano group-4-sec-butoxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-6),
(7) 2-(3-cyano group-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-cyano group-4-) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-8),
(9) 2-(3-cyano group-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-cyano group-4-n-octyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-10),
(11) 2-(3-cyano group-4-is to methylbenzyloxy) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-formic acid (CSL-MI-11),
(12) 2-(3-cyano group-4-methoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-1),
(13) 2-(3-cyano group-4-positive propoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-2),
(14) 2-(3-cyano group-4-isopropoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-3),
(15) 2-(3-cyano group-4-n-butoxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-4),
(16) 2-(3-cyano group-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-cyano group-4-isopentyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-7),
(19) 2-(the positive hexyloxy of 3-cyano group-4-) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-8),
(20) 2-(3-cyano group-4-oxygen base in positive heptan) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-9),
(21) 2-(3-cyano group-4-n-octyloxy) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-10),
(22) 2-(3-cyano group-4-methyl-benzyl) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-formic acid (CSL-HI-11).
2. prepare and according to claim 1ly have the compound of xanthine oxidase inhibitory activity or an intermediate for pharmacy acceptable salt, this intermediate is one of 2-(3-cyano group-4-alkoxyl group) phenyl-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate, 2-(3-cyano group-4-alkoxyl group) phenyl-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate.
3. according to intermediate according to claim 2, it is characterized in that: described ester is methyl esters or ethyl ester or propyl ester or the tert-butyl ester or benzyl ester or to methyl benzyl ester.
4. according to claim 1 have the compound of xanthine oxidase inhibitory activity or a preparation method for pharmacy acceptable salt, it is characterized in that:
1) with 4-hydroxy benzaldehyde for starting raw material, the bromo-4-hydroxy benzaldehyde of 3-is obtained through bromo, carry out alkylation reaction with hydrobromic ether and obtain 3-bromine 4--oxyl phenyl aldehyde, 3-cyano group-4--oxyl phenyl aldehyde is obtained by reacting again with cuprous cyanide, and then with 2-(hydroxyl imide base)-3-oxobutanoic acid esters ring and, obtain 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate;
2) 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate is through hydrolysis reaction, obtained compound 12-22;
3) 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-hydroxy-4-methyl-1H-imidazoles-5-manthanoate dimethyl sulfate methylation of ester, obtained 2-(3-cyano group-4-hydrocarbon oxygen phenyl)-1-methoxyl group-4-methyl isophthalic acid H-imidazoles-5-manthanoate, through hydrolysis reaction, obtained compound 1-11.
5. a pharmaceutical composition, it includes the compound or pharmacy acceptable salt and pharmaceutically acceptable auxiliary material, thinner and carrier as described in claim 1 with xanthine oxidase inhibitory activity.
6. according to pharmaceutical composition according to claim 5, it is characterized in that: the weight percent of the compound or pharmacy acceptable salt in said composition with xanthine oxidase inhibitory activity is 5%-20%, and acceptable auxiliary material, thinner and carrier are surplus.
7. treat and (or) prevent hyperuricemia and a goat medicine, it includes the compound or pharmacy acceptable salt as described in claim 1 with xanthine oxidase inhibitory activity.
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