CN101580495A - 5-substituted phenyl-3-isoxazole carboxylic acid and ester compounds, compositions and preparation method thereof - Google Patents
5-substituted phenyl-3-isoxazole carboxylic acid and ester compounds, compositions and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicaments, relates to 5-substituted phenyl-3-isoxazole carboxylic acid with xanthine oxidase inhibitory activity shown as in general expression I and ester compounds, tautomer, a pharmaceutical salt and a pharmaceutical solvate thereof and pharmaceutical compositions containing the components and a preparation method of the components, and also relates to application of the compounds and the compositions in preparing a medicament for treating hyperuricemia and gout (wherein R<1> independently is substituted or unsubstituted linear and branched C1-C10 alkyl, C2-C10 alkenyl, C3-C7 naphthenic base, C3-C7 cycloalkenyl groups, an aromatic group, an aralkyl group, a heterocyclic group, heteroaryl, heterocyclic-alkyl, heteroarylalkyl, C3-C7 cycloalkyl-alkyl, aminoalkyl, primary alkyl aminoalkyl, dialkyl aminoalkyl, alkoxyl-alkyl, aryl-oxyalkyl, aralkoxy-alkyl and fully halogenated alkyl; R<2> is a cyano-group, a nitro group, halogen and unsubstituted, monosubstituted or disubstituted aminocarbonyl; R is a hydrogen atom or ethyl; and A is an oxygen atom, a sulphur atom and a nitrogen atom).
Description
Technical field
The invention belongs to medical technical field, relate to 5-substituted phenyl-3-isoxazole carboxylic acid and ester compound thereof, composition and method of making the same, be specifically related to ester compound, derivative, isomer, pharmaceutically useful salt, the pharmaceutically useful solvate of 5-substituted phenyl-3-isoxazole carboxylic acid and the pharmaceutically useful composition and method of making the same that contains them, and the purposes of these compounds in medicine.
Background technology
Gout (gout) be long-term purine metabolic disturbance and (or) uric acid excretion reduces caused one group of heterogeneity, metabolic disease.Gout is the human second largest metabolism class disease that is only second to diabetes.The clinical characters of gout is acute arthritis, uratoma deposition, uratoma chronic arthritis and the joint deformity of hyperuricemia, outbreak repeatedly, involves kidney and causes chronic interstitial nephritis and urinary stone disease etc.Chang Bingfa cardiovascular and cerebrovascular diseases and threat to life.
The prerequisite of gout morbidity is a hyperuricemia, when hyperuricemia is meant 37 ℃ in the serum uric acid content (male sex surpasses 70mg/L; The women surpasses 60mg/L).Urate can be deposited in the tissue when surpassing this concentration, causes gout Histological change.5%～12% hyperuricemia patient is finally developed into gout, and hyperuricemia patient only occurs urate crystal deposition, sacroiliitis, ephrosis, urinary stone disease etc. and is called gout.
Xanthine oxidoreductase enzyme (xanthine oxidoreductase, XOR) contain the molybdoprotein enzyme for high conservative, in mammal, be xanthine dehydrogenase (xanthine dehydrogenase with two kinds of forms that can transform mutually, XDH) and XOD (Xanthine Oxidase, XO) exist, mainly exist under the normal circumstances with desaturase (XDH) form, it is converted into oxydase (XO) by two kinds of approach: a kind of is that cysteine residues is oxidized on the enzyme, form disulfide linkage around FAD, this transforms for reversibility; The another kind of non-reversibility that is formed by proteolytic enzyme such as pancreatin hydrolysis transforms.
XOD (XO) participates in purine katabolism, and catalysis xanthoglobulin and xanthine generate uric acid.Because no uriKoxidase in the human body can not transform uric acid and decompose, therefore the XO activity increases unusually in body, generates a large amount of uric acid.But uric acid solubleness in body fluid is limited, when concentration in the body fluid surpasses its saturation concentration, easily separates out crystallization in tissue, just forms hyperuricemia and gout.Epidemiologic data finds, about 10% primary hyperuricemia and gout are mainly due to due to purine metabolism enzymatic defect or the activity change, and the XO activity increases to its principal element.Have a good application prospect aspect preventing and treating in hyperuricemia and gout at the active XO inhibitor that increases exploitation of XO.
Find no the relevant report of pass 5-substituted phenyl-3-isoxazole carboxylic acid and ester compound thereof, composition and method of making the same in the prior art.
Summary of the invention
The new compound that the object of the present invention is to provide a kind of general formula I to represent, it has inhibition XOD (XO) effect, can be used for preparation treatment hyperuricemia and goat medicine.
Another object of the present invention is to provide the preparation method of the new compound that general formula I represents.
The new compound that described general formula I is represented comprises 5-substituted phenyl-3-isoxazole carboxylic acid and ester compound thereof and derivative thereof, tautomer, pharmaceutically useful salt, pharmaceutically useful solvate and the pharmaceutically useful composition that contains them.
Compound general formula provided by the invention is as follows:
Wherein:
Each R
2For cyano group, nitro, halogen, nothing replace, the single replacement or two substituted aminocarbonyl;
Each R hydrogen atom or ethyl;
Each A is Sauerstoffatom, sulphur atom, no substituted nitrogen atom, single substituted nitrogen atom.
Each R
1Replace for optional.
Preferred each R
1Independent C for replacement or unsubstituted straight or branched
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkenyl group, aryl, aralkyl, heterocyclic radical, heteroaryl, heterocyclic radical alkyl, heteroaralkyl, C
3-C
7Cycloalkylalkyl, aminoalkyl group, an alkylamino alkyl, dialkyl aminoalkyl, alkoxyalkyl, aryl oxide alkyl, sweet-smelling alkoxy alkyl, fully halogenated alkyl.
This invention also comprises the as above preparation method of definition I compound:
(1) preparation of 5-(3-nitro-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid
With the 4-hydroxy acetophenone is raw material, through nitration reaction make 3-nitro-4-hydroxy acetophenone, make 3-nitro-4-alkoxy benzene ethyl ketone with the halohydrocarbon hydrocarbonylation again, make 4-(3-nitro-4-alkoxyl group) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester with oxalic acid diethyl ester generation condensation reaction then, then get 5-(3-nitro-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid ethyl ester with the oxammonium hydrochloride cyclization, after sodium hydroxide hydrolysis, the reaction of five steps makes target compound 5-(3-nitro-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid altogether.
(2) preparation of 5-(3-iodo-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid
With the 4-hydroxy acetophenone is raw material, through iodo make 3-iodo-4-hydroxy acetophenone, get 3-iodine 4-alkoxy benzene ethyl ketone with the halohydrocarbon hydrocarbonylation again, get 4-(3-iodo-4-alkoxyl group) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester with the oxalic acid diethyl ester condensation then, then make 5-(3-iodo-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid ethyl ester with oxammonium hydrochloride generation ring-closure reaction, after sodium hydroxide hydrolysis, the reaction of five steps makes target compound 5-(3-iodo-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid altogether.
(3) preparation of 5-(3-cyano group-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid
With the 4-hydroxy acetophenone is raw material, through iodo make 3-iodo-4-hydroxy acetophenone, get 3-iodo-4-alkoxy benzene ethyl ketone, make 3-cyano group-4-alkoxy benzene ethyl ketone with cupric cyanide generation cyanogenation again, make 4-(3-cyano group 4-alkoxyl group) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester with the oxalic acid diethyl ester condensation then, then get 5-(3-cyano group-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid ethyl ester with the oxammonium hydrochloride cyclization with the halohydrocarbon hydrocarbonylation, after sodium hydroxide hydrolysis, six steps made 5-(3-cyano group-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid altogether.
Optional pharmacy acceptable salt or the solvate that forms the formula I compound that is obtained.
Be defined as follows as pharmaceutical salts of the present invention, but be not limited to this: the salt of carboxylic moiety, as an alkali metal salt such as Li, Na and K salt; Alkaline earth salt such as Ca and Mg salt; Organic alkali salt is as Methionin, arginine, guanidine, diethanolamine, choline, Trometamol or the like; The ammonium salt of ammonium or replacement and aluminium salt.Salt can be acid salt, its include but not limited to vitriol, nitrate, phosphoric acid salt, perchlorate, borate, hydrohalogen, acetate, tartrate, maleate, Citrate trianion, succinate, palmitate, mesylate, benzoate, salicylate, benzene sulfonate, ascorbate salt, glycerophosphate, ketoglutarate or the like.Pharmaceutically useful solvate can be a hydrate, or contains other recrystallisation solvents such as alcohol.
Compound of Formula I or its pharmacy acceptable salt or solvate, they are selected from:
5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
5-[3-nitro-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-nitro-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(4-cyano group) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
Another aspect of the present invention comprises a kind of pharmaceutical composition, it contains the compound of at least a general formula I, with and derivative, analogue, tautomer, polymorphic form, pharmaceutically useful salt, pharmaceutically useful solvate as activeconstituents, and pharmaceutically useful carrier, thinner etc.
The pharmaceutical composition that contains The compounds of this invention can prepare by ordinary method, 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 form injection solution or suspension in suitable sterile media.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 composition contains compound or its pharmaceutically useful salt of formula I, and pharmaceutically useful excipient, and it can be carrier or thinner, or the suppressed by vector dilution, or is wrapped in the carrier, and 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, 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, season becomes the tetrol 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 uses separately or mixes with wax.Can also comprise wetting agent in the preparation, emulsifying agent, suspensoid, sanitas, sweeting agent or sweetener.Can prepare preparation of the present invention by methods known in the art, 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 be with any administration, as long as it is sent to active medicine suitable or required reactive site effectively, 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 makes 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 contain dissolving or be suspended in formula I compound in liquid vehicle, the especially aqueous carrier, as the aerosol administration.This carrier can contain additive, comprises solubilizing agent such as propylene glycol, tensio-active agent, absorption enhancer such as Yelkin TTS (phosphatide phenol choline) or cyclodextrin, 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.
Tablet, drageeing or capsule with talcum and/or carbohydrate carrier or tackiness agent etc. are 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.
Can contain by the typical tablet of conventional pressed disc technique preparation:
Core:
Active compound (free cpds or its salt) 5.0mg
Colloid silica (KCrOSil) 1.5mg
Wei ﹠amp; Mierocrystalline cellulose (AVicel) 70.0mg
Modified cellulose gum (Ac-Di-Sol) 7.5mg
Magnesium Stearate an amount of (ad.)
Coatings:
The about 9.0mg of HPMC
*The about 0.9mg of Mywacett 9-40T
*The phenolic group monoglyceride is as film-coated softening agent
Among the present invention, the compound of general formula I or its preparation of compositions method are simple, and product can be used as the XO inhibitor, are used for the treatment of and/or prevent hyperuricemia and goat.
Embodiment:
Explain the present invention in detail by the following examples, these embodiment just illustrate, and never are in order to limit the scope of the invention.
Embodiment 1
The preparation of 5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-nitro-4-hydroxy acetophenone
(15.00g 110.00mmol) is dissolved in the Glacial acetic acid (40mL), and 45 ℃ are stirred down, and (10.5mL, 110.00mmol), control reaction temperature is dripped and finished at 50 ℃-60 ℃, continues to stir 0.5h slowly to drip concentrated nitric acid with parahydroxyacet-ophenone.Reaction solution is poured in the mixture of ice and water, had yellow solid to separate out, suction filtration, the dehydrated alcohol recrystallization is used in seasoning under the room temperature then, gets yellow crystal 10.50g, yield 52.6%, m.p.131.0-132.6 ℃.
(2) preparation of 3-nitro-4-isobutoxy methyl phenyl ketone
With 3-nitro-4-hydroxy acetophenone (15.80g, 87.30mmol), Anhydrous potassium carbonate (42.20g, 306.00mmol), DMF (150.0mL), PEG-400 (4.0mL) add in the 250mL round-bottomed flask, after stirring 20min under 80 ℃, add isobutane bromide (41.60g, 306.00mmol), under this temperature, continue reaction 7h.Reaction is finished, and in reaction solution impouring water (400mL), (3 * 80mL) extractions merge organic layer, and the 3%KOH aqueous solution washes twice, adds anhydrous sodium sulfate drying 6h then with methylene dichloride.Filter, neat solvent is steamed in decompression, adds water (100mL), has solid matter to separate out, suction filtration, and washing, natural drying at room temperature gets dark yellow solid 12.10g, yield 58.4%, m.p.64.4-66.4 ℃..
(3) preparation of 4-(3-nitro-4-isobutoxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.31g, 13.40mmol), make sodium alkoxide with absolute ethanol (15mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (1.78g, 12.20mmol), make mixed solution, then with 3-nitro-4-isobutoxy methyl phenyl ketone (2.90g, 12.20mmol) 25ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature again, is transferred to stirring at room 4h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (80mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and the dehydrated alcohol recrystallization gets white plates crystalline product 2.30g, yield 55.8%, m.p.102.5-104.1 ℃.
1H-NMR(300MHz，CDCl
3)δppm：15.14(s，1H)，8.48(d，1H，J＝2.4)，8.17(dd，1H，J＝2.4，J＝9.0)，7.16(d，1H，J＝9.0)，7.02(s，1H)，4.42(m，2H)，3.96(d，2H))，2.20(m，1H)，1.43(t，3H)，1.08(d，6H)。
(4) preparation of 5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-(3-nitro-4-isobutoxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (2.00g, 5.93mmol), oxammonium hydrochloride (0.46g, 5.93mmol) and dehydrated alcohol (60ml), back flow reaction 6h.Reaction is finished, the solvent of pressure reducing and steaming 1/3 volume, and the room temperature cooling crystallization, suction filtration, dehydrated alcohol is washed, and drying gets white crystalline solid 1.60g, yield 80.7%,
m.p.134.8-136.1℃。
1H-NMR(300MHz，CDCl
3)δppm：8.27(d，1H，J＝2.2)，7.96(dd，1H，J＝2.2，J＝8.8)，7.19(d，1H，J＝8.8)，6.91(s，1H)，4.48(m，2H)，3.94(d，2H)，2.19(m，1H)，1.45(t，3H)，1.08(d，6H)。
(5) preparation of 5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
In the 50ml round-bottomed flask, add 5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester (0.80g, 2.33mmol), 1M sodium hydroxide (23.3ml, 23.30mmol) aqueous solution and tetrahydrofuran (THF) (10ml), reflux 2h.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash faint yellow solid.The anhydrous methanol recrystallization gets faint yellow needle crystal 0.30g, yield 41.0%, m.p.174.6-175.9 ℃.
MS：m/z?260.9[M-CO
2-H]
-，307.2[M+H]
+，329.2[M+Na]
+，345[M+K]
+.
IR(cm
-1)：3453，2964，1720，1624，1531，1498，1447，1384，1397，1351，1286，1167，1001，920，762.
1H-NMR(300MHz，DMSO)δppm：14.12(s，1H)，8.46(d，1H，J＝2.2)，8.19(dd，1H，J＝2.2，J＝8.8)，7.55(d，1H，J＝9)，7.48(s，1H)，4.04(d，2H)，2.06(m，1H)，0.99(d，6H)。
13C-NMR(300MHz，DMSO)δppm：168.84，160.72，157.97，152.79，139.86，131.47，122.39，118.62，116.01，101.17，75.52，27.68，18.74。
Embodiment 2
The preparation of 5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-nitro-4-hydroxy acetophenone
In the concrete operations reference example 1 (1)
(2) preparation of 3-nitro-4-benzyloxy methyl phenyl ketone
In the 250ml round-bottomed flask, add 3-nitro-4-hydroxy acetophenone (5.00g, 27.60mmol), Anhydrous potassium carbonate (11.40g, 82.90mmol), potassiumiodide (0.27g, 1.38mmol) and DMF (50mL), behind 65 ℃ of following stirring 20min, add benzyl chloride (6.4mL, 55.20mmol), under this temperature, continue reaction 3h.With in the reaction solution impouring water (300mL), separate out solid then, suction filtration gets thick product, and re-crystallizing in ethyl acetate gets light yellow crystallization 5.00g, yield 66.8%, m.p.132.7-134.7 ℃.
(3) preparation of 4-(3-nitro-4-benzyloxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.19g, 8.12mmol), make sodium alkoxide with absolute ethanol (15mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (1.19g, 8.12mmol), make mixed solution, then with 3-nitro-4-benzyloxy methyl phenyl ketone (2.00g, 7.38mmol) 25ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 4h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (60mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and the dehydrated alcohol recrystallization gets faint yellow plate crystal 1.50g, yield 36.5%, m.p.116.4-117.4 ℃.
1H-NMR(300MHz，CDCl
3)δppm：15.00(s，1H)，8.49(d，1H，J＝2.3)，8.15(dd，1H，J＝2.3，J＝8.9)，7.36-7.47(m，4H+1H)，7.24(d，1H，J＝8.9)，7.01(s，1H)，5.35(s，2H)，4.41(m，2H)，1.42(t，3H)。
(4) preparation of 5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-(3-nitro-4-benzyloxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (0.70g, 1.85mmol), oxammonium hydrochloride (0.13g, 1.85mmol) and dehydrated alcohol (20ml), back flow reaction 2h.Reaction is finished, the solvent of pressure reducing and steaming 1/3 volume, and the room temperature cooling crystallization, suction filtration, dehydrated alcohol is washed, and drying gets white crystalline solid 0.60g, yield 86.4%, m.p.171.8-173.0 ℃.
(5) preparation of 5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
In the 50ml round-bottomed flask, add 5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid ethyl ester (0.60g, 1.72mmol), 1M sodium hydroxide (17.2ml, 17.20mmol) aqueous solution and 10ml tetrahydrofuran (THF), reflux 2h.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash faint yellow solid.The Glacial acetic acid recrystallization gets faint yellow needle crystal 0.37g, yield 67.0%, m.p.189.6-191.5 ℃.
IR(cm
-1)：3453，2926，1711，1625，1531，1496，1445，1385，1356，1301，1268，1171，1017，937，820，744.
1H-NMR(300MHz，DMSO)δppm：12.10(s，1H)，8.47(d，1H，J＝2.1)，8.22(dd，1H，J＝2.1，J＝8.7)，7.64(d，1H，J＝8.7)，7.36-7.49(m，5H+1H)，5.42(s，2H)。
Embodiment 3
5-[3-nitro-4-(4-methyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-nitro-4-hydroxy acetophenone
In the concrete operations reference example 1 (1)
(2) preparation of 3-nitro-4-(4-methyl) benzyloxy methyl phenyl ketone
In the 250ml round-bottomed flask, add 3-nitro-4-hydroxy acetophenone (5.00g, 27.60mmol), Anhydrous potassium carbonate (11.40g, 82.90mmol), potassiumiodide (0.30g, 1.38mmol) and DMF (50mL), behind 65 ℃ of following stirring 20min, add 4-methyl benzyl chloride (7.80g, 55.20mmol), under this temperature, continue reaction 3h.With in the reaction solution impouring water (300mL), separate out solid then, suction filtration gets thick product, and re-crystallizing in ethyl acetate gets yellow crystal 5.20g, yield 66.0%, m.p.108.8-110.8 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.40(d，1H，J＝2.1))，8.20(dd，1H，J＝2.1，J＝9.0)，7.56(d，1H，J＝9.0)，7.35(d，2H，J＝7.8)，7.22(d，2H，J＝8.1)，5.37(s，2H)，2.58(s，3H)，2.31(s，3H)。
(3) 4-[3-nitro-4-(4-methyl) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.44g, 19.30mmol), make sodium alkoxide with absolute ethanol (10mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (2.80g, 19.30mmol), make mixed solution, then with 3-nitro-4-(4-methyl) benzyloxy methyl phenyl ketone (5.00g, 17.50mmol) 40ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 0.5h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 4h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (80mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and re-crystallizing in ethyl acetate gets brown crystallization 2.80g, yield 41.5%, m.p.109.4-111.2 ℃.
1H-NMR(300MHz，DMSO)δppm：8.24(s，1H)，8.03(d，1H，J＝8.6)，7.44(d，2H，J＝7.7)，7.35(d，2H，J＝7.8)，7.21(d，2H，J＝7.8)，6.25(s，1H)，5.29(s，2H)，4.07-4.13(m，2H)，2.31(s，3H)，1.19-1.26(m，3H)。
(4) 5-[3-nitro-4-(4-methyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-[3-nitro-4-(4-methyl) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (2.50g, 6.49mmol), oxammonium hydrochloride (0.45g, 6.49mmol) and dehydrated alcohol (50ml), back flow reaction 1h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, drying, the acetonitrile recrystallization gets white crystalline solid 1.79g, yield 72.0%, m.p.189.0-189.7 ℃.
1H-NMR(300MHz，DMSO)δppm：8.49(d，1H，J＝2.1)，8.21(dd，1H，J＝8.7，J＝2.1)，7.63(d，1H，J＝8.7)，7.57(s，1H)，7.35(d，2H，J＝8.1)，7.22(d，2H，J＝7.8)，5.36(s，2H)，4.40(m，2H)，2.31(s，3H)，1.34(t，3H)。
(5) 5-[3-nitro-4-(4-methyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 50ml round-bottomed flask, add 5-[3-nitro-4-(4-methyl) benzyloxy] and phenyl-3-isoxazole carboxylic acid ethyl ester (1.00g, 2.62mmol), 1M sodium hydroxide (26.2ml, 26.20mmol) aqueous solution and 15ml tetrahydrofuran (THF), reflux 2h.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash faint yellow solid.The anhydrous methanol recrystallization gets pale yellow powder 0.57g, yield 61.0%, m.p.173.2-174.7 ℃.
IR(cm
-1)：3511，3139，2920，1725，1624，1596，1531，1449，1384，1354，1277，1173，996，922，827，763.
1H-NMR(300MHz，DMSO)δppm：8.47(d，1H，J＝2.1，8.20(dd，1H，J＝8.8，J＝2.3)，7.62(d，1H，J＝8.9)，7.48(s，1H)，7.35(d，2H，J＝8.0)，7.22(d，2H，J＝8.1)，5.36(s，2H)，2.31(s，3H)。
Embodiment 4
5-[3-nitro-4-(4-chloro) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-nitro-4-hydroxy acetophenone
In the concrete operations reference example 1 (1)
(2) preparation of 3-nitro-4-(4-chloro) benzyloxy methyl phenyl ketone
In the 250ml round-bottomed flask, add 3-nitro-4-hydroxy acetophenone (5.00g, 27.60mmol), Anhydrous potassium carbonate (11.40g, 82.90mmol), potassiumiodide (0.30g, 1.38mmol) and DMF (50mL), behind 65 ℃ of following stirring 20min, add 4-chloro benzyl chloride (5.30g, 33.10mmol), under this temperature, continue reaction 3h.With in the reaction solution impouring water (300mL), separate out solid then, suction filtration gets thick product, and re-crystallizing in ethyl acetate gets faint yellow crystallization 4.50g, yield 53.3%, m.p.118.7-120.0 ℃.
1H-NMR(300MHz，DMSO)δppm：，8.42(d，1H，J＝2.1)，8.22(dd，1H，J＝2.1，J＝8.8)，7.56(d，1H，J＝8.8)，7.50(s，4H)，5.43(s，2H)，2.59(s，3H)。
(3) 4-[3-nitro-4-(4-chloro) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.36g, 15.50mmol), make sodium alkoxide with absolute ethanol (10mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (2.26g, 15.50mmol), make mixed solution, then with 3-nitro-4-(4-chloro) benzyloxy methyl phenyl ketone (4.30g, 14.10mmol) 30ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 0.5h dropwises, and continues to stir 1h in this temperature again, is transferred to stirring at room 4h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (80mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, acetone: dehydrated alcohol (7: 3) recrystallization gets yellow crystal 2.80g, yield 49.0%, m.p.130.9-132.1 ℃.
1H-NMR(300MHz，DMSO)δppm：8.61(s，1H)，8.38(d，1H，J＝7.5)，7.59(d，1H，J＝7.5)，7.50(s，4H)，7.18(s，1H)，5.45(s，2H)，4.32(m，2H)，1.31(t，3H).
(4) 5-[3-nitro-4-(4-chloro) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-[3-nitro-4-(4-chloro) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (2.80g, 6.90mmol), oxammonium hydrochloride (0.53g, 7.60mmol) and dehydrated alcohol (50ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, and drying gets platinum sponge shape solid 2.40g, yield 86.4%, m.p.174.3-175.2 ℃.
1H-NMR(300MHz，DMSO)δppm：8.51(s，1H)，8.24(dd，1H，J＝8.8，J＝2.1)，7.62(d，1H，J＝8.9)，7.58(s，1H)，7.50(s，4H)，5.41(s，2H)，4.40(m，2H)，1.34(t，3H)。
(5) 5-[3-nitro-4-(4-chloro) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 50ml round-bottomed flask, add 5-[3-nitro-4-(4-chloro) benzyloxy] and phenyl-3-isoxazole carboxylic acid ethyl ester (2.50g, 6.21mmol), 1M sodium hydroxide (62.0ml, 62.00mmol) aqueous solution and 20ml tetrahydrofuran (THF), reflux 2h.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash faint yellow solid.Dehydrated alcohol: THF (1: 1) recrystallization twice gets faint yellow crystallization 0.60g, yield 25.8%, m.p.195.5-196.9 ℃.
IR(cm
-1)：3487，3145，3075，1719，1624，1533，1494，1444，1383，1352，1304，1264，1176，1011，907，817，766.
1H-NMR(300MHz，DMSO)δppm：8.49(d，1H，J＝2.1)，8.23(dd，1H，J＝2.1，J＝8.8)，7.62(d，1H，J＝8.9)，7.5(s，4H+1H)，5.41(s，2H)。
Embodiment 5
5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-nitro-4-hydroxy acetophenone
In the concrete operations reference example 1 (1)
(2) preparation of 3-nitro-4-(the 4-tertiary butyl) benzyloxy methyl phenyl ketone
In the 250ml round-bottomed flask, add 3-nitro-4-hydroxy acetophenone (5.00g, 27.60mmol), Anhydrous potassium carbonate (9.50g, 69.10mmol), potassiumiodide (0.23g, 1.38mmol) and DMF (50mL), behind 65 ℃ of following stirring 20min, add 4-tertiary butyl benzyl chloride (8.40g, 41.40mmol), under this temperature, continue reaction 3h.With in the reaction solution impouring water (300mL), separate out solid then, suction filtration gets thick product, and the dehydrated alcohol recrystallization gets faint yellow crystallization 5.40g, yield 59.8%, m.p.96.1-97.3 ℃.
1H-NMR(300MHz，DMSO)δppm：8.41(d，1H，J＝2.3)，8.20(dd，1H，J＝2.3，J＝8.8)，7.58(d，1H，J＝8.9)，7.44(d，2H，J＝8.4)，7.39(d，2H，J＝8.3)，5.38(s，2H)，2.58(s，3H)，1.28(s，9H)。
(3) 4-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.42g, 18.20mmol), make sodium alkoxide with absolute ethanol (10mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (2.65g, 18.20mmol), make mixed solution, then with 3-nitro-4-(the 4-tertiary butyl) benzyloxy methyl phenyl ketone (5.40g, 16.50mmol) 30ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 0.5h dropwises, and continues to stir 1h in this temperature again, is transferred to stirring at room 4h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (80mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and re-crystallizing in ethyl acetate gets yellow crystal 2.70g, yield 38.3%, m.p.128.3-130.0 ℃.
1H-NMR(300MHz，DMSO)δppm：8.29(s，1H)，8.06(s，1H)，7.42(m，5H)，6.45(s，1H)，5.31(s，2H)，4.12(m，2H)，1.28(s，9H)，1.23(m，3H)。
(4) 5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (2.70g, 8.25mmol), oxammonium hydrochloride (0.63g, 9.07mmol) and dehydrated alcohol (50ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, and drying gets white plates solid 2.50g, yield 71.4%, m.p.165.5-166.4 ℃.
1H-NMR(300MHz，DMSO)δppm：8.50(d，1H，J＝2.2)，8.23(dd，1H，J＝8.8，J＝2.2)，7.62(d，1H，J＝8.9)，7.58(s，1H)，7.50(m，4H)，5.37(s，2H)，4.40(m，2H)，1.32(t，3H)。
(5) 5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 50ml round-bottomed flask, add 5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] and phenyl-3-isoxazole carboxylic acid ethyl ester (2.40g, 5.66mmol), 1M sodium hydroxide (56.6ml, 56.60mmol) aqueous solution and 20ml tetrahydrofuran (THF), reflux 2h.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash yellow solid.The dehydrated alcohol recrystallization gets yellow crystal 1.40g, yield 62.5%, m.p.158.5-159.8 ℃.
IR(cm
-1)：3458，3143，2962，1732，1625，1596，1532，1449，1384，1357，1284，1173，1088，821，751.
1H-NMR(300MHz，DMSO)δppm：8.47(d，1H，J＝2.1)，8.21(dd，1H，J＝2.1，J＝8.8)，7.64(d，1H，J＝8.9)，7.5(m，4H+1H)，5.36(s，2H)，1.28(s，9H)。
Embodiment 6
The preparation of 5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
In the 1000ml three-necked bottle, add potassiumiodide (60.10g, 368.00mmol), (18.70g 73.50mmol) and water (160ml) stirring and dissolving, uses the 500ml strong aqua with parahydroxyacet-ophenone (10.00g to iodine then, 73.50mmol) dissolve in the above-mentioned reaction solution of back adding the about 12h of room temperature reaction.Reaction is finished, suction filtration, and filtrate is transferred PH to 1 with concentrated hydrochloric acid, and suction filtration gets yellow solid.Methyl alcohol: water (7: 3) recrystallization gets yellow solid 10.80g, yield 56.1%, m.p.153.4-156 ℃.
(2) preparation of 3-iodo-4-isobutoxy methyl phenyl ketone
In the 250ml three-necked bottle, add 3-iodo-4 hydroxy acetophenone (10.80g, 41.20mmol), Anhydrous potassium carbonate (14.20g, 102.70mmol), poly(oxyethylene glycol) 400 (2.0ml) and DMF (80ml), at 60 ℃ of following mechanical stirring 20min, add isobutane bromide (19.60g then, 144.00mmol), under this temperature, continue reaction 7h.Reaction is finished, and reaction solution is poured in the 400ml water, with methylene dichloride (80ml * 3) extraction, merges organic phase, washes with saturated nacl aqueous solution, adds anhydrous sodium chlorate dried overnight.Filter, concentrated filtrate gets pale brown look oily matter.Column chromatography for separation gets faint yellow solid 9.20g, yield 70.2%, m.p.50.6-51.7 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.38(d，1H，J＝2.2)，7.91(dd，1H，J＝2.2，J＝8.6)，6.79(d，1H，J＝8.6)，3.84(d，2H，J＝6.3)，2.54(s，3H)，2.18(m，1H)，1.10(d，6H)。
(3) preparation of 4-(3-iodo-4-isobutoxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.72g, 31.10mmol), make sodium alkoxide with absolute ethanol (15mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (4.55g, 31.10mmol), make mixed solution, then with 3-iodo-4-isobutoxy methyl phenyl ketone (9.00g, 28.30mmol) 30ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 8h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (80mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and re-crystallizing in ethyl acetate gets light green solid 4.70g, yield 39.8%, m.p.138.3-140.0 ℃.
1H-NMR(300MHz，DMSO)δppm：8.23(s，1H)，7.85(s，1H)，7.00(d，1H)，6.50(s，1H)，4.16(d，2H)，3.87(d，2H)，2.06(m，1H)，1.24(q，3H)，1.03(d，6H)。
(4) preparation of 5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester
In the 250ml round-bottomed flask, add 4-(3-iodo-4-isobutoxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (4.65g, 11.50mmol), oxammonium hydrochloride (0.88g, 12.70mmol) and dehydrated alcohol (75ml), back flow reaction 5h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, drying, dehydrated alcohol: ethyl acetate (2: 1) recrystallization gets white powder 3.60g, yield 75.5%, m.p.113.3-114.4 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.20(d，1H，J＝2.1)，7.74(dd，1H，J＝8.6，J＝2.1)，4.46(q，2H)，3.84(d，2H)，2.19(m，1H)，1.44(t，3H)，1.10(d，6H)。
(5) preparation of 5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
In the 100ml round-bottomed flask, add 5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester (2.54g, 6.12mmol), 1M sodium hydroxide (8.0ml, 7.96mmol) aqueous solution, 15ml tetrahydrofuran (THF) and 20ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash faint yellow solid.The Glacial acetic acid recrystallization gets little yellow needle crystal 1.10g, yield 46.4%, m.p.183.2-184.5 ℃.
IR(cm
-1)：2957，2870，1708，1605，1465，1441，1383，1280，1264，1163，1046，1011，932，807，772.
1H-NMR(300MHz，DMSO)δppm：13.85(s，1H)，8.33(s，1H)，7.92(d，1H)，7.37(s，1H)，7.11(d，1H)，3.90(d，2H)，2.07(m，1H)，1.04(d，6H)。
Embodiment 7
The preparation of 5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
Step in the reference example 6 (1)
(2) preparation of 3-iodo-4-isobutoxy methyl phenyl ketone
Step in the reference example 6 (2)
(3) preparation of 3-cyano-4-isobutoxy methyl phenyl ketone
In the 100ml eggplant-shape bottle, add 3-iodo-4-isobutoxy methyl phenyl ketone (5.81g, 18.30mmol), cuprous cyanide (2.63g, 29.30mmol) and DMF (50ml), heating reflux reaction 6h.Reaction is finished, and cold slightly reaction solution is poured in the 400ml water, separates out solid, standing over night, suction filtration, seasoning.Chloroform heat is extracted, and filtrate decompression is steamed neat solvent, and the dehydrated alcohol recrystallization gets light yellow solid 3.00g, yield 75.7%, mp 97.1-97.9 ℃.
1H-NMR(300MHz，DMSO)δppm：8.34(d，1H，J＝2.2)，8.20(dd，1H，J＝2.2，J＝8.9)，
7.37(d，1H，J＝8.9)，4.03(d，2H，J＝6.5)，2.51(s，3H)，2.09(m，1H)，1.02(d，6H)。
(4) preparation of 4-(3-cyano-4-isobutoxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.23g, 10.12mmol), make sodium alkoxide with absolute ethanol (10mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (1.34g, 9.20mmol), make mixed solution, then with 3-cyano-4-isobutoxy methyl phenyl ketone (2.00g, 9.20mmol) 10ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 12h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (40mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and the dehydrated alcohol recrystallization gets white solid 1.54g, yield 55.2%, m.p.106.7-107.3 ℃.
1H-NMR(300MHz，DMSO)δppm：15.06(s，1H)，8.23(d，1H，J＝2.2)，8.18(dd，1HJ＝2.3，J＝8.9)，7.06(d，1H，J＝8.9)，6.99(s，1H)，4.41(m，2H)，3.94(d，2H)，2.22(m，1H)，1.42(t，3H)，1.10(d，6H)。
(5) preparation of 5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-(3-cyano-4-isobutoxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (1.25g, 4.12mmol), oxammonium hydrochloride (0.29g, 4.12mmol) and dehydrated alcohol (50ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, and drying gets white powder 1.11g, yield 85.4%, m.p.176.6-177.5 ℃.
1H-NMR(300MHz，DMSO)δppm：8.39(d，1H，J＝2.2)，8.21(dd，1H，J＝8.9，J＝2.3)，7.51(s，1H)，7.42(d，1H，J＝8.9)，4.39(q，2H)，4.02(d，2H)，2.09(m，1H)，1.34(t，3H)，1.02(d，6H)。
(6) preparation of 5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
In the 250ml round-bottomed flask, add 5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester (3.00g, 9.60mmol), 1M sodium hydroxide (12.4ml, 12.40mmol) aqueous solution, 30ml tetrahydrofuran (THF) and 25ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash white solid.The anhydrous methanol recrystallization gets white powder 2.44g, yield 88.7%, m.p.180.0-180.5 ℃.
IR(cm
-1)：3543，2964，2228，1730，1618，1495，1451，1385，1397，1302，1264，1177，1123，1015，925，822，778，758.
1H-NMR(300MHz，DMSO)δppm：14.06(s，1H)，8.36(d，1H，J＝2.1)，8.20(dd，1H，J＝8.9，J＝2.1)，7.44(s，1H)，7.42(d，1H，J＝8.9)，4.02(d，2H)，2.09(m，1H)，1.02(d，6H)。
Embodiment 8
The preparation of 5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
Step in the reference example 6 (1)
(2) preparation of 3-iodo-4-benzyloxy methyl phenyl ketone
In the 250ml three-necked bottle, add 3-iodo-4-hydroxy acetophenone (5.00g, 19.10mmol), Anhydrous potassium carbonate (7.91g, 57.30mmol), poly(oxyethylene glycol) 400 (2.0ml) and DMF (50ml), at 60 ℃ of following mechanical stirring 20min, add benzyl chloride (4.84g then, 38.20mmol), under this temperature, continue reaction 7h.Reaction is finished, and reaction solution is poured in the 400ml water, separates out yellow solid, and re-crystallizing in ethyl acetate gets pale yellow powder 3.00g, yield 44.7%, mp 126.0-127.3 ℃.
(3) preparation of 3-cyano group-4-benzyloxy methyl phenyl ketone
In the 100ml eggplant-shape bottle, add 3-iodo-4-benzyloxy methyl phenyl ketone (2.95g, 8.40mmol), cuprous cyanide (0.90g, 10.10mmol) and DMF (30ml), heating reflux reaction 6h.Reaction is finished, and cold slightly reaction solution is poured in the 200ml water, separates out solid, standing over night, suction filtration, seasoning.Chloroform heat is extracted, and filtrate decompression is steamed neat solvent, and the dehydrated alcohol recrystallization gets light yellow solid 1.40g, yield 66.7%, mp 126.5-127.3 ℃.
(4) preparation of 4-(3-cyano group-4-benzyloxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.37g, 16.30mmol), make sodium alkoxide with absolute ethanol (10mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (1.91g, 13.10mmol), make mixed solution, then with 3-cyano group-4-benzyloxy methyl phenyl ketone (2.73g, 10.90mmol) 35ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 12h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (40mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, dehydrated alcohol: ethyl acetate (1: 1) recrystallization gets yellow solid 2.00g, yield 52.3%, m.p.125.2-126.3 ℃.
1H-NMR(300MHz，DMSO)δppm：8.55(s，1H)，8.35(d，1H)，7.41(m，7H)，7.17(s，1H)，5.14(s，2H)，4.31(q，2H)，1.31(t，3H)。
(5) preparation of 5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-(3-cyano group-4-benzyloxy) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (2.00g, 5.70mmol), oxammonium hydrochloride (0.43g, 6.26mmol) and dehydrated alcohol (50ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, and drying gets pale yellow powder 1.71g, yield 86.5%, m.p.184.0-184.7 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.02(d，1H，J＝2.4)，7.92(dd，1H，J＝9.0，J＝2.4)，7.41(m，5H)，7.13(d，1H，J＝9.0)，6.86(s，1H)，5.30(s，2H)，4.47(q，2H)，1.44(t，3H)。
(6) preparation of 5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
In the 100ml round-bottomed flask, add 5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid ethyl ester (1.70g, 4.89mmol), 1M sodium hydroxide (6.4ml, 6.40mmol) aqueous solution, 15ml tetrahydrofuran (THF) and 10ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash yellow solid.The Glacial acetic acid recrystallization gets yellow powder 1.05g, yield 65.5%, m.p.183.4-184.1 ℃.
IR(cm
-1)：3423，2225，1708，1616，1490，1455，1385，1295，1261，1179，1121，991，817，781，742.
1H-NMR(300MHz，DMSO)δppm：8.40(d，1H，J＝2.1)，8.22(dd，1H，J＝8.9，J＝2.1)，7.46(m，7H)，5.39(s，2H)。
Embodiment 9
5-[3-cyano group-4-(4-methyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
Step in the reference example 6 (1)
(2) preparation of 3-iodo-4-(4-methyl) benzyloxy methyl phenyl ketone
In the 250ml three-necked bottle, add 3-iodo-4-hydroxy acetophenone (5.00g, 19.10mmol), Anhydrous potassium carbonate (7.91g, 57.30mmol), poly(oxyethylene glycol) 400 (2ml) and DMF (50ml), at 60 ℃ of following mechanical stirring 20min, add 4-methyl benzyl chloride (5.41g then, 38.20mmol), under this temperature, continue reaction 7h.Reaction is finished, and reaction solution is poured in the 400ml water, separates out yellow solid, and re-crystallizing in ethyl acetate gets pale yellow powder 3.75g, yield 53.7%, m.p.117.3-118.9 ℃.
1H-NMR(300MHz，CDCl
3)ppm：8.40(d，1H，J＝2.0)，7.90(dd，1H，J＝2.0，J＝8.6)，7.36(d，2H，J＝7.9)，7.20(d，2H，J＝7.8)，6.86(d，1H，J＝8.6)，5.18(s，2H)，2.53(s，3H)，2.36(s，3H)。
(3) preparation of 3-cyano group-4-(4-methyl) benzyloxy methyl phenyl ketone
In the 100ml eggplant-shape bottle, add 3-iodo-4-(4-methyl) benzyloxy methyl phenyl ketone (3.75g, 10.20mmol), cuprous cyanide (1.10g, 12.20mmol) and DMF (50ml), heating reflux reaction 6h.Reaction is finished, and cold slightly reaction solution is poured in the 300ml water, separates out solid, standing over night, suction filtration, seasoning.Chloroform heat is extracted, and filtrate decompression is steamed neat solvent, and the dehydrated alcohol recrystallization gets deep yellow solid 1.40g, yield 52.2%, m.p.102.9-103.8 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.20(d，1H，J＝2.2)，8.12(dd，1H，J＝2.3，J＝8.9)，7.35(d，2H，J＝8.0)，7.22(d，2H，J＝8.0)，7.08(d，1H，J＝8.9)，5.28(s，2H)，2.58(s，3H)，2.38(s，3H)。
(4) 4-[3-cyano group-4-(4-methyl) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.61g, 26.60mmol), make sodium alkoxide with absolute ethanol (20mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (3.11g, 21.30mmol), make mixed solution, then with 3-cyano group-4-(4-methyl) benzyloxy methyl phenyl ketone (4.70g, 17.70mmol) 40ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 12h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (60mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, dehydrated alcohol: ethyl acetate (1: 1) recrystallization gets pale brown look solid 4.30g, yield 66.6%, m.p.154.2-155.4 ℃.
1H-NMR(300MHz，DMSO)δppm：8.55(s，1H)，8.35(d，1H，)，7.50(d，1H，)，7.39(d，1H，J＝7.7)，7.23(d，1H，J＝7.7)，7.19(s，1H)，5.36(s，2H)，4.32(q，2H)，2.32(s，3H)，1.32(t，3H)。
(5) 5-[3-cyano group-4-(4-methyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 250ml round-bottomed flask, add 4-[3-cyano group-4-(4-methyl) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (4.30g, 11.80mmol), oxammonium hydrochloride (0.97g, 13.90mmol) and dehydrated alcohol (100ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, drying, re-crystallizing in ethyl acetate gets sheet white solid 2.75g, yield 63.7%, m.p.190.3-191.5 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.01(d，1H，J＝2.2)，7.91(dd，1H，J＝8.9，J＝2.2)，7.33(d，2H，J＝8.0)，7.21(d，2H，J＝8.0)，7.15(d，1H，J＝8.9)，6.86(s，1H)，5.25(s，2H)，4.47(q，2H)，2.36(s，3H)，1.45(t，3H)。
(6) 5-[3-cyano group-4-(4-methyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 100ml round-bottomed flask, add 5-[3-cyano group-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester (2.75g, 7.60mmol), 1M sodium hydroxide (9.1ml, 9.10mmol) aqueous solution, 15ml tetrahydrofuran (THF) and 20ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, behind the stirring 20min, suction filtration, wash white solid.Dehydrated alcohol: tetrahydrofuran (THF) (4: 1) recrystallization gets flocculence crystallization 1.61g, yield 63.4%, m.p.194.7-195.1 ℃.
IR(cm
-1)：3423，2225，1729，1616，1490，1453，1385，1295，1270，1179，1121，985，818，785.
1H-NMR(300MHz，DMSO)δppm：8.37(s，1H)，8.20(d，1H)，7.51(d，1H)，7.41(s，1H)，7.39(d，2H，J＝7.9)，7，23(d，2H，J＝7.8)，5.33(s，2H)，2.31(s，3H)。
Embodiment 10
5-[3-cyano group-4-(4-chloro) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
Step in the reference example 6 (1)
(2) preparation of 3-iodo-4-(4-chloro) benzyloxy methyl phenyl ketone
In the 250ml three-necked bottle, add 3-iodo-4-hydroxy acetophenone (6.00g, 22.90mmol), Anhydrous potassium carbonate 9.48g, 68.70mmol), poly(oxyethylene glycol) 400 (2ml) and DMF (50ml), at 60 ℃ of following mechanical stirring 20min, add 4-chlorobenzyl chloride (5.54g then, 34.40mmol), under this temperature, continue reaction 7h.Reaction is finished, and reaction solution is poured in the 400ml water, and separate out yellow solid, dehydrated alcohol: chloroform (3: 1) recrystallization gets pale yellow powder 6.50g, yield 73.4%, m.p.126.5-127.7 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.40(d，1H，J＝2.1)，7.92(dd，1H，J＝2.1，J＝8.6)，7.40(m，4H)，6.85(d，1H，J＝8.6)，5.18(s，2H)，2.54(s，3H)。
(3) preparation of 3-cyano group-4-(4-chloro) benzyloxy methyl phenyl ketone
In the 100ml eggplant-shape bottle, add 3-iodo-4-(4-chloro) benzyloxy methyl phenyl ketone (6.44g, 16.70mmol), cuprous cyanide (1.49g, 18.37mmol) and DMF (50ml), heating reflux reaction 6h.Reaction is finished, and cold slightly reaction solution is poured in the 250ml water, separates out solid, standing over night, suction filtration, seasoning.Chloroform heat is extracted, and filtrate decompression is steamed neat solvent, and the dehydrated alcohol recrystallization gets faint yellow solid 3.80g, yield 79.8%, m.p.119.6-120.9 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.20(d，1H，J＝2.2)，8.12(dd，1H，J＝2.2，J＝8.9)，7.39(s，4H)，7.05(d，1H，J＝8.9)，5.26(s，2H)，2.57(s，3H)。
(4) 4-[3-cyano group-4-(4-chloro) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.50g, 20.060mmol), make sodium alkoxide with absolute ethanol (20mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (2.33g, 16.00mmol), make mixed solution, then with 3-cyano group-4-(4-chloro) benzyloxy methyl phenyl ketone (3.80g, 13.30mmol) 25ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 12h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (40mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, dehydrated alcohol: ethyl acetate (1: 1) recrystallization gets tawny solid 4.60g, yield 59.7%, m.p.132.2-133.1 ℃.
1H-NMR(300MHz，DMSO)δppm：8.58(s，1H)，8.37(d，1H)，7.52(s，4H)，7.48(s，1H)，7.20(s，1H)，5.42(s，2H)，4.32(q，2H)，1.32(t，3H)。
(5) 5-[3-cyano group-4-(4-chloro) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 250ml round-bottomed flask, add 4-[3-cyano group-4-(4-chloro) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (3.00g, 7.80mmol), oxammonium hydrochloride (0.64g, 9.10mmol) and dehydrated alcohol (70ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, drying, re-crystallizing in ethyl acetate gets sheet white solid 2.30g, yield 76.7%, m.p.175.1-175.8 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.02(d，1H，J＝2.2)，7.94(dd，1H，J＝8.9，J＝2.2)，7.39(s，4H)，7.11(d，1H，J＝8.9)，6.87(s，1H)，5.25(s，2H)，4.47(q，2H)，1.44(t，3H)。
(6) 5-[3-cyano group-4-(4-chloro) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 100ml round-bottomed flask, add 5-[3-cyano group-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester (2.30g, 6.01mmol), 1M sodium hydroxide (7.2ml, 7.20mmol) aqueous solution, 15ml tetrahydrofuran (THF) and 20ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, after stirring 20min, suction filtration, wash white solid, dehydrated alcohol: tetrahydrofuran (THF) (4: 1) recrystallization, get the little yellow crystal 1.45g of sheet, yield 68.1%, m.p.191.5-192.3 ℃.
IR(cm
-1)：3474，2223，1731，1617，1496，1454，1385，1291，1269，1242，1124，993，826，747.
1H-NMR(300MHz，DMSO)δppm：8.40(d，1H，J＝2.1)，8.22(d，1H，J＝8.9，J＝2.1)，7.52(s，4H)，7.50(d，1H，J＝7.9)，7，43(s，1H)，5.39(s，2H)。
Embodiment 11
5-[3-cyano group-4-(4-cyano group) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
Step in the reference example 6 (1)
(2) preparation of 3-iodo-4-(4-cyano group) benzyloxy methyl phenyl ketone
In the 250ml three-necked bottle, add 3-iodo-4-hydroxy acetophenone (14.00g, 53.40mmol), Anhydrous potassium carbonate 21.10g, 160.03mmol), poly(oxyethylene glycol) 400 (4ml) and DMF (100ml), at 60 ℃ of following mechanical stirring 20min, add 4-cyano group benzyl chloride (12.20g then, 80.20mmol), under this temperature, continue reaction 7h.Reaction is finished, and reaction solution is poured in the 500ml water, separates out yellow solid, and re-crystallizing in ethyl acetate gets yellow powder 15.70g, yield 78.5%, m.p.156.9-158.2 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.42(d，1H，J＝2.1)，7.93(dd，1H，J＝2.1，J＝8.6)，7.68(m，4H)，6.85(d，1H，J＝8.6)，5.27(s，2H)，2.56(s，3H)。
(3) preparation of 3-cyano group-4-(4-cyano group) benzyloxy methyl phenyl ketone
In the 100ml eggplant-shape bottle, add 3-iodo-4-(4-cyano group) benzyloxy methyl phenyl ketone (8.00g, 21.20mmol), cuprous cyanide (2.19g, 24.40mmol) and DMF (60ml), heating reflux reaction 6h.Reaction is finished, and cold slightly reaction solution is poured in the 250ml water, separates out solid, standing over night, suction filtration, seasoning.Chloroform heat is extracted, and filtrate decompression is steamed neat solvent, and column purification (ethyl acetate is an eluent) gets yellow solid 4.80g, yield 81.9%, m.p.166.7-167.9 ℃ fast.
1H-NMR(300MHz，CDCl
3)δppm：8.22(d，1H，J＝2.1)，8.15(dd，1H，J＝2.1，J＝8.8)，7.73(d，2H，J＝8.3)，7.59(d，2H，J＝8.2)，7.04(d，1H，J＝8.9)，5.33(s，2H)，2.58(s，3H)。
(4) 4-[3-cyano group-4-(4-cyano group) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.56g, 24.45mmol), make sodium alkoxide with absolute ethanol (20mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (2.85g, 19.50mmol), make mixed solution, then with 3-cyano group-4-(4-cyano group) benzyloxy methyl phenyl ketone (4.50g, 16.30mmol) 45ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 12h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (50mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, dehydrated alcohol: ethyl acetate (1: 4) recrystallization gets tawny solid 2.70g, yield 44.0%, m.p.172.8-173.7 ℃.
1H-NMR(300MHz，DMSO)δppm：8.57(s，1H)，8.36(d，1H)，7.93(d，2H，J＝8.2)，7.68(d，2H，J＝8.2)，7.48(d，1H)，7.15(s，1H)，5.53(s，2H)，4.30(q，2H)，1.31(t，3H)。
(5) 5-[3-cyano group-4-(4-cyano group) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 250ml round-bottomed flask, add 4-[3-cyano group-4-(4-cyano group) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (2.70g, 7.18mmol), oxammonium hydrochloride (0.55g, 7.90mmol) and dehydrated alcohol (60ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, drying, rapid column chromatography purifying (ethyl acetate is an eluent) gets white solid 2.37g, yield 88.4%, m.p.200.7-201.5 ℃.
1H-NMR(300MHz，DMSO)δppm：8.45(d，1H，J＝2.2)，8.25(dd，1H，J＝8.9，J＝2.2)，7.93(d，2H，J＝8.2)，7.68(d，2H，J＝8.2)，7.52(d，1H，J＝8.9)，7.49(s，1H)，5.51(s，2H)，4.40(q，2H)，1.34(t，3H)。
(6) 5-[3-cyano group-4-(4-cyano group) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 100ml round-bottomed flask, add 5-[3-cyano group-4-(4-cyano group) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester (2.37g, 7.31mmol), 1M sodium hydroxide (8.8ml, 8.78mmol) aqueous solution, 15ml tetrahydrofuran (THF) and 20ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, after stirring 20min, suction filtration, wash yellow solid, tetrahydrofuran (THF): methyl-sulphoxide (1: 1) recrystallization, get yellow powder 1.54g, yield 61.1%, m.p.160.3-161.0 ℃.
IR(cm
-1)：3439，2231，1708，1692，1616，1505，1489，1447，1383，1303，1263，1122，1033，1014，949，825，782，752.
1H-NMR(300MHz，DMSO)δppm：14.10(s，1H)，8.42(d，1H，J＝2.2)，8.23(dd，1H，J＝8.9，J＝2.2)，7.93(d，2H，J＝8.2)，7.68(d，2H，J＝8.2)，7.49(d，1H，J＝8.9)，7.44(s，1H)，5.50(s，2H)。
Embodiment 12
5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
Method according to following flow process prepares title compound
(1) preparation of 3-iodo-4-hydroxy acetophenone
Step in the reference example 6 (1)
(2) preparation of 3-iodo-4-(the 4-tertiary butyl) benzyloxy methyl phenyl ketone
In the 250ml three-necked bottle, add 3-iodo-4-hydroxy acetophenone (9.10g, 34.70mmol), Anhydrous potassium carbonate (14.40g, 104.20mmol), poly(oxyethylene glycol) 400 (4ml) and DMF (60ml), at 60 ℃ of following mechanical stirring 20min, add 4-tertiary butyl benzyl chloride (9.50g then, 52.10mmol), under this temperature, continue reaction 7h.Reaction is finished, and reaction solution is poured in the 500ml water, separates out yellow solid, and the dehydrated alcohol recrystallization gets yellow powder 9.50g, yield 66.9%, m.p.107.9-108.8 ℃.
1H-NMR(300MHz，CDCl
3)δppm：8.41(d，1H，J＝2.1)，7.91(dd，1H，J＝2.1，J＝8.6)，7.42(s，4H)，6.89(d，1H，J＝8.6)，5.20(s，2H)，2.53(s，3H)，1.33(s，9H)。
(3) preparation of 3-cyano group-4-(the 4-tertiary butyl) benzyloxy methyl phenyl ketone
In the 100ml eggplant-shape bottle, add 3-iodo-4-(the 4-tertiary butyl) benzyloxy methyl phenyl ketone (7.50g, 18.40mmol), cuprous cyanide (1.81g, 20.20mmol) and DMF (50ml), heating reflux reaction 6h.Reaction is finished, and cold slightly reaction solution is poured in the 250ml water, separates out solid, standing over night, suction filtration, seasoning.Chloroform heat is extracted, and filtrate decompression is steamed neat solvent, and column purification (ethyl acetate is an eluent) gets yellow solid 4.20g, yield 70.9%, m.p.106.9-108.3 ℃ fast.
1H-NMR(300MHz，CDCl
3)δppm：8.19(d，1H，J＝2.2)，8.11(dd，1H，J＝2.2，J＝8.9)，7.42(m，4H)，7.08(d，1H，J＝8.9)，5.26(s，2H)，2.56(s，3H)，1.32(s，9H)。
(4) 4-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester
Take by weighing sodium Metal 99.5 (0.42g, 17.40mmol), make sodium alkoxide with absolute ethanol (15mL) dissolving, under-6 ℃ of mechanical stirring conditions, drip oxalic acid diethyl ester (2.03g, 13.90mmol), make mixed solution, then with 3-cyano group-4-(the 4-tertiary butyl) benzyloxy methyl phenyl ketone (3.56g, 11.58mmol) 25ml dry THF solution slowly drop in the above-mentioned mixed solution that makes, about 1h dropwises, and continues to stir 1h in this temperature, is transferred to stirring at room 10h then.Reaction finishes, and neat solvent is steamed in decompression, adds water (60mL), transfers pH to 3 with 5% dilute hydrochloric acid, and suction filtration gets thick product, and the Glacial acetic acid recrystallization gets tawny solid 1.86g, yield 39.4%, m.p.110.9-112.1 ℃.
1H-NMR(300MHz，DMSO)δppm：8.57(s，1H)，8.36(dd，1H)，7.52(d，2H，J＝9)，7.44(m，4H)，7.19(s，1H)，5.37(s，2H)，4.32(q，2H)，1.32(t，3H+9H)。
(5) 5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid ethyl ester
In the 100ml round-bottomed flask, add 4-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester (1.50g, 3.70mmol), oxammonium hydrochloride (0.28g, 4.10mmol) and dehydrated alcohol (40ml), back flow reaction 2h.Reaction is finished, the room temperature cooling crystallization, and suction filtration, dehydrated alcohol is washed, drying, rapid column chromatography purifying (ethyl acetate is an eluent) gets yellow solid 1.24g, yield 83.2%, m.p.181.3-182.2 ℃.
1H-NMR(300MHz，DMSO)δppm：8.42(s，1H)，8.23(d，1H)，7.54(d，1H+1H)，7.44(d，4H)，5.34(s，2H)，4.40(q，2H)，1.33(t，3H+9H)。
(6) 5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] preparation of phenyl-3-isoxazole carboxylic acid
In the 100ml round-bottomed flask, add 5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester (1.90g, 4.70mmol), 1M sodium hydroxide (6.1ml, 6.10mmol) aqueous solution, 15ml tetrahydrofuran (THF) and 20ml dehydrated alcohol, 60 ℃ of reaction 40min down.Reaction is finished, and neat solvent is steamed in decompression, adds little water, transfers pH to 1 with 4% dilute hydrochloric acid then, stir 20min after, suction filtration, wash yellow solid, the dehydrated alcohol recrystallization gets yellow powder 1.30g, yield 73.5%, m.p.165.0-166.1 ℃.
IR(cm
-1)：3453，3137，2962，2229，1732，1692，1618，1501，1451，1384，1302，1277，1123，995，821，779.
1H-NMR(300MHz，DMSO)δppm：8.39(d，1H，J＝2.4)，8.22(dd，1H，J＝8.9，J＝2.3)，7.53(d，2H，J＝9.0)，7.46(m，4H)，7.40(s，1H)，5.50(s，2H)，1.29(s，9H)。
Embodiment 13
Xanthine oxidoreductase enzyme (XOD) inhibitor activity detects
(1) experimental principle
By the XOD of Sigma purchase Niu Yuan, be that substrate detects the XOD activity with xanthine (xanthine).Observation sample suppresses the activity of enzyme, with the inhibition effect of assess sample.The positive reference compound that adopts is Zyloric (allopurinol).
(2) experimental technique
Contain an amount of XOD, pH7.4 phosphoric acid buffer, xanthine (SIGMA) and sample in the 200 μ L reaction systems, set up blank (not containing enzyme and sample) and negative control (not containing sample) simultaneously, 25 ℃ of reaction 90min, 293nM measures the OD value.Calculate inhibiting rate, inhibiting rate=[1-(OD sample-OD blank)/(OD enzyme work-OD blank)] * 100 according to the OD value.Each sample list concentration is established two multiple holes during primary dcreening operation, and inhibiting rate is greater than 50% sample determination IC
50Value, ten concentration of each sample gradient dilution during mensuration, each concentration are established two multiple holes.According to inhibiting rate, the 4 ParameterLogistic Model that use in the Xlfit software calculate IC
50
(3) experimental result
IC
50The mensuration of value
The enzyme level evidence, the compound of general formula I has xanthine oxidase inhibitory activity preferably, and hyperuricemia, goat are had prevention and therapeutic action preferably.
Claims (7)
1. compound or its pharmacy acceptable salt or solvate as a general formula I
Wherein:
Each R
2For cyano group, nitro, halogen, nothing replace, the single replacement or two substituted aminocarbonyl;
Each R is hydrogen atom or ethyl;
Each A is Sauerstoffatom, sulphur atom, nitrogen-atoms;
R
1Replace for optional.
2. compound according to claim 1, wherein each R
1Independent C for replacement or unsubstituted straight or branched
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkenyl group, aryl, aralkyl, heterocyclic radical, heteroaryl, heterocyclic radical alkyl, heteroaralkyl, C
3-C
7Cycloalkylalkyl, aminoalkyl group, an alkylamino alkyl, dialkyl aminoalkyl, alkoxyalkyl, aryl oxide alkyl, sweet-smelling alkoxy alkyl, fully halogenated alkyl.
3, the compound of general formula I according to claim 1 and 2 or its pharmacy acceptable salt or solvate, they are selected from:
5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
5-(3-nitro-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester
5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
5-(3-nitro-4-benzyloxy) phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-nitro-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-nitro-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-nitro-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-nitro-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-nitro-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester
5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
5-(3-iodo-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester
5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid
5-(3-cyano-4-isobutoxy) phenyl-3-isoxazole carboxylic acid ethyl ester
5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid
5-(3-cyano group-4-benzyloxy) phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-cyano group-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(4-methyl) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-cyano group-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(4-chloro) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-cyano group-4-(4-cyano group) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(4-cyano group) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester
5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid
5-[3-cyano group-4-(the 4-tertiary butyl) benzyloxy] phenyl-3-isoxazole carboxylic acid ethyl ester.
4, a kind of method for preparing the formula I compound of claim 1 or 2 definition, this method comprises:
(1) preparation of 5-(3-nitro-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid
With the 4-hydroxy acetophenone is raw material, through nitration reaction make 3-nitro-4-hydroxy acetophenone, make 3-nitro-4-alkoxy benzene ethyl ketone with the halohydrocarbon hydrocarbonylation again, make 4-(3-nitro-4-alkoxyl group) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester with oxalic acid diethyl ester generation condensation reaction then, then get 5-(3-nitro-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid ethyl ester with the oxammonium hydrochloride cyclization, after sodium hydroxide hydrolysis, the reaction of five steps makes target compound 5-(3-nitro-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid altogether;
(2) preparation of 5-(3-iodo-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid
With the 4-hydroxy acetophenone is raw material, through iodo make 3-iodo-4-hydroxy acetophenone, get 3-iodine 4-alkoxy benzene ethyl ketone with the halohydrocarbon hydrocarbonylation again, get 4-(3-iodo-4-alkoxyl group) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester with the oxalic acid diethyl ester condensation then, then make 5-(3-iodo-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid ethyl ester with oxammonium hydrochloride generation ring-closure reaction, after sodium hydroxide hydrolysis, the reaction of five steps makes target compound 5-(3-iodo-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid altogether;
(3) preparation of 5-(3-cyano group-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid
With the 4-hydroxy acetophenone is raw material, through iodo make 3-iodo-4-hydroxy acetophenone, get 3-iodo-4-alkoxy benzene ethyl ketone, make 3-cyano group-4-alkoxy benzene ethyl ketone with cupric cyanide generation cyanogenation again, make 4-(3-cyano group 4-alkoxyl group) phenyl-2-hydroxyl-4-oxo-2-butylene acetoacetic ester with the oxalic acid diethyl ester condensation then, then get 5-(3-cyano group-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid ethyl ester with the oxammonium hydrochloride cyclization with the halohydrocarbon hydrocarbonylation, after sodium hydroxide hydrolysis, six steps made 5-(3-cyano group-4-alkoxyl group) phenyl-3-isoxazole carboxylic acid altogether.
5, a kind of medicinal compositions, it comprises claim 1 or 2 formula of I compounds or its pharmacy acceptable salt or solvate and acceptable accessories, diluent or carrier.
6, a kind of preparation method of medicinal compositions as claimed in claim 5, it is characterized in that: compound of Formula I or its pharmacy acceptable salt or solvate and acceptable accessories, diluent or carrier are mixed, the active compound that wherein contains 5-20% weight, surplus are pharmaceutically useful carrier, excipient, thinner, solvent.
7, compound of Formula I or its pharmacy acceptable salt or the solvate purposes in preparation treatment hyperuricemia and goat medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104086435A (en) * | 2014-07-22 | 2014-10-08 | 天津力生制药股份有限公司 | Synthetic method of formoterol fumarate important intermediate benzyl ether compound |
| 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 |
| CN110156757A (en) * | 2019-06-06 | 2019-08-23 | 沈阳海诺威医药科技有限公司 | Tetrazole xanthine oxidase inhibitor compound and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5614520A (en) * | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
| CN1240432A (en) * | 1996-10-25 | 2000-01-05 | 吉富制药株式会社 | 1-phenylpyrazole compounds and medicinal application thereof |
| CN101389352A (en) * | 2006-02-24 | 2009-03-18 | 安斯泰来制药株式会社 | Agent for treating or preventing digestive ulcer |
-
2009
- 2009-05-25 CN CNA2009100116914A patent/CN101580495A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5614520A (en) * | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
| CN1240432A (en) * | 1996-10-25 | 2000-01-05 | 吉富制药株式会社 | 1-phenylpyrazole compounds and medicinal application thereof |
| CN101389352A (en) * | 2006-02-24 | 2009-03-18 | 安斯泰来制药株式会社 | Agent for treating or preventing digestive ulcer |
Non-Patent Citations (2)
| Title |
|---|
| LAN SHEN ET AL.: "Synthesis and structure–activity relationships of thiadiazole-derivatives as potent and orally active peroxisome proliferator-activated receptors α/δ dual agonists", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| REMI BRAGA ET AL.: "Slow-binding inhibition of 2-keto-3-deoxy-6-phosphogluconate （KDPG）aldolase", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104086435A (en) * | 2014-07-22 | 2014-10-08 | 天津力生制药股份有限公司 | Synthetic method of formoterol fumarate important intermediate benzyl ether compound |
| CN104086435B (en) * | 2014-07-22 | 2016-03-02 | 天津力生制药股份有限公司 | A kind of synthetic method of Formoterol Fumarate important intermediate benzyl oxide compound |
| 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 |
| CN110156757A (en) * | 2019-06-06 | 2019-08-23 | 沈阳海诺威医药科技有限公司 | Tetrazole xanthine oxidase inhibitor compound and its preparation method and application |
| CN110156757B (en) * | 2019-06-06 | 2021-04-16 | 沈阳海诺威医药科技有限公司 | Tetrazole type xanthine oxidase inhibitor compound and preparation method and application thereof |
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