WO2014023104A1 - Compound with xanthine oxidase inhibitory activity and salt thereof, preparation method and usage for the same - Google Patents
Compound with xanthine oxidase inhibitory activity and salt thereof, preparation method and usage for the same Download PDFInfo
- Publication number
- WO2014023104A1 WO2014023104A1 PCT/CN2013/073327 CN2013073327W WO2014023104A1 WO 2014023104 A1 WO2014023104 A1 WO 2014023104A1 CN 2013073327 W CN2013073327 W CN 2013073327W WO 2014023104 A1 WO2014023104 A1 WO 2014023104A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- csl
- cyano
- methyl
- imidazole
- phenyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 166
- 150000001875 compounds Chemical class 0.000 title claims abstract description 42
- 108010093894 Xanthine oxidase Proteins 0.000 title claims abstract description 31
- 102100033220 Xanthine oxidase Human genes 0.000 title claims abstract description 31
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 22
- 150000003839 salts Chemical class 0.000 title claims abstract description 19
- 201000005569 Gout Diseases 0.000 claims abstract description 14
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- -1 n-octyl Chemical group 0.000 claims description 75
- 238000006243 chemical reaction Methods 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 239000007858 starting material Substances 0.000 claims description 18
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- 229940079593 drug Drugs 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
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- 238000000034 method Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 4
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- GBWWACPNHLMSMJ-UHFFFAOYSA-N 2-(3-cyano-4-hydroxyphenyl)-3-hydroxy-5-methylimidazole-4-carboxylic acid Chemical compound CC1=C(N(C(=N1)C2=CC(=C(C=C2)O)C#N)O)C(=O)O GBWWACPNHLMSMJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- LBVIWYRIQOZIRO-UHFFFAOYSA-N 2-hydroxyimino-3-oxobutanoic acid Chemical compound CC(=O)C(=NO)C(O)=O LBVIWYRIQOZIRO-UHFFFAOYSA-N 0.000 claims description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 2
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- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000004702 methyl esters Chemical group 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
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Classifications
-
- 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
Definitions
- the present invention belongs to the field of medical technology, and particularly relates to a compound having xanthine oxidase inhibitory activity, a salt thereof, an intermediate, a preparation method, a pharmaceutical composition and use. Background technique
- Gout is a group of heterogeneous, metabolic diseases caused by long-term hyperuricemia leading to deposition of urate in joints and soft tissues.
- the normal male blood uric acid is 150-380 ⁇ /L, and the female menopause is 100-300 ⁇ / ⁇ . After menopause, the value is close to that of male.
- the saturated concentration of serum uric acid at 37 ° C is about 416 ⁇ 0 1 / ⁇ , which is higher than this value is hyperuricemia.
- Hyperuricemia is the biochemical basis of gout.
- Xanthine oxidase is a key enzyme in the production of uric acid.
- jaundice produces uric acid under the action of xanthine oxidase, thus inhibiting yellow.
- the activity of oxime oxidase can effectively reduce the production of uric acid.
- xanthine oxidase inhibitors play a very important role.
- the mechanism of action of this class of drugs is mainly to inhibit the activity of xanthine oxidase and thus effectively reduce the production of uric acid. It plays a role in the treatment of hyperuricemia and gout.
- An object of the present invention is to provide a compound having xanthine oxidase inhibitory activity, a salt thereof, an intermediate, a preparation method, a pharmaceutical composition and use.
- the present invention provides a compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, and the structural formula of the compound is as shown in Fig. 1, wherein: R is a methyl group, an ethyl group, a n-propyl group or a different form Propyl, n-butyl, iso Butyl, sec-butyl, isopentyl, n-hexyl, n-heptyl, n-octyl or 4-methylbenzyl.
- the present invention provides a compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, and the compound is preferably any one of the following compounds (1) to (29):
- the present invention also provides an intermediate for preparing the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, the intermediate including but not limited to 2-(3-cyano-4-alkoxy) ;) phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylate, 2-(3-cyano-4-alkoxy;)phenyl-1-hydroxy- 4-methyl-1H-imidazole-5-formate and 2-(3-cyano-4-alkoxy)phenyl-4-methyl-1H-imidazol-5-carboxylate;
- the ester is methyl ester, ethyl ester, propyl ester, tert-butyl ester, benzyl ester or p-methylbenzyl ester.
- the present invention also provides a process for the preparation of the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, which is as follows:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, or a derivative thereof, an analog, a tautomer, a polymorph A pharmaceutically acceptable solvate as an active ingredient, and a pharmaceutically acceptable adjuvant, carrier, diluent, and the like.
- compositions containing a compound of the invention can be prepared by conventional methods, for example in Remington: the
- the composition may be in a conventional dosage form such as a capsule, tablet, powder, solution, suspension, syrup, aerosol, or topical administration. They may contain a suitable solid or liquid carrier or form an injection solution or suspension in a suitable sterile medium.
- the composition may contain 5-20%, preferably 5-10% by weight of active ingredient, the balance being pharmaceutically acceptable carriers, excipients, diluents Release agents, solvents, etc.
- a typical composition contains a compound of formula I, II or III or a solvate thereof, and a pharmaceutically acceptable excipient which may be a carrier or diluent, or diluted by a carrier, or packaged In the carrier, it may be in the form of a capsule, pouch, paper or other container.
- a pharmaceutically acceptable excipient which may be a carrier or diluent, or diluted by a carrier, or packaged In the carrier, it may be in the form of a capsule, pouch, paper or other container.
- the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which can be employed as a carrier, excipient or medium for the active ingredient.
- the active ingredient can be absorbed in the form of a particulate solid in a container such as a sachet.
- Some suitable carriers are water, salt solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, coconut oil, gelatin, lactose, gypsum powder, sucrose, cyclodextrin, amylose, hard Magnesium st era te, talc, gelatin, agar, pectin, gum arabic, lower alkyl ether of stearic acid or cellulose, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride , pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
- the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, used alone or in admixture with a wax.
- Wetting agents, emulsifiers, suspensions, preservatives, sweeteners or flavoring agents may also be included in the formulation.
- the formulations of the invention may be formulated by methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.
- the pharmaceutical composition may be sterilized, and if necessary, may be mixed with an adjuvant, an emulsifier, a buffer, and/or a coloring agent or the like as long as it does not react with the active ingredient.
- It can be administered by any route as long as it is effective to deliver the active drug to the appropriate or desired active site, for example, orally, nasally, transdermally, pulmonaryly, or parenterally, such as rectal, depot, subcutaneous, Intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments are preferably administered by the oral route.
- the preparation may be compressed into tablets, or in the form of a powder or pellet, or as a lozenge or lozenge.
- a liquid carrier is employed, the preparation may be a syrup, emulsion, soft gelatin capsule or sterile injection, such as an aqueous or nonaqueous liquid suspension or solution.
- the preparation may contain a compound of formula I, II or III dissolved or suspended in a liquid carrier, especially an aqueous carrier, for administration as an aerosol.
- a liquid carrier especially an aqueous carrier
- the carrier may contain additives including solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
- an injection solution or suspension is particularly suitable, and an aqueous solution in which the active ingredient is dissolved in polyhydroxylated castor oil is preferred.
- Tablets, dragees or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral administration.
- the carrier of the tablet, dragee or capsule comprises lactose, corn starch and/or potato starch.
- a syrup or elixir may be used when a sugar-containing carrier can be used.
- the present invention provides a medicament for treating or preventing hyperuricemia or gout, which comprises the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof.
- Figure 1 is a structural diagram of the compound of the present invention.
- FIG. 2 is a flow diagram of the preparation of the compounds of the invention. detailed description
- reaction solution was slowly poured into 1000 mL (16%) aqueous sodium hydrogen sulfite solution, stirred for 30 min, filtered, washed with water, and dried to give a crude product 120.0 g, yield: 72.7%. It was directly used for the next reaction by purification.
- the ethyl bromide was used as the starting material, and the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next step without purification.
- CSL-2-1 (CSL-3-1 is a product to be prepared, it cannot be used as a raw material, please confirm! The same as below!)
- the preparation method is the same as (CSL-3-7), and the obtained crude product is not purified. Used directly in the next step.
- Ethyl 2-(3-cyano-4-isobutoxy)phenyl-1-hydroxy-4-methyl-1H-imidazol-5-carboxylate (2.0 g, 5.824 mol) : trimethylchlorosilane (2.5g, 23.298mmol) Sodium iodide (3.5g, 23.298mmol) and anhydrous acetonitrile (12ml) were added to a 50ml reaction flask, refluxed under nitrogen for 6h, the completeness of the reaction was detected by TLC, the reaction was completed, and the reaction solution was placed. The mixture was cooled to room temperature, and filtered with suction. The filter cake was washed with methanol 2-3 times. The filtrate was concentrated to dryness under reduced pressure.
- the excipients that have passed the 100 mesh sieve are mixed with the main drug through a 60 mesh sieve, made of 95% ethanol soft material, sieved with 18 mesh, ventilated and dried at 60 ° C, and sieved with 16 mesh sieves with magnesium stearate. Mix evenly, punch with ⁇ 6mm shallow concave.
- Preparation of the coating solution Add an appropriate amount of 95% ethanol in a suitable container, start the mixer, and uniformly add the prescribed amount of Opadry (03B28796) solid powder to the vortex, while avoiding the floating of the powder on the surface of the liquid.
- Opadry 03B28796
- Reagents xanthine oxidase, astragalus, sodium pyrophosphate, disodium edetate.
- Xanthine oxidase was purchased from Sigma and diluted with the reaction diluent at the time of use. In the reaction system, xanthine oxidase 25 U/L, Astragalus 200 ⁇ ⁇ 1/ ⁇ . In the reaction, xanthine oxidase and test drug were added in sequence (the positive drug was incubated with febuxostat FBST-OO at 25 ° C for 15 min, then added to xanthine, and incubated at 25 ° C for 2 h, and the absorbance was measured at 295 nm. The corresponding drug solvent served as a control.
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Compound with xanthine oxidase inhibitory activity and salt, a midbody, a preparation method, and pharmaceutical composition thereof are provided. The preparation method of the compound is simple and easy to be implemented. The product can be used as an inhibitor of the xanthine oxidase, and used for curing or preventing hyperuricemia or gout disease.
Description
具有黄嘌吟氧化酶抑制活性的化合物及其盐、 制备方法和用途 技术领域 Compound having xanthine oxidase inhibitory activity and salt thereof, preparation method and use thereof
本发明属于医药技术领域， 具体涉及具有黄嘌吟氧化酶抑制活性的化合物及其 盐、 中间体、 制备方法、 药物组合物和用途。 背景技术 The present invention belongs to the field of medical technology, and particularly relates to a compound having xanthine oxidase inhibitory activity, a salt thereof, an intermediate, a preparation method, a pharmaceutical composition and use. Background technique
痛风 （Gout) 是由于长期高尿酸血症 （Hyperuricemia) 导致尿酸盐沉积于关节和 软组织而形成的一组异质性、 代谢类疾病。 正常男性血尿酸为 150-380 μιηοΙ/L, 女性 更年期以前为 100-300 μιηοΐ/ί, 更年期后其值接近男性。 37°C时血清尿酸的饱和浓度 约为 416 μιη01/ί， 高于此值即为高尿酸血症。 高尿酸血症是痛风病的生化基础。 Gout is a group of heterogeneous, metabolic diseases caused by long-term hyperuricemia leading to deposition of urate in joints and soft tissues. The normal male blood uric acid is 150-380 μιηοΙ/L, and the female menopause is 100-300 μιηοΐ/ί. After menopause, the value is close to that of male. The saturated concentration of serum uric acid at 37 ° C is about 416 μιη 0 1 / ί, which is higher than this value is hyperuricemia. Hyperuricemia is the biochemical basis of gout.
痛风在普通人群中的发病率为 1%-2%， 发达国家的发病率较高， 英国和德国的发 病率达到 1.4%。据有关文献报道，痛风已经成为了世界上仅次于糖尿病的第二大代谢 类疾病 （Clin. 2003, 25: 1593-1610)。 我国在 1980年还是痛风病很少见的国家， 近年 来随着人们生活水平的提高， 饮食结构的改变， 痛风的发病率逐年增加， 到 2008年 我国痛风患病率在一般人群达 1.1% (The Journal of Foot and Ankle Surgery 48 (1): 70-73. ), 给社会带来了巨大的压力和沉重的经济负担。 The prevalence of gout in the general population is 1% to 2%, and the incidence is higher in developed countries, with a prevalence of 1.4% in the UK and Germany. According to relevant literature reports, gout has become the second largest metabolic disease in the world after diabetes (Clin. 2003, 25: 1593-1610). In 1980, China was still a rare country for gout. In recent years, with the improvement of people's living standards and the changes in diet structure, the incidence of gout has increased year by year. By 2008, the prevalence of gout in China was 1.1% in the general population. The Journal of Foot and Ankle Surgery 48 (1): 70-73. ) has brought enormous pressure and a heavy financial burden to society.
嘌吟代谢过程中的黄嘌吟氧化酶 (Xanthine oxidase, XO)是尿酸生成的关键酶， 在 嘌吟代谢的最后阶段， 黄嘌吟在黄嘌吟氧化酶的作用下生成尿酸， 因此抑制黄嘌吟氧 化酶的活性可以有效的减少尿酸的生成。 在高尿酸血症和痛风的治疗中， 黄嘌吟氧化 酶抑制剂占有非常重要的地位， 该类药物的作用机理主要是抑制黄嘌吟氧化酶的活性 从而可以有效地减少尿酸的生成， 从而起到治疗高尿酸血症和痛风的作用。 Xanthine oxidase (XO) is a key enzyme in the production of uric acid. In the final stage of sputum metabolism, jaundice produces uric acid under the action of xanthine oxidase, thus inhibiting yellow. The activity of oxime oxidase can effectively reduce the production of uric acid. In the treatment of hyperuricemia and gout, xanthine oxidase inhibitors play a very important role. The mechanism of action of this class of drugs is mainly to inhibit the activity of xanthine oxidase and thus effectively reduce the production of uric acid. It plays a role in the treatment of hyperuricemia and gout.
鉴于目前市场上的痛风治疗药物种类十分有限， 研制高效低毒的抗痛风药物具有 重要意义。 发明内容 In view of the limited variety of gout treatment drugs currently on the market, it is of great significance to develop high-efficiency and low-toxic anti-gout drugs. Summary of the invention
本发明的目的是提供具有黄嘌吟氧化酶抑制活性的化合物及其盐、 中间体、 制备 方法、 药物组合物和用途。 SUMMARY OF THE INVENTION An object of the present invention is to provide a compound having xanthine oxidase inhibitory activity, a salt thereof, an intermediate, a preparation method, a pharmaceutical composition and use.
本发明提供了具有黄嘌吟氧化酶抑制活性的化合物或其药学上可接受的盐， 该化 合物的结构通式如图 1所示， 其中： R为甲基、 乙基、 正丙基、 异丙基、 正丁基、 异
丁基、 仲丁基、 异戊基、 正己基、 正庚基、 正辛基或 4-甲基苄基。 The present invention provides a compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, and the structural formula of the compound is as shown in Fig. 1, wherein: R is a methyl group, an ethyl group, a n-propyl group or a different form Propyl, n-butyl, iso Butyl, sec-butyl, isopentyl, n-hexyl, n-heptyl, n-octyl or 4-methylbenzyl.
本发明提供的具有黄嘌吟氧化酶抑制活性的化合物或其药学上可接受的盐， 该类 化合物优选地是下述化合物 （1) ~ (29) 中的任一个： The present invention provides a compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, and the compound is preferably any one of the following compounds (1) to (29):
(1) 2-(3-氰基 -4-乙氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-1)、 (1) 2-(3-Cyano-4-ethoxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-1),
(2) 2-(3-氰基 -4-正丙氧基 '苯基 -1-甲氧基 -4-甲基 -1H-咪唑- 甲酸 （CSL-MI-2)、(2) 2-(3-Cyano-4-n-propoxy[phenyl-1-methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-2),
(3) 2-(3-氰基 -4-异丙氧基 '苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑- 甲酸 (CSL-MI-3),(3) 2-(3-Cyano-4-isopropoxy 'phenyl- 1 -methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-3),
(4) 2-(3-氰基 -4-正丁氧基 '苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑- 甲酸 （CSL-MI-4)、(4) 2-(3-Cyano-4-n-butoxy]phenyl- 1 -methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-4),
(5) 2-(3-氰基 -4-异丁氧基 '苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑- 甲酸 （CSL-MI-5)、(5) 2-(3-Cyano-4-isobutoxy 'phenyl- 1 -methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-5),
(6) 2-(3-氰基 -4-仲丁氧基 '苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑- 甲酸 （CSL-MI-6)、(6) 2-(3-Cyano-4-sec-butoxy)phenyl- 1 -methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-6),
(7) 2-(3-氰基 -4-异戊氧基 '苯基 -1-甲氧基 -4-甲基 咪唑- 甲酸 （CSL-MI-7)、(7) 2-(3-Cyano-4-isopentyloxy 'phenyl-1-methoxy-4-methylimidazole-carboxylic acid (CSL-MI-7),
(8) 2-(3-氰基 -4-正己氧基 '苯基 -1-甲氧基 -4-甲基 -1H-咪唑- 甲酸 （CSL-MI-8)、(8) 2-(3-Cyano-4-n-hexyloxy 'phenyl-1-methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-8),
(9) 2-(3-氰基 -4-正庚氧基 '苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑- 甲酸 （CSL-MI-9)、(9) 2-(3-Cyano-4-n-heptyloxy 'phenyl- 1 -methoxy-4-methyl-1H-imidazole-carboxylic acid (CSL-MI-9),
(10) 2-(3-氰基 -4-正辛氧基 )苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑 •甲酸（CSL-MI-10)、(10) 2-(3-Cyano-4-n-octyloxy)phenyl- 1 -methoxy-4-methyl-1H-imidazole•carboxylic acid (CSL-MI-10),
(11) 2-(3-氰基 -4-甲基苄氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 (11) 2-(3-Cyano-4-methylbenzyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid
(CSL-MI-11)、 (CSL-MI-11),
(12) 2-(3 -氰基 -4-甲氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-1)、 (12) 2-(3-Cyano-4-methoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-1),
(13) 2-(3 -氰基 -4-正丙氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑- -5-甲酸 (CSL-HI-2)(13) 2-(3-Cyano-4-n-propoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-2)
(14) 2-(3 -氰基 -4-异丙氧基)苯基- 1 -羟基 -4-甲基- 1H-咪唑- -5-甲酸 (CSL-HI-3)、(14) 2-(3-Cyano-4-isopropoxy)phenyl-1 -hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-3),
(15) 2-(3 -氰基 -4-正丁氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑- -5-甲酸 (CSL-HI-4)(15) 2-(3-Cyano-4-n-butoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-4)
(16) 2-(3 -氰基 -4-仲丁氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑- -5-甲酸 (CSL-HI-5)、(16) 2-(3-Cyano-4-sec-butoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-5),
(17) 2-(3 -氰基 -4-异丁氧基;)苯基 -1-羟基 -4-甲基 咪唑- 5-甲酸 (CSL-HI-6),(17) 2-(3-Cyano-4-isobutoxy;)phenyl-1-hydroxy-4-methylimidazole-5-carboxylic acid (CSL-HI-6),
(18) 2-(3 -氰基 -4-异戊氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑- 5-甲酸 (CSL-HI-7)、(18) 2-(3-Cyano-4-isopentyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-7),
(19) 2-(3 -氰基 -4-正己氧基)苯基 - 1 -羟基 -4-甲基- 1H-咪唑- 5-甲酸 (CSL-HI-8)、(19) 2-(3-Cyano-4-n-hexyloxy)phenyl-1 -hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-8),
(20) 2-(3 -氰基 -4-正庚氧基;)苯基- 1 -羟基 -4-甲基- 1H-咪唑- 5-甲酸 (CSL-HI-9)、(20) 2-(3-Cyano-4-n-heptyloxy;)phenyl-1-hydroxy--4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-9),
(21) 2-(3 -氰基—4-正辛氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑- 5-甲酸 (CSL-HI-10)、(21) 2-(3-Cyano-4-n-octyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-10),
(22) 2-(3- -氰基 -4-甲基苄基;)苯基- 1 -羟基 -4-甲基- 1H-咪唑- 5-甲酸 (CSL-HI-11)、(22) 2-(3--Cyano-4-methylbenzyl;)phenyl-1-hydroxy--4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-11),
(23) 2-(3- -氰基 -4-正丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 (CSL-I-1)、 (23) 2-(3- -Cyano-4-n-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-1),
(24) 2-(3- -氰基 -4-异丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 (CSL-I-2)、 (24) 2-(3-Cyano-4-isobutoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-2),
(25) 2-(3- -氰基 -4-仲丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 (CSL-I-3)、 (25) 2-(3- -Cyano-4-sec-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-3),
(26) 2-(3- -氰基 -4-异戊氧基)苯基 -4-甲基- 1H-咪唑 -5-甲酸 (CSL-I-4)、
(27) 2-(3-氰基 -4-正己氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-5 )、 (26) 2-(3-Cyano-4-isopentyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-4), (27) 2-(3-Cyano-4-n-hexyloxy)phenyl-4-methyl-1H-imidazol-5-carboxylic acid (CSL-I-5),
(28) 2-(3-氰基 -4-正庚氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-6)、 (28) 2-(3-Cyano-4-n-heptyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-6),
(29) 2-(3-氰基 -4-正辛氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-7)。 (29) 2-(3-Cyano-4-n-octyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-7).
本发明还提供了一种制备上述具有黄嘌吟氧化酶抑制活性的化合物或其药学上 可接受的盐的中间体， 该中间体包括但不限于 2-(3-氰基 -4-烷氧基；)苯基 -1-甲氧基 -4-甲 基- 1H-咪唑—5-甲酸酯、 2-(3 -氰基 -4-烷氧基；)苯基- 1 -羟基基 -4-甲基- 1H-咪唑 -5-甲酸酯和 2-(3-氰基 -4-烷氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸酯； 其中， 所述酯为甲酯、 乙酯、 丙 酯、 叔丁酯、 苄酯或对甲基苄酯。 The present invention also provides an intermediate for preparing the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, the intermediate including but not limited to 2-(3-cyano-4-alkoxy) ;) phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylate, 2-(3-cyano-4-alkoxy;)phenyl-1-hydroxy- 4-methyl-1H-imidazole-5-formate and 2-(3-cyano-4-alkoxy)phenyl-4-methyl-1H-imidazol-5-carboxylate; The ester is methyl ester, ethyl ester, propyl ester, tert-butyl ester, benzyl ester or p-methylbenzyl ester.
本发明还提供了一种用于上述具有黄嘌吟氧化酶抑制活性的化合物或其药学上 可接受的盐的制备方法， 步骤如下： The present invention also provides a process for the preparation of the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, which is as follows:
1 ) 以 4-羟基苯甲醛为起始原料， 经溴代得到 3-溴 -4-羟基苯甲醛， 与溴代烃进行 烃化反应得到 3-溴 4-烃氧基苯甲醛， 再与氰化亚铜反应得到 3-氰基 -4-烃氧基苯甲醛， 然后再与 2- (羟基亚胺基 )-3-氧代丁酸酯环化， 得到 2-(3-氰基 -4-烃氧苯基) -1-羟基 -4-甲 基 咪唑 -5-甲酸酯； 1) 4-bromobenzaldehyde as starting material, bromination to give 3-bromo-4-hydroxybenzaldehyde, alkylation with brominated hydrocarbon to give 3-bromo-4-hydrocarbylbenzaldehyde, and then cyanide The cuprous reaction is carried out to give 3-cyano-4-alkoxybenzaldehyde, which is then cyclized with 2-(hydroxyimino)-3-oxobutanoate to give 2-(3-cyano-4) - alkoxy phenyl)-1-hydroxy-4-methylimidazole-5-carboxylate;
2) 2-(3-氰基 -4-烃氧苯基) -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸酯经水解反应，制得通式 I所示的系列化合物； 2) 2-(3-Cyano-4-hydroxyphenyl)-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate is hydrolyzed to obtain a series of compounds of formula I ;
3 ) 2-(3-氰基 -4-烃氧苯基;) -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸酯用硫酸二甲酯甲基化， 制得 2-(3-氰基 -4-烃氧苯基) -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸酯， 经水解反应， 制得通 式 Π所示的系列化合物； 3) 2-(3-Cyano-4-hydrocarbylphenyl;)-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate methylated with dimethyl sulfate to obtain 2- (3-Cyano-4-hydrocarbylphenyl)-1-methoxy-4-methyl-1H-imidazole-5-carboxylate, obtained by hydrolysis to obtain a series of compounds represented by the formula:
4) 2-(3-氰基 -4-烃氧苯基) -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸酯用三甲基卤硅烷与碘 化盐脱羟基制得 2-(3-氰基 -4-烃氧苯基; ) -4-甲基 -1H-咪唑 -5-甲酸酯， 经水解反应， 制得 通式 III所示的系列化合物。 4) 2-(3-Cyano-4-hydroxyphenyl)-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate is obtained by dehydroxylation of trimethylhalosilane with iodide salt 2-(3-Cyano-4-hydrocarbylphenyl;)-4-methyl-1H-imidazole-5-carboxylate is hydrolyzed to obtain a series of compounds of the formula III.
本发明还提供了一种药物组合物， 其包含上述具有黄嘌吟氧化酶抑制活性的化合 物或其药学上可接受的盐， 或其衍生物、 类似物、 互变异构体、 多晶型物、 可药用的 溶剂化物作为活性成分， 以及可药用的辅料、 载体、 稀释剂等。 The present invention also provides a pharmaceutical composition comprising the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, or a derivative thereof, an analog, a tautomer, a polymorph A pharmaceutically acceptable solvate as an active ingredient, and a pharmaceutically acceptable adjuvant, carrier, diluent, and the like.
含有本发明化合物的药物组合物可以通过常规方法制备， 例如在 Remington: the Pharmaceutical compositions containing a compound of the invention can be prepared by conventional methods, for example in Remington: the
Science and Practice of Pharmacy, 19th Ed. , 1995中描述的。该组合物可以是常规的剂 型如胶囊、 片剂、 粉末、 溶液、 混悬液、 糖浆、 气溶胶、 或局部给药形式。 它们可以 含有适当的固体或液体载体， 或在适当的无菌介质中形成注射溶液或混悬液。 该组合 物可以含有 5-20%、 优选 5-10%重量的活性成分， 余量为可药用的载体、 赋形剂、 稀
释剂、 溶剂等。 Science and Practice of Pharmacy, 19th Ed., 1995. The composition may be in a conventional dosage form such as a capsule, tablet, powder, solution, suspension, syrup, aerosol, or topical administration. They may contain a suitable solid or liquid carrier or form an injection solution or suspension in a suitable sterile medium. The composition may contain 5-20%, preferably 5-10% by weight of active ingredient, the balance being pharmaceutically acceptable carriers, excipients, diluents Release agents, solvents, etc.
典型的组合物含有式 I、 II或 III所示的化合物或其溶剂化物， 以及可药用的赋形 齐 u， 该赋形剂可以是载体或稀释剂， 或被载体稀释， 或被包装到载体中， 其可以是胶 囊、 小袋、 纸或其它容器的形式。 当载体用作稀释剂时， 它可以是固体、 半固体或液 体物质， 其可以用作活性成分的载体、 赋形剂或介质。 该活性成分可以以在容器例如 小袋中的颗粒状固体的形式被吸收。 一些适合的载体为水、 盐溶液、 醇、 聚乙二醇、 聚羟基乙氧基化蓖麻油、 花生油、 椰揽油、 明胶、 乳糖、 石膏粉、 蔗糖、 环糊精、 直 链淀粉、 硬脂酸镁 （magnesium sterate)、 滑石、 明胶、 琼脂、 果胶、 ***胶、 硬脂 酸或纤维素的低级烷基醚、 硅酸、 脂肪酸、 脂肪酸胺、 脂肪酸甘油单酯和甘油二酯、 季戊四醇脂肪酸酯、 聚氧乙烯、 羟基甲基纤维素和聚乙烯吡咯烷酮。 同样地， 载体或 稀释剂可以包括任何本领域已知的缓释材料， 如单硬脂酸甘油酯或二硬脂酸甘油酯， 其单独使用或与蜡混合后使用。制剂中还可以包括润湿剂， 乳化剂， 混悬剂， 防腐剂， 甜味剂或增香剂。 可以通过本领域己知的方法配制本发明的制剂， 以提供活性成分给 药患者后的快速、 持续或延迟释放。 A typical composition contains a compound of formula I, II or III or a solvate thereof, and a pharmaceutically acceptable excipient which may be a carrier or diluent, or diluted by a carrier, or packaged In the carrier, it may be in the form of a capsule, pouch, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which can be employed as a carrier, excipient or medium for the active ingredient. The active ingredient can be absorbed in the form of a particulate solid in a container such as a sachet. Some suitable carriers are water, salt solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, coconut oil, gelatin, lactose, gypsum powder, sucrose, cyclodextrin, amylose, hard Magnesium st era te, talc, gelatin, agar, pectin, gum arabic, lower alkyl ether of stearic acid or cellulose, silicic acid, fatty acid, fatty acid amine, fatty acid monoglyceride and diglyceride , pentaerythritol fatty acid ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone. Likewise, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, used alone or in admixture with a wax. Wetting agents, emulsifiers, suspensions, preservatives, sweeteners or flavoring agents may also be included in the formulation. The formulations of the invention may be formulated by methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.
所述药物组合物可以是无菌的，并且如果需要可以与辅剂、乳化剂、缓冲剂和 (或) 着色剂等混合， 只要其不与活性成分反应。 The pharmaceutical composition may be sterilized, and if necessary, may be mixed with an adjuvant, an emulsifier, a buffer, and/or a coloring agent or the like as long as it does not react with the active ingredient.
可以以任何途径给药， 只要其有效地将活性药物传送到适当的或所需的活性部 位， 例如口服， 鼻腔， 经皮， 肺部， 或肠胃外给药， 例如直肠、 贮库、 皮下、 静脉内、 尿道内、 肌肉内、 鼻内、 眼用溶液或油膏， 优选通过口服途径给药。 It can be administered by any route as long as it is effective to deliver the active drug to the appropriate or desired active site, for example, orally, nasally, transdermally, pulmonaryly, or parenterally, such as rectal, depot, subcutaneous, Intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments are preferably administered by the oral route.
如果使用固体载体用于口服给药， 则制剂可以被压成片剂， 或以粉末或小球形式 装入胶囊中， 或者制成锭剂或糖锭。如果使用液体载体， 则制剂可以是糖浆剂、乳剂、 软明胶胶囊或无菌注射液， 如水性或非水性液体混悬液或溶液。 If a solid carrier is used for oral administration, the preparation may be compressed into tablets, or in the form of a powder or pellet, or as a lozenge or lozenge. If a liquid carrier is employed, the preparation may be a syrup, emulsion, soft gelatin capsule or sterile injection, such as an aqueous or nonaqueous liquid suspension or solution.
对于鼻内给药，制剂可以含有溶解或混悬于液体载体，尤其是水性载体中的式 I、 II或 III化合物， 作为气溶胶给药。 该载体可以含有添加剂， 包括增溶剂如丙二醇， 表面活性剂， 吸收促进剂如卵磷脂 （磷脂酚胆碱） 或环糊精， 或防腐剂如对羟基苯甲 酸酯类。 For intranasal administration, the preparation may contain a compound of formula I, II or III dissolved or suspended in a liquid carrier, especially an aqueous carrier, for administration as an aerosol. The carrier may contain additives including solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
对于肠胃外给药， 特别适合的是注射溶液或混悬液， 优选活性成分溶解于多羟基 化蓖麻油中的水性溶液。 For parenteral administration, an injection solution or suspension is particularly suitable, and an aqueous solution in which the active ingredient is dissolved in polyhydroxylated castor oil is preferred.
具有滑石和 (或)碳水化合物载体或粘合剂等的片剂、 糖衣丸或胶囊特别适合于口 服给药。 优选地， 片剂、 糖衣丸或胶囊的载体包括乳糖、 玉米淀粉和 (或)马铃薯淀粉。
当可以使用加糖载体时， 可以使用糖浆剂或酗剂。 Tablets, dragees or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral administration. Preferably, the carrier of the tablet, dragee or capsule comprises lactose, corn starch and/or potato starch. A syrup or elixir may be used when a sugar-containing carrier can be used.
本发明提供了一种治疗或预防高尿酸血症或痛风病药物， 其包含上述具有黄嘌吟 氧化酶抑制活性的化合物或其药学上可接受的盐。 附图说明 The present invention provides a medicament for treating or preventing hyperuricemia or gout, which comprises the above compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof. DRAWINGS
图 1是本发明化合物的结构通式图； Figure 1 is a structural diagram of the compound of the present invention;
图 2是本发明化合物的制备流程图。 具体实施方式 Figure 2 is a flow diagram of the preparation of the compounds of the invention. detailed description
下面的实施例将对本发明予以进一步的说明， 但并不因此而限制本发明。 The invention is further illustrated by the following examples, which are not intended to limit the invention.
按照如图 2所示流程进行制备。 Prepare according to the procedure shown in Figure 2.
实施例 1. 3-溴 -4-羟基苯甲酵 (CSL-1)的制备 Example 1. Preparation of 3-bromo-4-hydroxybenzamide (CSL-1)
于 2000 mL三颈瓶中， 加入对羟基苯甲醛 （100 g， 0.820 mol)、 碘 （5 g， 0.0192 mol)和二氯甲烷 600 mL， -5 °C下机械搅拌 10 min。 将溴 （ 143.4 g， 0.902 mol)和二氯 甲烷 （200 mL) 的混合溶液缓慢滴入上述反应液中， 滴毕， 室温反应 24h。 反应毕， 将上述反应液缓慢倒入 1000 mL (16%)亚硫酸氢钠水溶液中， 搅拌 30 min后， 抽滤， 水洗， 干燥， 得粗品 120.0g， 产率： 72.7%， 所得粗产品未经纯化直接用于下一步反 应。 In a 2000 mL three-necked flask, p-hydroxybenzaldehyde (100 g, 0.820 mol), iodine (5 g, 0.0192 mol) and dichloromethane 600 mL were added, and mechanically stirred at -5 °C for 10 min. A mixed solution of bromine (143.4 g, 0.902 mol) and methylene chloride (200 mL) was slowly dropped into the above reaction solution, and the mixture was allowed to react at room temperature for 24 hours. After the reaction, the reaction solution was slowly poured into 1000 mL (16%) aqueous sodium hydrogen sulfite solution, stirred for 30 min, filtered, washed with water, and dried to give a crude product 120.0 g, yield: 72.7%. It was directly used for the next reaction by purification.
实施例 2. 3-溴 -4-垸氧基苯甲酵 (CSL-2)的制备 Example 2. Preparation of 3-bromo-4-decyloxybenzamide (CSL-2)
2.1 3-溴 -4-异丁氧基苯甲醛 (CSL-2-7)的制备 Preparation of 3-bromo-4-isobutoxybenzaldehyde (CSL-2-7)
将 3-溴 -4-羟基苯甲醛 （10.0g, 0.05mol)、 溴代异丁烷 （ 10.275g, 0.075mol)、 无水 碳酸钾 （8.97g, 0.065mol)、 碘化钾 ( 0.166g, O.OOlmol)加入到 100ml单口瓶内， 50 °C 氮气保护下搅拌反应 8小时， 反应毕， 抽滤， 滤饼用 DMF洗 2次， 减压旋转蒸去约 3/4的 DMF， 残留物用乙酸乙酯溶解， 水洗， 饱和食盐水洗， 无水硫酸钠干燥过夜， 旋去乙酸乙酯， 所得粗产品未经纯化直接用于下一步反应。 3-Bromo-4-hydroxybenzaldehyde (10.0 g, 0.05 mol), bromoisobutane (10.275 g, 0.075 mol), anhydrous potassium carbonate (8.97 g, 0.065 mol), potassium iodide (0.166 g, O. OOlmol) was added to a 100 ml single-mouth bottle, and the reaction was stirred under a nitrogen atmosphere at 50 °C for 8 hours. After completion of the reaction, the filter cake was washed twice with DMF, and about 3/4 of DMF was distilled off under reduced pressure. The ethyl ester was dissolved, washed with water, washed with brine, dried over anhydrous sodium sulfate, and evaporated.
2.2 3-溴 -4-甲氧基苯甲醛 (CSL-2-1)的制备 2.2 Preparation of 3-bromo-4-methoxybenzaldehyde (CSL-2-1)
将 3-溴 -4-羟基苯甲醛（10g, 0.05mol)、无水碳酸钾（13.8g, O.OOmol)和 DMF (40ml) 加入 100ml反应瓶内， 冰浴下滴加硫酸二甲酯 (6.6g, 0.035mol)， 滴毕， 室温下搅拌反 应 2h， TLC检测反应的完全程度，反应毕，将反应液倒入 100ml水中，室温搅拌 20min， 抽滤， 得粗品 9.7g， 产率： 90.6%， 所得粗产品未经纯化直接用于下一步反应。
2.3 3-溴 -4-乙氧基苯甲醛 (CSL-2-2)的制备 3-Bromo-4-hydroxybenzaldehyde (10 g, 0.05 mol), anhydrous potassium carbonate (13.8 g, 0.001 mol) and DMF (40 ml) were placed in a 100 ml reaction flask, and dimethyl sulfate was added dropwise under ice bath ( 6.6g, 0.035mol), after completion, the reaction was stirred at room temperature for 2 h, and the completeness of the reaction was detected by TLC. After completion of the reaction, the reaction solution was poured into 100 ml of water, stirred at room temperature for 20 min, and suction filtered to give 9.7 g of crude product. %, the crude product obtained was used in the next reaction without purification. Preparation of 3-bromo-4-ethoxybenzaldehyde (CSL-2-2)
以溴乙烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一步。 The ethyl bromide was used as the starting material, and the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next step without purification.
2.4 3-溴 -4-正丙氧基苯甲醛 (CSL-2-3)的制备 Preparation of 4-bromo-4-n-propoxybenzaldehyde (CSL-2-3)
以溴代正丙烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromo-n-propane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.5 3-溴 -4-异丙氧基苯甲醛 (CSL-2-4)的制备 Preparation of 2.5 3-bromo-4-isopropoxybenzaldehyde (CSL-2-4)
以溴代异丙烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromoisopropane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.6 3-溴 -4-正丁氧基苯甲醛 (CSL-2-5)的制备 Preparation of 2.6 3-bromo-4-n-butoxybenzaldehyde (CSL-2-5)
以溴代正丁烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromo-n-butane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.7 3-溴 -4-仲丁氧基苯甲醛 (CSL-2-6)的制备 Preparation of 2.7 3-bromo-4-sec-butoxybenzaldehyde (CSL-2-6)
以溴代仲丁烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromo sec-butane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.8 3-溴 -4-异戊氧基苯甲醛 (CSL-2-8)的制备 Preparation of 2.8 3-bromo-4-isopentyloxybenzaldehyde (CSL-2-8)
以溴代异戊烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromoisopentane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.9 3-溴 -4-正己基苯甲醛 (CSL-2-9)的制备 Preparation of 2.9 3-bromo-4-n-hexylbenzaldehyde (CSL-2-9)
以溴代正己烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromo-n-hexane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.10 3-溴 -4-正庚氧基苯甲醛 (CSL-2-10)的制备 2.10 Preparation of 3-bromo-4-n-heptyloxybenzaldehyde (CSL-2-10)
以溴代正庚烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromo-n-heptane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.11 3-溴 -4-正辛氧基苯甲醛 (CSL-2-11)的制备 2.11 Preparation of 3-bromo-4-n-octyloxybenzaldehyde (CSL-2-11)
以溴代正辛烷为原料， 制备方法同 (CSL-2-7), 所得粗产品未经纯化直接用于下一 少。 Starting from bromo-n-octane, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
2.12 3-溴 -4-甲基苄氧基苯甲醛 (CSL-2-12)的制备 2.12 Preparation of 3-bromo-4-methylbenzyloxybenzaldehyde (CSL-2-12)
以 4-甲基苄基氯为原料，制备方法同 (CSL-2-7),所得粗产品未经纯化直接用于下 少。 Using 4-methylbenzyl chloride as the starting material, the preparation method was the same as (CSL-2-7), and the obtained crude product was used in the next one without purification.
实施例 3. 3-氰基 -4-垸氧基苯甲酵 (CSL-3) 的制备
3.1 3-氰基 -4-异丁氧基苯甲醛 （CSL-3-7) 的制备 Example 3. Preparation of 3-cyano-4-nonyloxybenzamide (CSL-3) 3.1 Preparation of 3-cyano-4-isobutoxybenzaldehyde (CSL-3-7)
将 3-溴 -4-异丁氧基苯甲醛 (25.7g, 0.1mol)、 氰化亚铜 (9.9g, O. llmol) 和 DMF (100ml)加入 250ml反应瓶内， 150°C氮气保护下搅拌反应 6h， TLC检测反应的完全程 度， 反应毕， 反应液放置冷至室温， 将二氯甲烷加入反应液内， 抽滤， 滤饼用二氯甲 烷洗 2次， 取滤液， 依次用氨水、 水、 饱和食盐水洗， 无水硫酸钠干燥过夜， 减压除 去二氯甲烷， 所得粗产品未经纯化直接用于下一步。 Add 3-bromo-4-isobutoxybenzaldehyde (25.7 g, 0.1 mol), cuprous cyanide (9.9 g, O. llmol) and DMF (100 ml) to a 250 ml reaction flask under nitrogen at 150 ° C. The reaction was stirred for 6 h, and the completeness of the reaction was detected by TLC. After the reaction was completed, the reaction solution was allowed to stand to cool to room temperature, dichloromethane was added to the reaction mixture, and the mixture was filtered with suction. The filter cake was washed twice with dichloromethane, and the filtrate was taken, and then aqueous ammonia was used. The organic layer was washed with EtOAc (EtOAc m.
3.2 3-氰基 -4-甲氧基苯甲醛 （CSL-3-1) 的制备 3.2 Preparation of 3-cyano-4-methoxybenzaldehyde (CSL-3-1)
以 CSL-2-1 (CSL-3-1 是要制备的产物， 不能作为原料， 请确认！ 下同！！） 为原 料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一步。 With CSL-2-1 (CSL-3-1 is a product to be prepared, it cannot be used as a raw material, please confirm! The same as below!!) As a raw material, the preparation method is the same as (CSL-3-7), and the obtained crude product is not purified. Used directly in the next step.
3.3 3-氰基 -4-乙氧基苯甲醛 （CSL-3-2) 的制备 Preparation of 3-cyano-4-ethoxybenzaldehyde (CSL-3-2)
以 CSL-2-2为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-2 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.4 3-氰基 -4-正丙氧基苯甲醛 （CSL-3-3) 的制备 Preparation of 3.4 3-cyano-4-n-propoxybenzaldehyde (CSL-3-3)
以 CSL-2-3为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-3 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.5 3-氰基 -4-异丙氧基苯甲醛 （CSL-3-4) 的制备 Preparation of 3.5 3-cyano-4-isopropoxybenzaldehyde (CSL-3-4)
以 CSL-2-4为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-4 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.6 3-氰基 -4-正丁氧基苯甲醛 （CSL-3-5) 的制备 Preparation of 3.6 3-cyano-4-n-butoxybenzaldehyde (CSL-3-5)
以 CSL-2-5为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-5 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.7 3-氰基 -4-仲丁氧基苯甲醛 （CSL-3-6) 的制备 Preparation of 3.7 3-cyano-4-secutoxybenzaldehyde (CSL-3-6)
以 CSL-2-6为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-6 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.8 3-氰基 -4-异戊氧基苯甲醛 （CSL-3-8) 的制备 Preparation of 3.8 3-cyano-4-isopentyloxybenzaldehyde (CSL-3-8)
以 CSL-2-8为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-8 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.9 3-氰基 -4-正己基苯甲醛 （CSL-3-9) 的制备 Preparation of 3.9 3-cyano-4-n-hexylbenzaldehyde (CSL-3-9)
以 CSL-2-9为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。
3.10 3-氰基 -4-正庚氧基苯甲醛 （CSL-3-10) 的制备 Using CSL-2-9 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification. 3.10 Preparation of 3-cyano-4-n-heptyloxybenzaldehyde (CSL-3-10)
以 CSL-2-10为原料， 制备方法同（CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-10 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.11 3-氰基 -4-正辛氧基苯甲醛 （CSL-3-11 ) 的制备 3.11 Preparation of 3-cyano-4-n-octyloxybenzaldehyde (CSL-3-11)
以 CSL-2-11为原料， 制备方法同 （CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-11 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
3.12 3-氰基 -4-甲基苄氧基苯甲醛 （CSL-3-12) 的制备 3.12 Preparation of 3-cyano-4-methylbenzyloxybenzaldehyde (CSL-3-12)
以 CSL-2-12为原料， 制备方法同（CSL-3-7), 所得粗产品未经纯化直接用于下一 少。 Using CSL-2-12 as a raw material, the preparation method was the same as (CSL-3-7), and the obtained crude product was used in the next one without purification.
实施例 4. 2-(3-氰基 -4-垸氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-4)的制 备 Example 4. Preparation of ethyl 2-(3-cyano-4-oxooxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate (CSL-4)
4.1 2-(3-氰基 -4-异丁氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-4-7)的制备 将 3-氰基 -4-异丁氧基苯甲醛 ( 8.8g, 0.0432mol)、2-羟基亚胺 -3-氧代丁酸乙酯（8.3g, 0.0520mol)、 醋酸铵（33.3g, 0.4320mol)和醋酸（176ml)加入 500ml反应瓶内， 50°C 氮气保护下搅拌反应 24小时，反应毕，加反应液倒入水（500ml)中，室温下搅拌 30min, 抽滤， 滤饼用乙酸乙酯重结晶， 得白色固体粉末 10.3g, 收率： 69.4%, mp: 147.4-148.3 °C 4.1 Preparation of ethyl 2-(3-cyano-4-isobutoxy)phenyl-1-hydroxy-4-methyl-1H-imidazol-5-carboxylate (CSL-4-7) 3-cyano 4-isobutoxybenzaldehyde (8.8 g, 0.0432 mol), ethyl 2-hydroxyimine-3-oxobutanoate (8.3 g, 0.0520 mol), ammonium acetate (33.3 g, 0.4320 mol) and Acetic acid (176 ml) was added to a 500 ml reaction flask, and the reaction was stirred under a nitrogen atmosphere at 50 ° C for 24 hours. After the reaction was completed, the reaction solution was poured into water (500 ml), stirred at room temperature for 30 min, filtered, and filtered. Crystallization, white solid powder 10.3 g, yield: 69.4%, mp: 147.4-148.3 °C
MS (ESI): m/z 344.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 12.12 ( s, IH, NO-H) , 8.30d, IH, J=2.2Hz, Ar-H) ,8.28(dd, IH, J=2.2 & 9.6Hz, Ar-H), 7.39(d, IH, J=9.6Hz, Ar-H), 4.29(q, 2H, J=7.1Hz, CH2), 4.00(t, 2H, J=6.5Hz, CH2), 2.38(s, 3H, CH3), 2.08(m, IH, CH), 1.32(t, 3H, J=7.1Hz, CH3), 1.02(d, 6H, J=6.7Hz, CH3)。 MS (ESI): m/z 344.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 12.12 (s, IH, NO-H), 8.30d, IH, J=2.2Hz , Ar-H) , 8.28 (dd, IH, J=2.2 & 9.6Hz, Ar-H), 7.39(d, IH, 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, IH, CH), 1.32(t, 3H, J=7.1Hz, CH 3 ), 1.02 (d, 6H, J = 6.7 Hz, CH 3 ).
4.2 2-(3-氰基 -4-甲氧基)苯基- 1 -羟基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-4-1)的制备 以 （CSL-3-1 ) 为原料， 制备方法同 （CSL-4-7), 得白色固体粉末 12.3g, 收率： 4.2 Preparation of ethyl 2-(3-cyano-4-methoxy)phenyl-1-hydroxy-4-methylimidazolium-5-carboxylate (CSL-4-1) as (CSL-3-1) As a raw material, the preparation method was the same as (CSL-4-7), and 12.3 g of a white solid powder was obtained.
65.8%, mp: 173.2-175.1 t 65.8%, mp: 173.2-175.1 t
MS (ESI): m/z 302.3 [M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.32(d, IH, J=2.1Hz, Ar-H), 8.21(dd, IH, J=2.1&9.0Hz, Ar-H), 7.14(d, IH, J=8.1Hz, Ar-H), 4.4 l(q, 2H, J=6.9Hz: CH2), 3.94(s, 3H, CH3), 2.19(s, 3H, CH3), 1.26(d, 6H, J=6.9Hz, CH3)。 MS (ESI): m / z 302.3 [M + H] +; 1H-MNR (300 MHz, DMSO-d 6) 5ppm: 8.32 (d, IH, J = 2.1Hz, Ar-H), 8.21 (dd, IH, J=2.1 & 9.0 Hz, Ar-H), 7.14 (d, IH, J=8.1 Hz, Ar-H), 4.4 l (q, 2H, J=6.9 Hz : CH 2 ), 3.94 (s, 3H, CH 3 ), 2.19 (s, 3H, CH 3 ), 1.26 (d, 6H, J = 6.9 Hz, CH 3 ).
4.3 2-(3-氰基 -4-乙氧基)苯基 -1-羟基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-4-2)的制备 以（CSL-3-2)为原料，制备方法同（CSL-4-7)得白色固体粉末 9.9g, 收率： 55.0%, mp: 153.5-155.8°C
MS (ESI): m/z 316.3[M+H]+ ; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.28 (d, IH, J=2.1Hz, Ar-H), 8.23(dd, IH, J=2.4 & 9.0Hz, Ar-H), 7.26(d, IH, J=9.0Hz, Ar-H), 4.26(q, 2H, J=7.2Hz: CH2), 4.21(q, 2H, J=7.2Hz, CH2), 2.29(s, 3H, CH3), 1.40(t, 3H, J=6.9Hz, CH3), 1.28(t, 3H, J=7.2Hz, CH3)。 4.3 Preparation of ethyl 2-(3-cyano-4-ethoxy)phenyl-1-hydroxy-4-methyl-IH-imidazole-5-carboxylate (CSL-4-2) as (CSL-3) -2) As a raw material, the preparation method is the same as (CSL-4-7) white powder 9.9 g, yield: 55.0%, mp: 153.5-155.8 °C MS (ESI): m/z 316.3 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.28 (d, IH, J = 2.1 Hz, Ar-H), 8.23 (dd, IH, J=2.4 & 9.0Hz, Ar-H), 7.26(d, IH, J=9.0Hz, Ar-H), 4.26(q, 2H, J=7.2Hz : CH 2 ), 4.21(q, 2H , J = 7.2 Hz, CH 2 ), 2.29 (s, 3H, CH 3 ), 1.40 (t, 3H, J = 6.9 Hz, CH 3 ), 1.28 (t, 3H, J = 7.2 Hz, CH 3 ).
4.4 2-0氰基 -4-正丙氧基)苯基- 1 -羟基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-4-3)的制备 以（CSL-3-3 )为原料，制备方法同（CSL-4-7)得白色固体粉末 10.8g, 收率： 62.1%, mp: 152.2-154.1 °C。 Preparation of 4.4 2-0 cyano-4-n-propoxy)phenyl-1-hydroxy-4-methylimidazolium-5-carboxylate (CSL-4-3) with (CSL-3-3) The raw material was prepared in the same manner as (CSL-4-7) as a white solid powder, 10.8 g, yield: 62.1%, mp: 152.2-154.1 °C.
MS (ESI): m/z 330.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.29 ( dd, IH, J=8.9Hz & 2.1Hz, Ar-H), 8.26(s, IH, Ar-H), 7.40(d, IH, J=9.0Hz, Ar-H), 4.38(q, 2H, J=7.2Hz, CH2), 4.22(t, 2H, J=6.6Hz, CH2), 2.25(s, 3H, CH3), 1.84(m, 2H, CH2), 1.35(t, 3H, J=7.3Hz, CH3), 1.03(t, 3H, J=7.1Hz, CH3)。 MS (ESI): m/z 330.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.29 ( dd, IH, J = 8.9 Hz & 2.1 Hz, Ar-H), 8.26 (s, IH, Ar-H), 7.40 (d, IH, J = 9.0 Hz, Ar-H), 4.38 (q, 2H, J = 7.2 Hz, CH 2 ), 4.22 (t, 2H, J = 6.6 Hz, 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=7.1 Hz, CH 3 ).
4.5 2-0氰基 -4-异丙氧基)苯基- 1 -羟基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-4-4)的制备 以（CSL-3-4)为原料，制备方法同（CSL-4-7)得白色固体粉末 12.2g,收率： 70.1%, mp: 150.2-151.9°C o Preparation of 4.5 2-0 cyano-4-isopropoxy)phenyl-1-hydroxy-4-methylimidazolium-5-carboxylate (CSL-4-4) with (CSL-3-4) The raw material was prepared in the same manner as (CSL-4-7) white solid powder 12.2 g, yield: 70.1%, mp: 150.2-151.9 °C o
MS (ESI): m/z 330.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.26 (dd, lH,J=8.8Hz & 2.1Hz, Ar-H), 8.23 (d, IH, J=2. lHz,Ar-H),7.40(d, IH, J=8.9Hz,Ar-H), 4.88(m,lH,CH), 4.35(q, 2H,J=7.2Hz,CH2), 2.42(s,3H,CH3), 1.38(d,6H,J=6.3Hz,CH3), 1.35(t,3H, MS (ESI): m/z 330.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.26 (dd, lH, J = 8.8 Hz & 2.1 Hz, Ar-H), 8.23 (d, IH, J = 2. lHz, Ar-H), 7.40 (d, IH, J = 8.9 Hz, Ar-H), 4.88 (m, lH, CH), 4.35 (q, 2H, J = 7.2 Hz, CH 2 ), 2.42 (s, 3H, CH 3 ), 1.38 (d, 6H, J = 6.3 Hz, CH 3 ), 1.35 (t, 3H,
J=7.0Hz,CH3)。 J = 7.0 Hz, CH 3 ).
4.6 2-(3-氰基 -4-正丁氧基)苯基 -1-羟基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-4-5)的制备 以（CSL-3-5 )为原料，制备方法同（CSL-4-7)得白色固体粉末 12.0g,收率： 71.0%, mp: 149.8-150.5°C。 4.6 Preparation of 2-(3-cyano-4-n-butoxy)phenyl-1-hydroxy-4-methyl-IH-imidazole-5-carboxylic acid ethyl ester (CSL-4-5) as (CSL- 3-5) As a raw material, the preparation method was the same as (CSL-4-7) white solid powder 12.0 g, yield: 71.0%, mp: 149.8-150.5 °C.
MS (ESI): m/z 344.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 12.16 ( s, IH, NO-H), 8.28 (dd,lH,J=2.1&8.7Hz, Ar-H), 8.26(d,lH,J=2.4Hz,Ar-H), MS (ESI): m/z 344.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 12.16 (s, IH, NO-H), 8.28 (dd, lH, J=2.1 &8.7Hz, Ar-H), 8.26 (d, lH, J = 2.4Hz, Ar-H),
7.39(d,lH,J=9.6Hz,Ar-H), 4.30 (q,2H,J=7.2Hz,CH2), 4.21(t,2H,J=6.3Hz,CH2), 7.39 (d, lH, J = 9.6 Hz, Ar-H), 4.30 (q, 2H, J = 7.2 Hz, CH 2 ), 4.21 (t, 2H, J = 6.3 Hz, CH 2 ),
2.37(s,3H,CH3), 1.77(m,2H,CH2), 1.48(m,2H, CH3), 1.32(t,3H,J=6.9Hz, CH3), 0.96(t, 3H,J=7.5Hz, CH3)。 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 = 7.5 Hz, CH 3 ).
4.7 2-(3-氰基 -4-仲丁氧基)苯基 -1-羟基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-4-6)的制备 以（CSL-3-6)为原料，制备方法同（CSL-4-7)得白色固体粉末 11.8g,收率： 69.8%, mp: 159.8-162.3 °C。 4.7 Preparation of ethyl 2-(3-cyano-4-sec-butoxy)phenyl-1-hydroxy-4-methyl-IH-imidazole-5-carboxylate (CSL-4-6) as (CSL- 3-6) As a raw material, the preparation method was the same as (CSL-4-7) white solid powder 11.8 g, yield: 69.8%, mp: 159.8-162.3 °C.
MS (ESI): m/z 344.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 12.11 ( s,lH, NO-H),
8.28 ( s,lH,Ar-H) ,8.24(d,lH,J=9.1Hz,Ar-H),7.41(d,lH,J=9.0Hz,Ar-H),4.67(m,lH,CH), 4.29(q,2H,J=9. lHz,CH2),2.38(s,3H,CH3), 1.77(m,2H,CH2), 1.7(m,2H,CH3), 1.30(m,6H,2CH3 ), 0.96((t,3H,J=7.4Hz, CH3)。 MS (ESI): m/z 344.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 12.11 (s,lH, NO-H), 8.28 ( s, lH, Ar-H) , 8.24 (d, lH, J = 9.1 Hz, Ar-H), 7.41 (d, lH, J = 9.0 Hz, Ar-H), 4.67 (m, lH, CH) ), 4.29 (q, 2H, J = 9. lHz, 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 = 7.4 Hz, CH 3 ).
4.8 2-0氰基 -4-异戊氧基)苯基- 1 -羟基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-4-8)的制备 以（CSL-3-8)为原料，制备方法同（CSL-4-7)得白色固体粉末 11.5g,收率： 69.7%, mp: 148.8-150.rC。 Preparation of 4.8 2-0 cyano-4-isopentyloxy)phenyl-1-hydroxy-4-methylimidazolium-5-carboxylate (CSL-4-8) with (CSL-3-8) The starting material was prepared in the same manner as (CSL-4-7) as a white solid powder (11.5 g, yield: 69.7%, mp: 148.8-150.r.
MS (ESI): m/z 358.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.41 MS (ESI): m/z 358.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.41
( s,lH,Ar-H) ,8.25 (dd,lH,J=2.1&8.7Hz，Ar-H),7.21(d,lH,J=9.0Hz,Ar-H), (s, lH, Ar-H), 8.25 (dd, lH, J = 2.1 & 8.7 Hz, Ar-H), 7.21 (d, lH, J = 9.0 Hz, Ar-H),
4.20(q,2H,J=6.9Hz,CH2), 4.18(t,2H,J=6.3Hz,CH2), 2.24(s,3H,CH3), 1.85(m, 1H,CH), 1.68(q,2H, J=6.6Hz,CH2), 1.27(t,3H, J=6.9Hz, CH3), 0.98((d,6H,J=6.6Hz, CH3)。 4.20 (q, 2H, J = 6.9 Hz, CH 2 ), 4.18 (t, 2H, J = 6.3 Hz, CH 2 ), 2.24 (s, 3H, CH 3 ), 1.85 (m, 1H, CH), 1.68 (q, 2H, J = 6.6 Hz, CH 2 ), 1.27 (t, 3H, J = 6.9 Hz, CH 3 ), 0.98 ((d, 6H, J = 6.6 Hz, CH 3 ).
4.9 2-0氰基 -4-正己氧基)苯基- 1 -羟基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-4-9)的制备 以（CSL-3-9)为原料，制备方法同（CSL-4-7)得白色固体粉末 10.3g,收率： 64.1%, mp: 109.3-112.8°C。 Preparation of 4.9 2-0 cyano-4-n-hexyloxy)phenyl-1-hydroxy-4-methylimidazolium-5-carboxylate (CSL-4-9) using (CSL-3-9) as raw material The preparation method was the same as (CSL-4-7) to obtain 10.3 g of a white solid powder, yield: 64.1%, mp: 109.3-112.8 °C.
MS (ESI): m/z 372.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 12.14( s,lH, NO-H), 8.29( s,lH,Ar-H),8.27(s,lH,Ar-H),7.38(d,lH,J=8.6Hz,Ar-H),4.29(q,2H,J=7.1Hz,CH2),4.20 (t,2H,J=6.4Hz, CH2),2.50(s,3H, CH3), 1.77(m,2H,CH2), 1.46(m,2H,CH3), MS (ESI): m / z 372.4 [M + H] +; 1H-MNR (300 MHz, DMSO-d 6) 5ppm: 12.14 (s, lH, NO-H), 8.29 (s, lH, Ar-H ), 8.27 (s, lH, Ar-H), 7.38 (d, lH, J = 8.6 Hz, Ar-H), 4.29 (q, 2H, J = 7.1 Hz, CH 2 ), 4.20 (t, 2H, J = 6.4 Hz, 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,CH2 &CH3), 0.87(t,3H,J=6.9Hz, CH3)。 1.35-1.29 (m, 7H, CH 2 &CH 3 ), 0.87 (t, 3H, J = 6.9 Hz, CH 3 ).
4.10 2-0氰基 -4-正庚氧基；)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-4-10)的制 备 4.10 Preparation of 2-0 cyano-4-n-heptyloxy;)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate (CSL-4-10)
以（CSL-3-10)为原料，制备方法同（CSL-4-7)得白色固体粉末 10.5g,收率： 66.8%, mp: 139.5-142.2 °C。 Using (CSL-3-10) as a raw material, the preparation method was the same as (CSL-4-7) white solid powder 10.5g, yield: 66.8%, mp: 139.5-142.2 °C.
MS (ESI): m/z 386.5[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.27 (d,lH,J=2.0Hz, Ar-H),8.24(dd,lH,J=2.2 & 8.6Hz,Ar-H),7.39(d,lH,J=8.9Hz,Ar-H),4.24(q,2H,J=7.1Hz,CH2), 4.18(t,2H,J=6.4Hz,CH2),2.3 l(s,3H,CH3), 1.75(m,2H,CH), 1.48-1.28(m, 11H,CH2 & CH3), 0.88 (t,3H,J=6.7Hz, CH3)。 MS (ESI): m/z 386.5 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.27 (d,lH,J=2.0 Hz, Ar-H), 8.24 (dd, lH, J = 2.2 & 8.6 Hz, Ar-H), 7.39 (d, lH, J = 8.9 Hz, Ar-H), 4.24 (q, 2H, J = 7.1 Hz, CH 2 ), 4.18 (t, 2H) , J = 6.4 Hz, CH 2 ), 2.3 l (s, 3H, CH 3 ), 1.75 (m, 2H, CH), 1.48-1.28 (m, 11H, CH2 & CH 3 ), 0.88 (t, 3H, J = 6.7 Hz, CH 3 ).
4.11 2-(3-氰基 -4-正辛氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-4-11)的制 备 4.11 Preparation of ethyl 2-(3-cyano-4-n-octyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate (CSL-4-11)
以（CSL-3-11 )为原料，制备方法同（CSL-4-7)得白色固体粉末 ll. lg,收率： 72.1%, mp: 143.2-145.rC。 (CSL-3-11) was used as the starting material, and the white powder was obtained by the method of (CSL-4-7). ll. lg, yield: 72.1%, mp: 143.2-145.rC.
MS (ESI): m/z 400.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.35 (d,lH,J=1.8Hz,
Ar-H) ,8.19(dd, lH,J=2.1&9.0Hz,Ar-H),7.39(d, lH,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,CH2),4.14(q,2H,J=7.2Hz,CH2),2.33(s,3H,CH3) 2.20(s, 3H,CH3), 125((t,3H,J=6.9Hz, CH3)。 MS (ESI): m/z 400.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.35 (d, lH, J = 1.8 Hz, Ar-H) , 8.19 (dd, lH, J = 2.1 & 9.0 Hz, Ar-H), 7.39 (d, lH, J = 8.1 Hz, Ar-H), 7.26 (d, 2H, J = 8.9 Hz, Ar- H), 7.24 (d, 2H, J = 8.4 Hz, Ar-H), 5.24 (s, 2H, CH 2 ), 4.14 (q, 2H, J = 7.2 Hz, CH 2 ), 2.33 (s, 3H, CH 3 ) 2.20 (s, 3H, CH 3 ), 125 ((t, 3H, J = 6.9 Hz, CH 3 ).
4.12 2-0氰基 -4-甲基苄氧基;)苯基- 1 -羟基 -4-甲基- 1H-咪唑 -5-甲酸乙酯 (CSL-4-12)的制 备 4.12 Preparation of 2-0 cyano-4-methylbenzyloxy;)phenyl-1-hydroxy--4-methyl-1H-imidazole-5-carboxylate (CSL-4-12)
以 （CSL-3-12) 为原料， 制备方法同 （CSL-4-7), 得白色固体粉末 10.9g,收率： 70.0%, mp: 150.3-151.5 °C。 (CSL-3-12) was used as the starting material, and the preparation method was the same as (CSL-4-7) to obtain a white solid powder, 10.9 g, yield: 70.0%, mp: 150.3-151.5 °C.
MS (ESI): m/z 392.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.27 ( dd, lH,J=2.1& 7.2Hz,Ar-H), 8.26(s, lH,Ar-H), 7.5 l(d, lH,J=7.2Hz,Ar-H), 7.39(d,2H,J=8. lHz,Ar-H), 7.24(d, 2H,j=7.8Hz,Ar-H), 5.32(s,2H,CH2), 4.31(q,2H,J=7.2Hz,CH2), 3.96(s,3H,CH3), 2.40(s,3H,CH3), 2.32(s,3H,CH3), 1.33((t,3H,J=7.2 Hz, CH3)。 MS (ESI): m/z 392.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.27 ( dd, lH, J = 2.1 & 7.2 Hz, Ar-H), 8.26 ( s, lH, Ar-H), 7.5 l (d, lH, J = 7.2 Hz, Ar-H), 7.39 (d, 2H, J = 8. lHz, Ar-H), 7.24 (d, 2H, j = 7.8 Hz, Ar-H), 5.32 (s, 2H, CH 2 ), 4.31 (q, 2H, J = 7.2 Hz, 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 = 7.2 Hz, CH 3 ).
实施例 5. 2-(3-氰基 -4-垸氧基)苯基 -1-羟基 -4-甲基 咪唑 -5-甲酸 Example 5. 2-(3-Cyano-4-indolyl)phenyl-1-hydroxy-4-methylimidazole-5-carboxylic acid
5.1 2-(3-氰基 -4-异丁氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-6) 5.1 2-(3-Cyano-4-isobutoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-6)
将 2-(3-氰基 -4-异丁氧基苯基）-1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 ( 1.0g,2.9mmol)、 氢氧化钠水溶液 ( lmol/L, l 1.0ml) 和四氢呋喃:无水乙醇 ( 1 : 1 ) 的 混合溶剂 （10ml) 加入 25ml反应瓶内， 50°C下搅拌反应 8小时， TLC检测反应的完 全程度， 反应毕， 减压蒸去部分有机溶剂， 然后用 5%的稀盐酸调节溶液 pH为 1， 静 置 30min， 抽滤， 滤饼自然干燥， 用甲醇：乙酸乙酯 （2: 1 ) 混合溶剂重结晶， 得白色 固体粉末 0.60g,收率： 65.2%， mp: 191.6-192.2°C。 2-(3-Cyano-4-isobutoxyphenyl)-1-hydroxy-4-methyl-1H-imidazol-5-carboxylic acid ethyl ester (1.0 g, 2.9 mmol), aqueous sodium hydroxide ( 1mol/L, l 1.0ml) and tetrahydrofuran: anhydrous ethanol (1:1) mixed solvent (10ml) was added to a 25ml reaction flask, stirred at 50 ° C for 8 hours, TLC detection of the complete degree of reaction, reaction, The organic solvent was distilled off under reduced pressure, and then the pH of the solution was adjusted to 1 with 5% diluted hydrochloric acid, allowed to stand for 30 min, suction filtered, and the filter cake was naturally dried and recrystallized from a solvent mixture of methanol:ethyl acetate (2:1). White solid powder 0.60 g, yield: 65.2%, mp: 191.6-192.2 °C.
MS (ESI): m/z 316.1291 [M+H]+ ; 1H-MNR (300 MHz, DMSO-d6) 5ppm:8.55 ( s, lH, Ar-H), 8.47(d, lH,J=8.8Hz,Ar-H), 7.46(d, lH,J=9.0Hz,Ar-H), 4.00(d,2H,J=6.4Hz,CH2), MS (ESI): m/z 316.1291 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.55 (s, lH, Ar-H), 8.47 (d, lH, J = 8.8 Hz, Ar-H), 7.46 (d, lH, J = 9.0 Hz, Ar-H), 4.00 (d, 2H, J = 6.4 Hz, CH 2 ),
2.51(s,3H,CH3), 2.10(m, lH,CH), 1.03(d,6H,J=6.7Hz,CH3)。 2.51 (s, 3H, CH 3 ), 2.10 (m, lH, CH), 1.03 (d, 6H, J = 6.7 Hz, CH 3 ).
5.2 2-(3-氰基 -4-甲氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-1 ) 的制备 以 （CSL-4-1 ) 为原料， 制备方法同 （CSL-HI-6) ，得白色固体粉末 0.50g ,收率： 5.2 Preparation of 2-(3-cyano-4-methoxy)phenyl-1-hydroxy-4-methyl-1H-imidazol-5-carboxylic acid (CSL-HI-1) as (CSL-4-1) ) As a raw material, the preparation method is the same as (CSL-HI-6), and 0.50 g of a white solid powder is obtained. Yield:
52.5%, mp: 214.1-214.5 °C。 52.5%, mp: 214.1-214.5 °C.
MS (ESI): m/z 296.0642 [M+Na]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.60 (d, lH, J=2.0Hz,Ar-H), 8.44(dd, lH,J=8.8Hz和 2.2Hz,Ar-H), 7.27(d, lH,8.9Hz, Ar-H), 3.88(s,3H,
MS (ESI): m / z 296.0642 [M + Na] +; 1H-MNR (300 MHz, DMSO-d 6) 5ppm: 8.60 (d, lH, J = 2.0Hz, Ar-H), 8.44 (dd, lH, J = 8.8 Hz and 2.2 Hz, Ar-H), 7.27 (d, lH, 8.9 Hz, Ar-H), 3.88 (s, 3H,
5.3 2-(3-氰基 -4-正丙氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-2) 的制备 以 （CSL-4-3 ) 为原料， 制备方法同 （CSL-HI-6), 得白色固体粉末 0.60g , 收率：
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75.0%, mp: 190.8-191.1 °C。 LZ££L0/£l0ZSLD/∑Jd WI O/ OZ OAV 75.0%, mp: 190.8-191.1 °C.
MS (ESI): m/z 344.1605[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.53 ( s,lH,Ar-H), 8.45(d,lH,J=8.7Hz,Ar-H), 7.45(d,lH,J=8.9Hz,Ar-H), 4.21(t,2H, J=5.9Hz,CH2), 2.50(s,3H, CH3), 1.78(m,2H,CH2), 1.46(m,2H,CH2), 1.34(m,4H, CH2), 0.89(s,3H, CH3)。 MS (ESI): m/z: 344.1 459 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.53 (s,lH,Ar-H), 8.45 (d,lH,J=8.7 Hz, Ar-H), 7.45 (d, lH, J = 8.9 Hz, Ar-H), 4.21 (t, 2H, J = 5.9 Hz, CH 2 ), 2.50 (s, 3H, CH 3 ), 1.78 ( m, 2H, CH 2 ), 1.46 (m, 2H, CH 2 ), 1.34 (m, 4H, CH 2 ), 0.89 (s, 3H, CH 3 ).
5.9 2-(3-氰基 -4-正庚氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-9) 的制备 以 （CSL-4-10) 为原料， 制备方法同 （CSL-HI-6)， 得白色固体粉末 0.68g ,收率： 70.8%, mp: 194.3-194.9°C o 5.9 Preparation of 2-(3-cyano-4-n-heptyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazol-5-carboxylic acid (CSL-HI-9) as (CSL-4- 10) As the raw material, the preparation method is the same as (CSL-HI-6), and the white solid powder is 0.68 g, the yield is 70.8%, mp: 194.3-194.9 °C o
MS (ESI): m/z 358.1761 [M+H]+; 1H-MNR (600 MHz, DMSO-d6) 5ppm: 17.31 ( s,lH, Ar-NOH) , 13.75(s, lH,COOH),8.55(s, lH,Ar-H),8.48(d, 1H, J=8.9Hz,Ar-H),7.47(d, 1H, J=9. lHz,Ar-H),4.22(t,2H,J=6.4Hz,CH2),2.51(s,3H,CH3), 1.78(m,2H,CH2), 1.45(m,2H,CH2), 1.35 (m,2H,CH2),1.29(m,4H,CH2),0.88(t,3H,J= 6.6 Hz,CH3)。 MS (ESI): m/z 358.1761 [M+H] + ; 1H-MNR (600 MHz, DMSO-d 6 ) 5 ppm: 17.31 (s,lH, Ar-NOH), 13.75 (s, lH, COOH), 8.55 (s, lH, Ar-H), 8.48 (d, 1H, J = 8.9 Hz, Ar-H), 7.47 (d, 1H, J = 9. lHz, Ar-H), 4.22 (t, 2H, J = 6.4 Hz, 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 = 6.6 Hz, CH 3 ).
5.10 2-(3-氰基 -4-正辛氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸（CSL-HI-10)的制备 以 （CSL-4-11 ) 为原料， 制备方法同 （CSL-HI-6), 得白色固体粉末 0.68g， 收率： 5.10 Preparation of 2-(3-cyano-4-n-octyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazol-5-carboxylic acid (CSL-HI-10) as (CSL-4- 11) As a raw material, the preparation method is the same as (CSL-HI-6), and a white solid powder is obtained in an amount of 0.68 g.
70.8%, mp: 186.5-187.5°C。 70.8%, mp: 186.5-187.5 °C.
MS (ESI): m/z 372.1918[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.76 MS (ESI): m/z 3721.918 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 13.76
( s,lH,COOH), 8.57(s,lH,Ar-H), 8.51(d,lH,J=9.2Hz,Ar-H), 7.50(d,lH,J=9.1Hz,Ar-H), 4.23(t,2H,J=6.4Hz,CH2), 2.52(s,3H,CH3), 1.78(m,2H,CH2), 1.44(m,2H,CH2), (s, lH, COOH), 8.57 (s, lH, Ar-H), 8.51 (d, lH, J = 9.2 Hz, Ar-H), 7.50 (d, lH, J = 9.1 Hz, Ar-H) , 4.23 (t, 2H, J = 6.4 Hz, 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,CH2), 0.86(t,3H,J=6.4Hz, CH3)。 1.41-1.27 (m, 8H, CH 2 ), 0.86 (t, 3H, J = 6.4 Hz, CH 3 ).
5.11 2-0氰基 -4-甲基苄氧基;)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-11 ) 的制 备 Preparation of 5.11 2-0 cyano-4-methylbenzyloxy;)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-11)
以 （CSL-4-12) 为原料， 制备方法同 （CSL-HI-6), 得白色固体粉末 0.69g ,收率： 71.9%, mp: 199.2-199.8°C o Using (CSL-4-12) as the starting material, the preparation method is the same as (CSL-HI-6), and the white solid powder is 0.69 g, the yield is 71.9%, mp: 199.2-199.8 °C o
MS (ESI): m/z 364.1292[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.81 MS (ESI): m/z 364.1292 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 13.81
( s,lH,COOH), 8.58(s,lH,Ar-H), 8.51(d,lH,J=8.9Hz,Ar-H), 7.60(d, 1H, J=9. lHz,Ar-H), 7.39(d,2H,J=8.0Hz,Ar-H), 7.24(d,2H,J=7.9Hz,Ar-H), 5.33(s,2H,CH2), 2.51(s,3H,CH2), 2.32(s,3H,CH3) o (s, lH, COOH), 8.58 (s, lH, Ar-H), 8.51 (d, lH, J = 8.9 Hz, Ar-H), 7.60 (d, 1H, J = 9. lHz, Ar-H ), 7.39 (d, 2H, J = 8.0 Hz, Ar-H), 7.24 (d, 2H, J = 7.9 Hz, Ar-H), 5.33 (s, 2H, CH 2 ), 2.51 (s, 3H, CH 2 ), 2.32(s,3H,CH 3 ) o
实施例 6. 2-(3-氰基 -4-垸氧基)苯基 -1-甲氧基 -4-甲基 咪唑 -5-甲酸乙酯 （CSL-5) 的制备 Example 6. Preparation of ethyl 2-(3-cyano-4-indolyl)phenyl-1-methoxy-4-methylimidazole-5-carboxylate (CSL-5)
6.1 2-(3-氰基 -4-异丁氧基)苯基 -1-甲氧基 -4-基 -1H-咪唑 -5-甲酸乙酯 (CSL -5-6)的制备 将 2-(3-氰基 -4-异丁氧基）苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （1.5g,
4.37mmol)、 无水碳酸钾 （ 1.2g, 8.74mmol) 禾 P DMF (6ml)加入 25ml反应瓶内， 加毕， 冰浴下滴加硫酸二甲酯， 滴毕， 室温下搅拌反应 1.5h， TLC检测反应的完全程度， 反 应毕， 将反应液倒入 50ml水中， 室温下搅拌 20min， 抽滤， 乙酸乙酯重结晶， 得灰 白色固体 1.45g, 产率： 92.9%， mp: 123.8-124.9°C。 6.1 Preparation of ethyl 2-(3-cyano-4-isobutoxy)phenyl-1-methoxy-4-yl-1H-imidazol-5-carboxylate (CSL-5-6) 2- (3-Cyano-4-isobutoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid ethyl ester (1.5 g, 4.37 mmol), anhydrous potassium carbonate (1.2 g, 8.74 mmol) and P DMF (6 ml) were added to a 25 ml reaction flask. After the addition, dimethyl sulfate was added dropwise under ice bath, and the reaction was stirred at room temperature for 1.5 h. TLC was used to detect the completeness of the reaction. After the reaction was completed, the reaction mixture was poured into 50 ml of water, stirred at room temperature for 20 min, filtered with suction, and ethyl acetate was recrystallized to give a white solid 1.45 g, yield: 92.9%, mp: 123.8-124.9 C.
MS (ESI): m/z 358.4[M+H]+。 MS (ESI): m/z 358.4 [M+H] + .
6.2 2-(3-氰基 -4-乙氧基)苯基- 1 -甲氧基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-5- 1)的制备 以 （CSL-4-2) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.33g,产率： 84.7%。 mp: 145.1-147.4°C。 6.2 Preparation of ethyl 2-(3-cyano-4-ethoxy)phenyl-1-methoxy-4-methylimidazolium-5-carboxylate (CSL-5-1) as (CSL-4- 2) As a raw material, the preparation method was the same as (CSL-5-6) to obtain a white solid 1.33 g, yield: 84.7%. Mp: 145.1-147.4 °C.
MS (ESI): m/z 330.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm:8.27 MS (ESI): m/z 330.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.
( dd, lH,J=2.3Hz& 8.8Hz,Ar-H), 8.24(d, IH, J=l .9Hz,Ar-H), 7.41(d, lH,J=8.9Hz,Ar-H), 4.31(m,4H,CH2), 3.96(s, 3H,CH3), 2.40(s,3H,CH3), 1.41(t,3H,J=6.9Hz,CH3),(dd, lH, J=2.3Hz & 8.8Hz, Ar-H), 8.24(d, IH, J=l.9Hz, Ar-H), 7.41(d, lH, 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 ),
6.3 2-0氰基 -4-正丙氧基;)苯基 -1-甲氧基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-5-2;)的制 备 6.3 Preparation of 2-2-cyano-4-n-propoxy;)phenyl-1-methoxy-4-methyl-IH-imidazole-5-carboxylic acid ethyl ester (CSL-5-2;)
以 （CSL-4-3 ) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.23g,产率： 78.8%。 mp: 143.2-144.5 °C。 Using (CSL-4-3) as a starting material, the preparation was carried out in the same manner as (CSL-5-6) to give a white solid, 1.23 g, yield: 78.8%. Mp: 143.2-144.5 °C.
MS (ESI): m/z 344.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.27 ( dd, lH,J=8.7Hz& 2.3Hz,Ar-H), 8.24(s, lH,Ar-H), 7.42(d, lH,J=8.8Hz,Ar-H), MS (ESI): m/z 344.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.27 ( dd, lH, J = 8.7 Hz & 2.3 Hz, Ar-H), 8.24 ( s, lH, Ar-H), 7.42 (d, lH, J = 8.8 Hz, Ar-H),
4.33(q,2H,J=7.2Hz,CH2), 4.19(t, 2H,J=6.4Hz,CH2), 3.96(s,3H,CH3), 2.40(s,3H,CH3), 1.80(m,2H,CH2), 1.33(t,3H,J=7.1Hz,CH3), 1.03(t,3H,J=7.3Hz,CH3)。 4.33 (q, 2H, J = 7.2 Hz, CH 2 ), 4.19 (t, 2H, J = 6.4 Hz, 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 = 7.1 Hz, CH 3 ), 1.03 (t, 3H, J = 7.3 Hz, CH 3 ).
6.4 2-(3-氰基 -4-异丙氧基)苯基 -1-甲氧基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-5-3)的制 备 6.4 Preparation of ethyl 2-(3-cyano-4-isopropoxy)phenyl-1-methoxy-4-methyl-IH-imidazole-5-carboxylate (CSL-5-3)
以 （CSL-4-4) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.26g, 产率： 80.8%， mp: 170.4-172.8°C。 Using (CSL-4-4) as a starting material, the preparation method was the same as (CSL-5-6), yielding a white solid 1.26 g, yield: 80.8%, mp: 170.4-172.8 °C.
MS (ESI): m/z 344.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.27 MS (ESI): m/z 344.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.27
( dd, lH,J=8.5Hz& 2.3Hz,Ar-H), 8.24(d, IH, J=2.3Hz,Ar-H), 7.45(d, lH,J=8.6Hz,Ar-H), 4.90(m, lH,CH),4.32(q,2H, J=7. lHz,CH2), 3.96(s,3H,CH3), 2.40(s,3H,CH3), (dd, lH, J=8.5Hz & 2.3Hz, Ar-H), 8.24(d, IH, J=2.3Hz, Ar-H), 7.45(d, lH, J=8.6Hz, Ar-H), 4.90 (m, lH, CH), 4.32 (q, 2H, J = 7. lHz, CH 2 ), 3.96 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ),
1.36(d,6H,J=5.9Hz,CH3), 1.31(t,3H,J=7.1 Hz,CH3)。 1.36 (d, 6H, J = 5.9 Hz, CH 3 ), 1.31 (t, 3H, J = 7.1 Hz, CH 3 ).
6.5 2-0氰基 -4-正丁氧基;)苯基 -1-甲氧基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-5-4;)的制 备
以 （CSL-4-5 ) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.35g,产率： 86.5%， mp: 135.4-136.2°C。 Preparation of 6.5 2-0 cyano-4-n-butoxy;)phenyl-1-methoxy-4-methyl-IH-imidazole-5-carboxylic acid ethyl ester (CSL-5-4;) Using (CSL-4-5) as a starting material, the preparation method was the same as (CSL-5-6), yielding white solid 1.35g, yield: 86.5%, mp: 135.4-136.2 °C.
MS (ESI): m/z 358.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.26 MS (ESI): m/z 358.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.26
( dd, lH,J=8.8Hz& 2.3Hz,Ar-H), 8.24(d, IH, J=l .9Hz,Ar-H), 7.42(d, IH, J=8.9Hz,Ar-H), 4.32(q,2H,J=7.1Hz,CH2),4.23(t,2H,J=6.4Hz,CH2), 3.96(s,3H,CH3), 2.34(s,3H,CH3), 1.77(m,2H,CH2), 1.48(m,2H,CH2), 1.33(t,3H,J=7.1Hz,CH3), 0.96(t,3H,J= 7.3Hz,CH3)。(dd, lH, J=8.8Hz & 2.3Hz, Ar-H), 8.24(d, IH, J=l.9Hz, Ar-H), 7.42(d, IH, J=8.9Hz, Ar-H), 4.32 (q, 2H, J = 7.1 Hz, CH 2 ), 4.23 (t, 2H, J = 6.4 Hz, 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 = 7.1 Hz, CH3), 0.96 (t, 3H, J = 7.3 Hz, CH3).
6.6 2-(3-氰基 -4-仲丁氧基)苯基 -1-甲氧基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-5-5)的制 备 Preparation of 6.6 2-(3-cyano-4-sec-butoxy)phenyl-1-methoxy-4-methyl-IH-imidazole-5-carboxylic acid ethyl ester (CSL-5-5)
以 （CSL-4-6) 为原料， 制备方法同 (CSL-5-6;), 得白色固体 1.38g, 产率： 88.5%， mp: 122.9-123.1 °C。 Using (CSL-4-6) as a starting material, the preparation method was the same as (CSL-5-6;), yielding white solid 1.38 g, yield: 88.5%, mp: 122.9-123.1 °C.
MS (ESI): m/z 358.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.26 MS (ESI): m/z 358.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.26
( dd, lH,J=8.8Hz& 2.1Hz,Ar-H), 8.24(s, lH,Ar-H), 7.5 l(d, lH,J=9.0Hz,Ar-H), (dd, lH, J=8.8Hz & 2.1Hz, Ar-H), 8.24(s, lH, Ar-H), 7.5 l(d, lH, J=9.0Hz, Ar-H),
4.69(m, lH,CH), 4..31(q,2H,J=6.9 Hz,CH2), 3.96(s,3H,CH3), 2.40(s,3H,CH3), 4.69 (m, lH, CH), 4..31 (q, 2H, J = 6.9 Hz, CH 2 ), 3.96 (s, 3H, CH3), 2.40 (s, 3H, CH 3 ),
1.70(m,2H,CH2), 134(t,3H,J=6.9Hz,CH3), 1.3 l(d, 3H,J=6.0Hz,CH3), 1.70 (m, 2H, CH 2 ), 134 (t, 3H, J = 6.9 Hz, CH 3 ), 1.3 l (d, 3H, J = 6.0 Hz, CH 3 ),
0.96(t,3H,J=7.2Hz,CH3) 0.96 (t, 3H, J = 7.2 Hz, CH 3 )
6.7 2-(3-氰基 -4-异戊氧基)苯基 -1-甲氧基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-5-7)的制 备 6.7 Preparation of ethyl 2-(3-cyano-4-isopentyloxy)phenyl-1-methoxy-4-methyl-IH-imidazole-5-carboxylate (CSL-5-7)
以 （CSL-4-8 ) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.15g, 产率： 73.7%， mp: 138.1-139.6°C。 Using (CSL-4-8) as a starting material, the preparation was carried out in the same manner as (CSL-5-6) to give a white solid, 1.15 g, yield: 73.7%, mp: 138.1-139.6 °C.
MS (ESI): m/z 372.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.27 MS (ESI): m/z 372.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.27
( dd, lH,J=8.8Hz& 2.0Hz,Ar-H), 8.24(d, IH, J=2.0Hz,Ar-H), 7.45(d, lH,J=8.9Hz,Ar-H), 4.33(t,2H,J=7.1Hz,CH2), 4.26(t,2H,J=6.6Hz,CH2), 3.96(s,3H,CH3), 2.40(s,3H,CH3), 1.82(m, lH,CH), 1.69(m,2H,CH2), 1.33(t,3H,J=7.1Hz,CH3), 0.96(d,6H,J=6.6Hz,CH3)。(dd, lH, J=8.8Hz & 2.0Hz, Ar-H), 8.24(d, IH, J=2.0Hz, Ar-H), 7.45(d, lH, J=8.9Hz, Ar-H), 4.33 (t, 2H, J = 7.1 Hz, CH 2 ), 4.26 (t, 2H, J = 6.6 Hz, CH 2 ), 3.96 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ), 1.82 (m, lH, CH), 1.69 (m, 2H, CH 2 ), 1.33 (t, 3H, J = 7.1 Hz, CH 3 ), 0.96 (d, 6H, J = 6.6 Hz, CH 3 ).
6.8 2-0氰基 -4-正己氧基;)苯基 -1-甲氧基 -4-甲基 -IH-咪唑 -5-甲酸乙酯 (CSL-5-8;)的制 备 Preparation of 6.8 2-0 cyano-4-n-hexyloxy;)phenyl-1-methoxy-4-methyl-IH-imidazole-5-carboxylic acid ethyl ester (CSL-5-8;)
以 （CSL-4-9) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.12g, 产率： 71.8%， mp: 118.7-120.6°C。 Using (CSL-4-9) as a starting material, the preparation method was the same as (CSL-5-6), yielding white solid 1.12g, yield: 71.8%, mp: 118.7-120.6 °C.
MS (ESI): m/z 386.5[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.26 MS (ESI): m/z 386.5 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.26
( dd, lH,J=8.7Hz& 2.3Hz,Ar-H), 8.24(d, IH, J=2.0Hz,Ar-H), 7.42(d, IH, J=8.9Hz,Ar-H), 4.32(q,2H,J=7.1Hz,CH2), 4.22(t,2H,J=6.4Hz,CH3), 3.96(s,3H,CH3), 2.40(s,3H,CH3),
1.78(m,2H,CH2), 1.49-1.3 l(m,9H, CH2&CH3), 0.89(t,3H,J=6.8 Hz, CH3)。 (dd, lH, J=8.7Hz & 2.3Hz, Ar-H), 8.24(d, IH, J=2.0Hz, Ar-H), 7.42(d, IH, J=8.9Hz, Ar-H), 4.32 (q, 2H, J = 7.1 Hz, CH 2 ), 4.22 (t, 2H, J = 6.4 Hz, CH 3 ), 3.96 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ), 1.78 (m, 2H, CH 2 ), 1.49-1.3 l (m, 9H, CH 2 & CH 3 ), 0.89 (t, 3H, J = 6.8 Hz, CH 3 ).
6.9 2-(3-氰基 -4-正庚氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-5-9)的制 备 6.9 Preparation of ethyl 2-(3-cyano-4-n-heptyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylate (CSL-5-9)
以 （CSL-4-10) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.19g,产率： 76.8%， mp: 166.2-166.6°C。 Using (CSL-4-10) as a starting material, the preparation was carried out in the same manner as (CSL-5-6) to give a white solid, 1.19 g, yield: 76.8%, mp: 166.2-166.6 °C.
MS (ESI): m/z 400.5[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.26 MS (ESI): m/z 400.5 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.26
( dd, lH,J=8.7Hz& 2.3Hz,Ar-H), 8.24(d, 1H, J=2.0Hz,Ar-H), 7.42(d, lH,J=8.8Hz,Ar-H), 4.32(q,2H,J=7. lHz,CH2), 4.22(t,2H,J=6.4Hz,CH2), 3.96(s,3H,CH3),2.34(s,3H,CH3), 1.78(m,2H,CH2), 1.48-1.28(m, l lH,CH2 & CH3), 0.87(t,3H, J=6.7Hz,CH3). (dd, lH, J=8.7Hz & 2.3Hz, Ar-H), 8.24(d, 1H, J=2.0Hz, Ar-H), 7.42(d, lH, J=8.8Hz, Ar-H), 4.32 (q, 2H, J = 7. lHz, CH2), 4.22 (t, 2H, J = 6.4 Hz, 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, l lH, CH 2 & CH 3 ), 0.87 (t, 3H, J = 6.7 Hz, CH 3 ).
6.10 2-(3-氰基 -4-正辛氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-5-10)的制 备 6.10 Preparation of ethyl 2-(3-cyano-4-n-octyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylate (CSL-5-10)
以 （CSL-4-11 )为原料， 制备方法同 (CSL-5-6), 得白色固体 1.21g, 产率： 78.1%， mp: 165.8-167.3 °C。 Using (CSL-4-11) as a starting material, the preparation was carried out in the same manner as (CSL-5-6) to give a white solid 1.21 g, yield: 78.1%, mp: 165.8-167.3 °C.
MS (ESI): m/z 414.5[M+H]+。 MS (ESI): m/z 414.5 [M+H] + .
6.11 2-0氰基 -4-甲基苄氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 (CSL-5-Ι ΐ;)的 制备 6.11 Preparation of 2-0 cyano-4-methylbenzyloxy;)Phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid ethyl ester (CSL-5-Ι ΐ;)
以 （CSL-4-12) 为原料， 制备方法同 (CSL-5-6), 得白色固体 1.10g,产率： 70.1%， mp: 147.5-149.5 °C。 (CSL-4-12) was used as the starting material, and the preparation method was the same as (CSL-5-6) to obtain white solid 1.10 g, yield: 70.1%, mp: 147.5-149.5 °C.
MS (ESI): m/z 405.5[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.27 ( dd, lH,J=2.1&MS (ESI): m/z 405.5 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.27 ( dd, lH, J=2.1&
7.2Hz,Ar-H), 8.26(s, lH,Ar-H), 7.5 l(d, lH,J=7.2Hz,Ar-H), 7.39(d,2H,J=8. lHz,Ar-H),7.2 Hz, Ar-H), 8.26 (s, lH, Ar-H), 7.5 l (d, lH, J = 7.2 Hz, Ar-H), 7.39 (d, 2H, J = 8. lHz, Ar- H),
7.24(d, 2H,j=7.8Hz,Ar-H), 5.32(s,2H,CH2), 4.31(q,2H,J=7.2Hz,CH2), 3.96(s,3H,CH3),7.24 (d, 2H, j = 7.8 Hz, Ar-H), 5.32 (s, 2H, CH 2 ), 4.31 (q, 2H, J = 7.2 Hz, CH 2 ), 3.96 (s, 3H, CH 3 ) ,
2.40(s,3H,CH3), 2.32(s,3H,CH3), 1.33((t,3H,J=7.2Hz, CH3) 2.40(s,3H,CH 3 ), 2.32(s,3H,CH 3 ), 1.33((t,3H,J=7.2Hz, CH 3 )
实施例 7. 2-(3-氰基 -4-垸氧基)苯基 -1-甲氧基 -4-甲基 咪唑 -5-甲酸的制备 Example 7. Preparation of 2-(3-cyano-4-indolyl)phenyl-1-methoxy-4-methylimidazole-5-carboxylic acid
7.1 2-(3-氰基 -4-异丁氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-5 ) 的制 备 7.1 Preparation of 2-(3-cyano-4-isobutoxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-5)
将 2-(3-氰基 -4-异丁氧基）苯基 -1-甲氧基基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 ( 1.0g,2.8mmol)、 氢氧化钠水溶液 ( lmol/L,7.0ml)和四氢呋喃:无水乙醇 ( 1 : 1 ) 的混 合溶剂 （10ml) 加入 25ml反应瓶内， 50°C下搅拌反应 2小时， TLC检测反应的完全 程度， 反应毕， 减压蒸除部分有机溶剂， 然后用 5%的稀盐酸调节溶液 pH为 1， 静置 30min, 抽滤， 滤饼自然干燥， 用甲醇：乙酸乙酯 （1 :2) 混合溶剂重结晶， 得白色固体
粉末 0.64g, 收率： 69.56%， mp: 190.8-191.3 °C。 Ethyl 2-(3-cyano-4-isobutoxy)phenyl-1-methoxy-4-methyl-1H-imidazol-5-carboxylate (1.0 g, 2.8 mmol), EtOAc A mixed solution of sodium aqueous solution (1 mol/L, 7.0 ml) and tetrahydrofuran: absolute ethanol (1:1) (10 ml) was added to a 25 ml reaction flask, and the reaction was stirred at 50 ° C for 2 hours, and the reaction was completely detected by TLC. After completion, a part of the organic solvent was distilled off under reduced pressure, and then the pH of the solution was adjusted to 1 with 5% diluted hydrochloric acid, allowed to stand for 30 min, suction filtered, and the filter cake was naturally dried and recrystallized from a mixed solvent of methanol:ethyl acetate (1:2). , got white solid Powder 0.64 g, Yield: 69.56%, mp: 190.8-191.3 °C.
MS (ESI): m/z 330.1448[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.0 MS (ESI): m/z 330.1448 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 13.0
( s,lH,-COOH), 8.27(d,lH,J=2.2Hz, Ar-H),8.24 ( s,lH,Ar-H), 7.41(d,lH,J=8.8Hz,Ar-H), 4.01(d,2H,J=6.4Hz, CH2), 3.96(s,3H,CH3), 2.39(s,3H,CH3), 2.10(m, 1H,CH), ( s, lH, -COOH), 8.27 (d, lH, J = 2.2 Hz, Ar-H), 8.24 (s, lH, Ar-H), 7.41 (d, lH, J = 8.8 Hz, Ar-H ), 4.01 (d, 2H, J = 6.4 Hz, 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,CH3) o 1.03 (d, 6H, J = 6.7 Hz, CH 3 ) o
7.2 2-(3-氰基 -4-乙氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-1 ) 的制备 以 （CSL-5-1 ) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.55g, 收率： 7.2 Preparation of 2-(3-cyano-4-ethoxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-1) as (CSL-5) -1 ) As a raw material, the preparation method was the same as (CSL-MI-5), and 0.55 g of a white solid powder was obtained. Yield:
60.4%, mp: 195.4-196.3 °C。 60.4%, mp: 195.4-196.3 °C.
MS (ESI): m/z 302.1135[M+H]+； 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.01 (s,lH,COOH), 8.26(dd,lH,J=2.0Hz和 9.0Hz,Ar-H), 8.24(s,lH,Ar-H), 7.40(d, lH,J=8.9Hz, Ar-H), 4.29(q,2H, J=7.0Hz,CH2), 3.95(s,3H,CH3), 2.40(s,3H,CH3), 1.41(t,3H, J=6.9Hz, CH3)。 MS (ESI): m / z 302.1135 [M + H] +; 1H-MNR 5ppm (300 MHz, DMSO-d 6): 13.01 (s, lH, COOH), 8.26 (dd, lH, J = 2.0Hz and 9.0 Hz, Ar-H), 8.24 (s, lH, Ar-H), 7.40 (d, lH, J = 8.9 Hz, Ar-H), 4.29 (q, 2H, J = 7.0 Hz, CH 2 ), 3.95 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ), 1.41 (t, 3H, J = 6.9 Hz, CH 3 ).
7.3 2-0氰基 -4-正丙氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-2) 的制 备 Preparation of 7.3 2-0 cyano-4-n-propoxy; phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-2)
以 （CSL-5-2) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.58g,收率： 63.0%, mp: 193.1-194.0°C o (CSL-5-2) was used as the raw material, and the preparation method was the same as (CSL-MI-5) to obtain white solid powder 0.58 g, yield: 63.0%, mp: 193.1-194.0 °C o
MS (ESI): m/z 316.1292[M+H]+ ; 1H-MNR (300 MHz, DMSO-d6)5ppm: MS (ESI): m/z 316.1292 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm:
13.06(s,lH,COOH), 8.28 (d,lH,J=2.1Hz,Ar-H), 8.24(s,lH,Ar-H), 13.06(s,lH,COOH), 8.28 (d,lH,J=2.1Hz,Ar-H), 8.24(s,lH,Ar-H),
7.41(d,lH,J=8.9Hz,Ar-H), 4.19(t,2H,J=6.4Hz, CH2), 3.95 (s, 3H, CH3), 2.39(s, 3H, CH3), 1.79(m, 2H, CH3), 1.03(t,3H,J=7.3Hz,CH3)。 7.41 (d, lH, J = 8.9 Hz, Ar-H), 4.19 (t, 2H, J = 6.4 Hz, 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 = 7.3 Hz, CH 3 ).
7.4 2-(3-氰基 -4-异丙氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-3 ) 的制 备 7.4 Preparation of 2-(3-cyano-4-isopropoxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-3)
以 （CSL-5-3 ) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.60g, 收率： 65.2%, mp: 189.0-189.3 °C o (CSL-5-3) was used as the raw material, and the preparation method was the same as (CSL-MI-5) to obtain white solid powder 0.60 g, yield: 65.2%, mp: 189.0-189.3 °C o
MS (ESI): m/z 316.1292[M+H]+ ; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.06 ( s,lH,Ar-H)， 8.27(d, 1H, J=2.2Hz,Ar-H), 8.24(s,lH,Ar-H), 7.40(d,lH,J=9Hz,Ar-H), 4.86(m,lH,CH), 3.93(s,3H,CH3), 2.39(s,3H,CH3), 1.37(d,6H,J=6.0Hz,CH3)。 MS (ESI): m / z 316.1292 [M + H] +; 1H-MNR 5ppm (300 MHz, DMSO-d 6): 13.06 (s, lH, Ar-H), 8.27 (d, 1H, J = 2.2 Hz,Ar-H), 8.24(s,lH,Ar-H), 7.40(d,lH,J=9Hz,Ar-H), 4.86(m,lH,CH), 3.93(s,3H,CH 3 ), 2.39 (s, 3H, CH 3 ), 1.37 (d, 6H, J = 6.0 Hz, CH 3 ).
7.5 2-0氰基 -4-正丁氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-4) 的制 备 Preparation of 7.5 2-0 cyano-4-n-butoxy;)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-4)
以 （CSL-5-4) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.67g,收率：
72.8%, mp: 193.1-194.0°C。 Using (CSL-5-4) as a raw material, the preparation method was the same as (CSL-MI-5), and 0.67 g of a white solid powder was obtained. Yield: 72.8%, mp: 193.1-194.0 °C.
MS (ESI): m/z 330.1448[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm:8.28(s,lH,Ar-H), 8.24(s,lH,Ar-H), 7.41(d,lH,J=8.9Hz,Ar-H), 4.23(t,2H,J=6.3Hz,CH2), 3.95(s,3H,CH3), 2.39(s, 3H,CH3), 1.78(m,2H,CH2), 1.50(m,2H,CH2), 0.96(t, 3H,J=7.3Hz,CH3)。 MS (ESI): m/z 330.1448 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.28 (s, lH, Ar-H), 8.24 (s, lH, Ar-H ), 7.41 (d, lH, J = 8.9 Hz, Ar-H), 4.23 (t, 2H, J = 6.3 Hz, 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 = 7.3 Hz, CH 3 ).
7.6 2-0氰基 -4-仲丁氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-6) 的制 备 7.6 Preparation of 2-0 cyano-4- sec-butoxy;)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-6)
以 （CSL-5-5 ) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.62g, 收率： 67.4%, mp: 181.5-182.3 °C。 Using (CSL-5-5) as a raw material, the preparation method was the same as (CSL-MI-5) to obtain a white solid powder: 0.62 g, yield: 67.4%, mp: 181.5-182.3 °C.
MS (ESI): m/z 330.1448[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.06 ( s,lH, COOH), 8.27(s,lH, ,Ar-H), 8.24(s,lH,Ar-H), 7.44(d,lH,J=8.8Hz,Ar-H), 4.69(m,lH,CH2), 3.97(s,3H,CH3),2.39(s,3H,CH3), 1.33(d,3H,J=5.9Hz,CH3), 0.97 (t,3H,J=7.3Hz,CH3)。 MS (ESI): m / z 330.1448 [M + H] +; 1H-MNR (300 MHz, DMSO-d 6) 5ppm: 13.06 (s, lH, COOH), 8.27 (s, lH,, Ar-H) , 8.24 (s, lH, Ar-H), 7.44 (d, lH, J = 8.8 Hz, Ar-H), 4.69 (m, lH, CH 2 ), 3.97 (s, 3H, CH 3 ), 2.39 ( s, 3H, CH 3 ), 1.33 (d, 3H, J = 5.9 Hz, CH 3 ), 0.97 (t, 3H, J = 7.3 Hz, CH 3 ).
7.7 2-0氰基 -4-异戊氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-7) 的制 备 Preparation of 7.7 2-0 cyano-4-isopentyloxy;)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-7)
以 （CSL-5-7) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.58g,收率： 63.0%, mp: 191.3-191.9°C o (CSL-5-7) was used as the raw material, and the preparation method was the same as (CSL-MI-5) to obtain white solid powder 0.58 g, yield: 63.0%, mp: 191.3-191.9 °C o
MS (ESI): m/z 344.1605[M+H]+; 1H-MNR (300 MHz, DMSO-d6)5ppm: MS (ESI): m/z 344.1 459 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm:
13.06(s,lH,COOH), 8.27 (dd,lH,J=8.9Hz和 2.2Hz,Ar-H), 8.24(d, 1H, J=2.0Hz,Ar-H), 7.44(d,lH,J=8.9Hz,Ar-H), 4.25(t,3H,J=6.5Hz,CH2), 3.95(s,3H,CH3), 2.40(s,3H,CH3), 1.86(m,lH,CH), 1.70(m,2H,CH2), 0.96(d,6H,J=6.6Hz,CH3)。 13.06 (s, lH, COOH), 8.27 (dd, lH, J = 8.9 Hz and 2.2 Hz, Ar-H), 8.24 (d, 1H, J = 2.0 Hz, Ar-H), 7.44 (d, lH, J=8.9 Hz, Ar-H), 4.25 (t, 3H, J=6.5 Hz, CH 2 ), 3.95 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ), 1.86 (m, lH) , CH), 1.70 (m, 2H, CH 2 ), 0.96 (d, 6H, J = 6.6 Hz, CH 3 ).
7.8 2-(3-氰基 -4-正己氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-8) 的制 备 Preparation of 7.8 2-(3-cyano-4-n-hexyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-8)
以 （CSL-5-8) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.60g, 收率： 64.5%, mp: 192.8-193.9°C。 (CSL-5-8) was used as a raw material, and the preparation method was the same as (CSL-MI-5) to obtain a white solid powder: 0.60 g, yield: 64.5%, mp: 192.8 to 193.9 °C.
MS (ESI): m/z 358.1761 [M+H]+; 1H-MNR (300 MHz, DMSO-d6)5ppm: MS (ESI): m/z 358.1761 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm:
13.02(s,lH,COOH), 8.26 (dd,lHJ=2.2Hz和 9.0Hz,Ar-H), 8.23(d,lH,J=2.0Hz,Ar-H), 7.41(d,lH,J=8.9Hz,Ar-H), 4.22(t,2H,J=6.4Hz,CH2), 3.95(s,3H,CH3), 2.39(s,3H,CH3), 1.78(m,2H,CH2), 1.46(m,2H,CH2), 1.32(m,4H,CH2), 0.89(t,3H,J=6.8Hz, CH3)。 13.02 (s, lH, COOH), 8.26 (dd, lHJ = 2.2 Hz and 9.0 Hz, Ar-H), 8.23 (d, lH, J = 2.0 Hz, Ar-H), 7.41 (d, lH, J = 8.9 Hz, Ar-H), 4.22 (t, 2H, J = 6.4 Hz, 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 = 6.8 Hz, CH 3 ).
7.9 2-0氰基 -4-正庚氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-9) 的制 备 Preparation of 7.9 2-0 cyano-4-n-heptyloxy;)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-9)
以 （CSL-5-9) 为原料， 制备方法同 (CSL-MI-5), 得白色固体粉末 0.59g,收率：
63.4%, mp: 193.9-194.2°C o Using (CSL-5-9) as the raw material, the preparation method was the same as (CSL-MI-5), and 0.59 g of white solid powder was obtained. Yield: 63.4%, mp: 193.9-194.2°C o
MS (ESI): m/z 372.1918[M+H]+; 1H-MNR (600 MHz, DMSO-d6) 5ppm: 13.05 MS (ESI): m/z 3721.918 [M+H] + ; 1H-MNR (600 MHz, DMSO-d 6 ) 5 ppm: 13.05
( s,lH,COOH), 8.26(dd,lH,J=2.2Hz和 9.0Hz,Ar-H), 8.23(d,lH,J=2.2Hz,Ar-H), (s, lH, COOH), 8.26 (dd, lH, J = 2.2 Hz and 9.0 Hz, Ar-H), 8.23 (d, lH, J = 2.2 Hz, Ar-H),
7.41(d,lH,J=9.0Hz,Ar-H), 4.21(t,2H,J=6.4Hz,CH2), 3.95(s,3H,CH3), 2.40(s,3H,CH3), 1.79(m,2H,CH2), 1.45(m,2H,CH2), 1.36(m,2H,CH2), 1.28(m,4H,CH2), 7.41 (d, lH, J = 9.0 Hz, Ar-H), 4.21 (t, 2H, J = 6.4 Hz, 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,CH3) o 0.87 (t, 3H, J = 6.7 Hz, CH 3 ) o
7.10 2-(3-氰基 -4-正辛氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-10) 的制 备 7.10 Preparation of 2-(3-cyano-4-n-octyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-10)
以 （CSL-5-10) 为原料， 制备方法同 (CSL-MI-5 得白色固体粉末 0.62g,收率： 66.7%, mp: 188.6-189.8°C。 Using (CSL-5-10) as a raw material, the preparation method was the same as (CSL-MI-5 gave white solid powder 0.62 g, yield: 66.7%, mp: 188.6-189.8 °C.
MS (ESI): m/z 386.2074[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 13.06 MS (ESI): m/z 386.2074 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 13.06
( s,lH,COOH), 8.26(dd,lH, J=2.2Hz禾 P 8.9Hz,Ar-H), 8.23(d,lH,J=2.0Hz,Ar-H), (s, lH, COOH), 8.26 (dd, lH, J = 2.2 Hz and P 8.9 Hz, Ar-H), 8.23 (d, lH, J = 2.0 Hz, Ar-H),
7.41(d,lH,J=8.9Hz,Ar-H), 4.21(t,3H,J=6.4Hz,CH2), 3.95(s,3H,CH3), 2.39(s,3H,CH3), 1.78(m,2H,CH3), 1.45-1.27(m,10H,CH3), 0.86(t,3H,J=6.3Hz,CH3)。 7.41 (d, lH, J = 8.9 Hz, Ar-H), 4.21 (t, 3H, J = 6.4 Hz, 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 = 6.3 Hz, CH 3 ).
7.11 2-0氰基 -4-甲基苄氧基;)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-11 ) 的 制备 7.11 Preparation of 2-0 cyano-4-methylbenzyloxy;)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-11)
以 （CSL-5-11 ) 为原料， 制备方法同 (CSL-MI-5 得白色固体粉末 0.54g,收率： 58.1%, mp: 189.0-190.1 °C。 Using (CSL-5-11) as a raw material, the preparation method was the same as (CSL-MI-5 gave white solid powder 0.54 g, yield: 58.1%, mp: 189.0-190.1 °C.
MS (ESI): m/z 378.1148[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm:8.31 ( s,lH,Ar-H), 8.30 (dd,lH,J=2.2Hz和 8.1Hz,Ar-H), 7.55(d,lH,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,CH2), 3.98(s,3H,CH3), 2.50(s,3H,CH3), MS (ESI): m/z 378.1148 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.31 (s,lH,Ar-H), 8.30 (dd,lH,J=2.2 Hz and 8.1 Hz, Ar-H), 7.55 (d, lH, J = 9.8 Hz, Ar-H), 7.40 (d, 2H, J = 8.0 Hz, Ar-H), 7.25 (d, 2H, J = 7.9 Hz, Ar-H), 5.34 (s, 2H, CH 2 ), 3.98 (s, 3H, CH 3 ), 2.50 (s, 3H, CH 3 ),
2.32(s,3H,CH3) o 2.32(s,3H,CH 3 ) o
实施例 8. 2-(3-氰基 -4-垸氧基)苯基 -4-甲基 咪唑 -5-甲酸乙酯 (CSL-6)的制备 Example 8. Preparation of ethyl 2-(3-cyano-4-indolyl)phenyl-4-methylimidazole-5-carboxylate (CSL-6)
8.1 2-(3-氰基 -4-异丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-2) 的制备 8.1 Preparation of ethyl 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-1H-imidazole-5-carboxylate (CSL-6-2)
将 2-(3-氰基 -4-异丁氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸乙酯（2.0g,5.824mol): 三甲基氯硅烷 (2.5g,23.298mmol) 碘化钠 (3.5g,23.298mmol) 和无水乙腈 ( 12ml) 加入 50ml反应瓶内， 氮气保护下回流反应 6h， TLC检测反应的完全程度， 反应毕， 反应液放冷至室温， 抽滤， 滤饼用甲醇洗 2-3次， 取滤液减压浓缩至干， 加入 20%氢 氧化钠水溶液（10ml)室温下搅拌 lh，抽滤， 乙酸乙酯重结晶，得白色固体粉末 1.68g, 收率： 70.6%, mp: 219.2-220.9°C + o
MS (ESI): m/z 328.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.53 ( d, lH,J=2.1Hz, Ar-H), 8.43(dd, lH,J=2.2 & 8.9Hz,Ar-H), 7.48(d, 1H, J=9.0Hz,Ar-H), Ethyl 2-(3-cyano-4-isobutoxy)phenyl-1-hydroxy-4-methyl-1H-imidazol-5-carboxylate (2.0 g, 5.824 mol) : trimethylchlorosilane (2.5g, 23.298mmol) Sodium iodide (3.5g, 23.298mmol) and anhydrous acetonitrile (12ml) were added to a 50ml reaction flask, refluxed under nitrogen for 6h, the completeness of the reaction was detected by TLC, the reaction was completed, and the reaction solution was placed. The mixture was cooled to room temperature, and filtered with suction. The filter cake was washed with methanol 2-3 times. The filtrate was concentrated to dryness under reduced pressure. White solid powder 1.68 g, yield: 70.6%, mp: 219.2-220.9 ° C + o MS (ESI): m/z 328.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.53 ( d, lH, J = 2.1 Hz, Ar-H), 8.43 (dd, lH, J = 2.2 & 8.9 Hz, Ar-H), 7.48 (d, 1H, J = 9.0 Hz, Ar-H),
4.35(q,2H,J=7.1Hz,CH2), 4.03(d,2H,J=6.5Hz,CH2), 2.56(s,3H,CH3), 2.10(m, lH,CH), 1.34(t,3H,J=7.1Hz,CH3), 1.02(d,6H,J=6.7Hz, CH3)。 4.35 (q, 2H, J = 7.1 Hz, CH 2 ), 4.03 (d, 2H, J = 6.5 Hz, CH 2 ), 2.56 (s, 3H, CH3), 2.10 (m, lH, CH), 1.34 ( t, 3H, J = 7.1 Hz, CH 3 ), 1.02 (d, 6H, J = 6.7 Hz, CH 3 ).
8.2 2-(3-氰基 -4-正丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-1 ) 的制备 8.2 Preparation of ethyl 2-(3-cyano-4-n-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylate (CSL-6-1)
以 （CSL-4-5 ) 为原料， 制备方法同 (CSL-6-2;), 得白色固体粉末 1.72g,收率： 72.3%, 198.7-200.6°C。 Using (CSL-4-5) as a raw material, the preparation method was the same as (CSL-6-2;) to obtain a white solid powder: 1.72 g, yield: 72.3%, 198.7-200.6 °C.
MS (ESI): m/z 328.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.23 ( s, lH,Ar-H), 8.20(s, lH,Ar-H), 7.31(d, lH,J=8.6Hz,Ar-H), 4.22(q,2H,J=7.1Hz,CH2), MS (ESI): m/z 328.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.23 (s, lH, Ar-H), 8.20 (s, lH, Ar-H ), 7.31 (d, lH, J = 8.6 Hz, Ar-H), 4.22 (q, 2H, J = 7.1 Hz, CH 2 ),
4.18(t,2H,J=6.6Hz,CH2), 2.44(s,3H,CH3), 1.75(m,2H,CH2), 1.52(m,2H,CH3), 4.18 (t, 2H, J = 6.6 Hz, 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,CH3), 0.96((t,3H,J=7.3Hz, CH3)。 1.29 (t, 3H, J = 7.1 Hz, CH 3 ), 0.96 ((t, 3H, J = 7.3 Hz, CH 3 ).
8.3 2-(3-氰基 -4-仲丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-3 ) 的制备 8.3 Preparation of ethyl 2-(3-cyano-4-sec-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylate (CSL-6-3)
以（CSL-4-6)为原料，制备方法同 (CSL-6-2;), 得白色固体粉末 1.69g,收率： 71.0%， mp: 192.4-194.3 °C。 Using (CSL-4-6) as a starting material, the preparation method was the same as (CSL-6-2;) to obtain a white solid powder: 1.69 g, yield: 71.0%, mp: 192.4-194.3 °C.
MS (ESI): m/z 328.2[M+H]+。 MS (ESI): m/z 328.2 [M+H] + .
8.4 2-(3-氰基 -4-异戊氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-4) 的制备 8.4 Preparation of ethyl 2-(3-cyano-4-isopentyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylate (CSL-6-4)
以（CSL-4-8 )为原料，制备方法同 (CSL-6-2;), 得白色固体粉末 1.74g,收率： 72.8%， mp: 148.8-149.3 °C。 Using (CSL-4-8) as a raw material, the preparation method was the same as (CSL-6-2;), and white solid powder 1.74 g, yield: 72.8%, mp: 148.8-149.3 °C.
MS (ESI): m/z 342.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 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), MS (ESI): m/z 342.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 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,CH2), 4.22 (t,2H,J=6.9Hz,CH2), 2.47(s,3H,CH3), 1.81(m, lH,CH), 1.68(q,2H,J=6.4Hz,CH2), 1.30(t,3H,J=7.1Hz,CH3), 0.95((d,6H,J=6.6Hz, 2CH3)。 4.27 (q, 2H, J = 6.9 Hz, CH 2 ), 4.22 (t, 2H, J = 6.9 Hz, CH 2 ), 2.47 (s, 3H, CH 3 ), 1.81 (m, lH, CH), 1.68 (q, 2H, J = 6.4 Hz, CH 2 ), 1.30 (t, 3H, J = 7.1 Hz, CH 3 ), 0.95 ((d, 6H, J = 6.6 Hz, 2CH 3 ).
8.5 2-(3-氰基 -4-正己氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-5 ) 的制备 Preparation of 8.5 2-(3-cyano-4-n-hexyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylate (CSL-6-5)
以（CSL-4-9)为原料，制备方法同 (CSL-6-2), 得白色固体粉末 1.69g,收率： 70.7%, mp: 151.2-152.0°C。 Using (CSL-4-9) as a raw material, the preparation method was the same as (CSL-6-2) to obtain a white solid powder: 1.69 g, yield: 70.7%, mp: 151.2-152.0 °C.
MS (ESI): m/z 356.4[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 10.51(s, 1H, NH) 8.15MS (ESI): m/z 356.4 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 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), (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, CH2), 4.11(t,2H,J=6.3Hz,CH2), 2.56(s,3H,CH3), 1.87(m,2H,CH), 1.48(m,2H,CH2), 1.45-1.34(m,7H,CH2&CH3), 0.91(t,3H,J=6.9Hz, CH3)。 4.38 (q, 2H, J = 7.1 Hz, CH 2 ), 4.11 (t, 2H, J = 6.3 Hz, 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 = 6.9 Hz, CH 3 ).
8.6 2-(3-氰基 -4-正庚氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-6) 的制备
以（CSL4-10)为原料，制备方法同 (CSL-6-2;), 得白色固体粉末 1.65g,收率： 68.7%， mp: 166.3-167.2°C。 Preparation of 8.6 2-(3-cyano-4-n-heptyloxy)phenyl-4-methyl-1H-imidazol-5-carboxylic acid ethyl ester (CSL-6-6) Using (CSL4-10) as a raw material, the preparation method was the same as (CSL-6-2;), and white solid powder was obtained, 1.65 g, yield: 68.7%, mp: 166.3-167.2 °C.
MS (ESI): m/z 370.5[M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 8.28 MS (ESI): m/z 370.5 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.28
( s, lH,Ar-H) ,8.24 (dd, lH,J=2.1&8.8Hz，Ar-H), 7.64(d, lH,J=8.9Hz,Ar-H), ( s, lH, Ar-H) , 8.24 (dd, lH, J = 2.1 & 8.8 Hz, Ar-H), 7.64 (d, lH, J = 8.9 Hz, Ar-H),
4.27(q,2H,J=7.1Hz,CH2), 4.19(d,2H,J=6.4Hz,CH2), 2.47(s,3H,CH3), 1.77(m,2H,CH2), 1.47-1.28(d, l lH,CH2&CH3), 0.87(t,3H,J=6.7 Hz,CH3)。 4.27 (q, 2H, J = 7.1 Hz, CH 2 ), 4.19 (d, 2H, J = 6.4 Hz, CH 2 ), 2.47 (s, 3H, CH 3 ), 1.77 (m, 2H, CH 2 ), 1.47-1.28 (d, l lH, CH 2 &CH 3 ), 0.87 (t, 3H, J = 6.7 Hz, CH 3 ).
8.7 2-(3-氰基 -4-正辛氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯 （CSL-6-7) 的制备 8.7 Preparation of ethyl 2-(3-cyano-4-n-octyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylate (CSL-6-7)
以（CSL-4-11 )为原料，制备方法同 (CSL-6-2), 得白色固体粉末 1.56g,收率： 65.0%， mp: 162.1-163.7°C。 Using (CSL-4-11) as a raw material, the preparation method was the same as (CSL-6-2) to obtain a white solid powder: 1.56 g, yield: 65.0%, mp: 162.1-163.7 °C.
MS (ESI): m/z 384.5[M+H]+; 1H-MNR (300 MHz, DMSO-d6)5ppm: 12.81(s, lH, H) ， 8.34 ( d, lH,J=8.8Hz,Ar-H), 8.16(d, lH,J=1.9Hz,Ar-H), 7.37(d, lH,J=9.3Hz,Ar-H), MS (ESI): m/z 384.5 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 12.81 (s, lH, H) , 8.34 ( d, lH, J = 8.8 Hz, Ar-H), 8.16 (d, lH, J = 1.9 Hz, Ar-H), 7.37 (d, lH, J = 9.3 Hz, Ar-H),
4.25(q,2H,J= 6.9Hz,CH2), 4.19(t,2H,J=6.4Hz,CH2), 2.50(s,3H,CH3), 1.77(m,2H,CH), 1.45(m,2H,CH2), 1.31-1.26(m, l lH,CH2&CH3), 0.86(t,3H,J=6.8Hz, CH3)。 4.25 (q, 2H, J = 6.9 Hz, CH 2 ), 4.19 (t, 2H, J = 6.4 Hz, CH 2 ), 2.50 (s, 3H, CH 3 ), 1.77 (m, 2H, CH), 1.45 (m, 2H, CH 2 ), 1.31-1.26 (m, l lH, CH 2 & CH 3 ), 0.86 (t, 3H, J = 6.8 Hz, CH 3 ).
实施例 9. 2-(3-氰基 -4-垸氧基)苯基 -4-甲基 咪唑 -5-甲酸的制备 Example 9. Preparation of 2-(3-cyano-4-indolyl)phenyl-4-methylimidazole-5-carboxylic acid
9.1 2-(3-氰基 -4-异丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-2) 的制备 9.1 Preparation of 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-2)
将 2-(3-氰基 -4-异丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸乙酯（1.0g,3.1mmol) ,氢氧 化钠水溶液 ( lmol/L,4.6ml ) 和四氢呋喃:无水乙醇 ( 1 : 1 ) 的混合溶剂 ( 10ml ) 加入 25ml反应瓶内， 回流下搅拌反应 36小时， 减压蒸除部分有机溶剂， 然后用 5%的稀 盐酸调溶液 pH为 3， 静置 30min， 抽滤， 滤饼自然干燥， 用甲醇：乙酸乙酯 （1 :2) 混 合溶剂重结晶， 得白色固体粉末 0.27g, 收率： mp: 29.7%， 234.6-235.4°C。 Ethyl 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-1H-imidazol-5-carboxylate (1.0 g, 3.1 mmol), aqueous sodium hydroxide (1 mol/L, 4.6ml) and tetrahydrofuran: anhydrous ethanol (1:1) mixed solvent (10ml) was added to a 25ml reaction flask, stirred under reflux for 36 hours, some organic solvent was distilled off under reduced pressure, and then the solution was adjusted with 5% diluted hydrochloric acid. The pH was 3, allowed to stand for 30 min, suction filtration, and the filter cake was dried naturally, and then recrystallized from methanol: ethyl acetate (1:2) to give a white solid powder 0.27 g, yield: mp: 29.7%, 234.6-235.4 °C.
MS (ESI): m/z 300.1314 [M+H]+; 1H-MNR (300 MHz,DMSO-d6)5ppm:8.45(d, 1H, J=1.9Hz, Ar-H),8.36(dd, lH,J=2.0Hz和 8.9Hz,Ar-H), 7.44(d,J=9.0Hz, Ar-H), 4.01(d, 2H, J=6.5Hz, CH2), 2.50(s,3H,CH3), 2.09(m, lH,CH), 1.02(d,6H, J=6.7Hz,CH3) MS (ESI): m / z 300.1314 [M + H] +; 1H-MNR (300 MHz, DMSO-d 6) 5ppm: 8.45 (d, 1H, J = 1.9Hz, Ar-H), 8.36 (dd, lH, J = 2.0 Hz and 8.9 Hz, Ar-H), 7.44 (d, J = 9.0 Hz, Ar-H), 4.01 (d, 2H, J = 6.5 Hz, CH 2 ), 2.50 (s, 3H, CH 3 ), 2.09 (m, lH, CH), 1.02 (d, 6H, J = 6.7 Hz, CH 3 )
9.2 2-(3-氰基 -4-正丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-1 ) 的制备 9.2 Preparation of 2-(3-cyano-4-n-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-1)
以（CSL-8-1 )为原料，制备方法同 (CSL-I-2 得白色固体粉末 0.22g,收率： 24.2%, mp: 218.1-218.8°C。 Using (CSL-8-1) as a raw material, the preparation method was the same as (CSL-I-2 obtained white solid powder 0.22 g, yield: 24.2%, mp: 218.1-218.8 °C).
MS (ESI): m/z 300.1314 [M+H]+； 1H-MNR (300 MHz,DMSO-d6)5ppm:8.47(d, 1H, J=2.1Hz, Ar-H),8.38(dd, lH,J=2.1Hz和 8.9Hz,Ar-H), 7.46(d, lH,J=9.0Hz, Ar-H), 4.24(t, 2H J=6.4Hz, CH2), 2.51(s, 3H, CH3), 1.77(m,2H,CH2), 1.47(m,2H, CH2), 0.96(t,3H,J=7.4Hz,CH3)o
9.3 2-(3-氰基 -4-仲丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-3 ) 的制备 MS (ESI): m / z 300.1314 [M + H] +; 1H-MNR (300 MHz, DMSO-d 6) 5ppm: 8.47 (d, 1H, J = 2.1Hz, Ar-H), 8.38 (dd, lH, J = 2.1 Hz and 8.9 Hz, Ar-H), 7.46 (d, lH, J = 9.0 Hz, Ar-H), 4.24 (t, 2H J = 6.4 Hz, 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 = 7.4 Hz, CH 3 ) o 9.3 Preparation of 2-(3-cyano-4-sec-butoxy)phenyl-4-methyl-1H-imidazol-5-carboxylic acid (CSL-I-3)
以（CSL-8-3 )为原料，制备方法同 (CSL-I-2 得白色固体粉末 0.26g,收率： 28.6%, mp: 218.1-218.5°C。 Using (CSL-8-3) as a raw material, the preparation method was the same as (CSL-I-2 obtained white solid powder 0.26 g, yield: 28.6%, mp: 218.1-218.5 °C).
MS (ESI): m/z 300.1314 [M+H]+; 1H-MNR (600 MHz, DMSO-d6) 5ppm: 12.88( s,lH,Ar-H): 12.49(s,lH,-COOH), 8.29(s,lH,Ar-H), 8.24(d,lH,J=7.9Hz, Ar-H), MS (ESI): m / z 300.1314 [M + H] +; 1H-MNR (600 MHz, DMSO-d 6) 5ppm: 12.88 (s, lH, Ar-H): 12.49 (s, lH, -COOH) , 8.29(s,lH,Ar-H), 8.24(d,lH,J=7.9Hz, Ar-H),
7.39(d,lH,J=9.1Hz,Ar-H), 4.66(m,lH,CH), 2.45(s,3H,CH3), 1.69(m,2H,CH2), 7.39 (d, lH, J = 9.1 Hz, Ar-H), 4.66 (m, lH, CH), 2.45 (s, 3H, CH 3 ), 1.69 (m, 2H, CH 2 ),
1.31(d,3H,J=6.1Hz,CH3), 0.96(t,3H,J=7.4Hz,CH3)。 1.31 (d, 3H, J = 6.1 Hz, CH 3 ), 0.96 (t, 3H, J = 7.4 Hz, CH 3 ).
9.4 2-(3-氰基 -4-异戊氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-4) 的制备 9.4 Preparation of 2-(3-cyano-4-isopentyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-4)
以（CSL-8-4)为原料，制备方法同 (CSL-I-2 得白色固体粉末 0.24g,收率： 26.1%, mp: 207.1-207.7°C。 Using (CSL-8-4) as a raw material, the preparation method was the same as (CSL-I-2 obtained white solid powder 0.24 g, yield: 26.1%, mp: 207.1-207.7 °C).
MS (ESI): m/z 314.1499 [M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm:8.46(d, lH,J=2.0Hz, Ar-H), 8.38(dd,lH,J=2.0Hz和 8.9Hz,Ar-H), 7.45(d, 1H, J=9.0Hz,Ar-H), 4.25(t,2H,J=6.5Hz, CH2),2.51(s,3H,CH3), 1.81(m, lH,CH3),1.68(q,2H,J= 6.4Hz,CH2), 0.96(d,6H,J=6.5Hz,CH3)o MS (ESI): m/z 314.1499 [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 8.46 (d, lH, J = 2.0 Hz, Ar-H), 8.38 (dd, lH, J = 2.0 Hz and 8.9 Hz, Ar-H), 7.45 (d, 1H, J = 9.0 Hz, Ar-H), 4.25 (t, 2H, J = 6.5 Hz, CH 2 ), 2.51 (s, 3H, CH 3 ), 1.81 (m, lH, CH 3 ), 1.68 (q, 2H, J = 6.4 Hz, CH 2 ), 0.96 (d, 6H, J = 6.5 Hz, CH 3 ) o
9.5 2-(3-氰基 -4-正己氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-5 ) 的制备 Preparation of 9.5 2-(3-cyano-4-n-hexyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-5)
以（CSL-8-5 )为原料，制备方法同 (CSL-I-2 得白色固体粉末 0.26g,收率： 28.3%, mp: 216.3-216.5°C。 Using (CSL-8-5) as a raw material, the preparation method was the same as (CSL-I-2 obtained white solid powder 0.26 g, yield: 28.3%, mp: 216.3-216.5 °C).
MS (ESI): m/z 328.1656 [M+H]+; 1H-MNR (600 MHz, DMSO-d6) 5ppm: 13.08 ( s,lH, -COOH), 8.38(d,lH,J=1.4Hz, Ar-H), 8.31(dd,lH,J=1.8Hz和 8.9Hz,Ar-H), 7.40(d,lH, J=8.9Hz,Ar-H), 4.21(t,2H,J=6.4Hz,CH2),2.48(s,3H,CH3), 1.77(m,2H,CH2), MS (ESI): m/z 328.1656 [M+H] + ; 1H-MNR (600 MHz, DMSO-d 6 ) 5 ppm: 13.08 (s,lH, -COOH), 8.38 (d, lH, J = 1.4 Hz , Ar-H), 8.31 (dd, lH, J = 1.8 Hz and 8.9 Hz, Ar-H), 7.40 (d, lH, J = 8.9 Hz, Ar-H), 4.21 (t, 2H, J = 6.4 Hz, CH 2 ), 2.48 (s, 3H, CH 3 ), 1.77 (m, 2H, CH 2 ),
1.45(m,2H,CH2), 1.35-1.30(m,4H,CH2), 0.89(t,3H,J=7.0Hz,CH3)。 1.45 (m, 2H, CH 2 ), 1.35-1.30 (m, 4H, CH 2 ), 0.89 (t, 3H, J = 7.0 Hz, CH 3 ).
9.6 2-(3-氰基 -4-正庚氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-6) 的制备 Preparation of 9.6 2-(3-cyano-4-n-heptyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-6)
以（CSL-8-6)为原料，制备方法同 CCSL-I-2), 得白色固体粉末 0.28g,收率： 30.0%, mp: 217.1-217.7°C。 Using (CSL-8-6) as a raw material, the preparation method was the same as CCSL-I-2), and 0.28 g of a white solid powder was obtained. Yield: 30.0%, mp: 217.1-217.7 °C.
MS (ESI): m/z 342.1812 [M+H]+; 1H-MNR (600 MHz, DMSO-d6) 5ppm: 13.5 ( s,lH, -COOH), 8.46(s,lH,Ar-H), 8.37(d,lH,J=8.9Hz,Ar-H), 7.45(d,lH,J= 8.9Hz,Ar-H), MS (ESI): m/z 3421.812 [M+H] + ; 1H-MNR (600 MHz, DMSO-d 6 ) 5 ppm: 13.5 (s,lH, -COOH), 8.46 (s,lH,Ar-H) , 8.37 (d, lH, J = 8.9 Hz, Ar-H), 7.45 (d, lH, J = 8.9 Hz, Ar-H),
4.22(t,2H, J=6.4Hz,CH2), 2.51(s,3H,CH3), 1.78(m,2H,CH2), 1.45(m,2H,CH2), 4.22 (t, 2H, J = 6.4 Hz, CH 2 ), 2.51 (s, 3H, CH 3 ), 1.78 (m, 2H, CH 2 ), 1.45 (m, 2H, CH 2 ),
1.35(m,2H,CH2), 1.32-1.29(m,4H,CH2) 0.87(t, 3H,J=6.9Hz, CH3)。 1.35 (m, 2H, CH 2 ), 1.32-1.29 (m, 4H, CH 2 ) 0.87 (t, 3H, J = 6.9 Hz, CH 3 ).
9.7 2-(3-氰基 -4-正辛氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-7) 的制备 9.7 Preparation of 2-(3-cyano-4-n-octyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-7)
以（CSL-8-7)为原料，制备方法同 (CSL-I-2), 得白色固体粉末.023g,收率： 24.7%,
mp: 216.5-217.3 °C。 Taking (CSL-8-7) as a raw material, the preparation method is the same as (CSL-I-2), and a white solid powder of .023 g is obtained, and the yield is 24.7%. Mp: 216.5-217.3 °C.
MS (ESI): m/z 356.1969 [M+H]+; 1H-MNR (300 MHz, DMSO-d6) 5ppm: 12.76 ( s,lH -COOH), 8.31(s,lH,Ar-H), 8.26(d,lH,J=8.9Hz,Ar-H), 7.31(d,lH,J=8.9Hz,Ar-H), MS (ESI): m/z 356. </RTI> [M+H] + ; 1H-MNR (300 MHz, DMSO-d 6 ) 5 ppm: 12.76 (s,lH -COOH), 8.31 (s,lH,Ar-H), 8.26 (d, lH, J = 8.9 Hz, Ar-H), 7.31 (d, lH, J = 8.9 Hz, Ar-H),
4.18(t,2H,J=6.3Hz,CH2), 2.45(s,3H,CH3), 1.76(m,2H,CH2), 1.43(m,2H,CH2),1.39- 1.26(s,8H,CH2), 0.85(t, 3H, J=6.7Hz, CH3)。 4.18 (t, 2H, J = 6.3 Hz, 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 = 6.7 Hz, CH 3 ).
实施例 10. 化合物 CSL-HI-6片剂的制备 Example 10. Preparation of Compound CSL-HI-6 Tablets
处方组成及含量 Prescription composition and content
化合物 CSL-HI-6 50g Compound CSL-HI-6 50g
乳糖 114g Lactose 114g
微晶纤维素 142g Microcrystalline cellulose 142g
羧甲基淀粉钠 24g Sodium Carboxymethyl Starch 24g
硬脂酸 t天 Stearic acid t days
制 成 1000片 Made 1000 pieces
包衣液处方： Coating liquid prescription:
欧巴代 （03B28796) 21g Oubaday (03B28796) 21g
95%乙醇 适量 95% ethanol
制成约 430ml Made of about 430ml
工艺 Process
将已过 100 目筛的辅料与主药过 60目筛混合， 以 95%乙醇制软材， 以 18 目筛制 粒， 60°C通风干燥， 以 16目筛制粒后与硬脂酸镁混合均匀， 以 Φ 6mm浅凹冲打片。 The excipients that have passed the 100 mesh sieve are mixed with the main drug through a 60 mesh sieve, made of 95% ethanol soft material, sieved with 18 mesh, ventilated and dried at 60 ° C, and sieved with 16 mesh sieves with magnesium stearate. Mix evenly, punch with Φ 6mm shallow concave.
包衣溶液的配制： 在适宜容器中加入适量的 95%乙醇， 开动搅拌机， 将处方量的 欧巴代（03B28796) 固体粉末均匀的加入到旋涡中， 同时尽量避免有粉末漂浮在液体 表面， 必要时， 可以提高转速以保持适当的旋涡， 待所有的欧巴代 （03B28796)全部 加入后， 降低搅拌速度， 使旋涡消失， 继续搅拌 45min， 即得。 Preparation of the coating solution: Add an appropriate amount of 95% ethanol in a suitable container, start the mixer, and uniformly add the prescribed amount of Opadry (03B28796) solid powder to the vortex, while avoiding the floating of the powder on the surface of the liquid. When the speed can be increased to maintain the proper vortex, after all the Opadry (03B28796) is added, the stirring speed is reduced, the vortex disappears, and the stirring is continued for 45 minutes.
薄膜包衣片的制备： 将片芯置于包衣锅内， 保持温度 60°C±5°C， 进行包衣， 即得。 实施例 11. 目标化合物的黄嘌吟氧化酶抑制活性研究 Preparation of film-coated tablets: The cores were placed in a coating pan and kept at a temperature of 60 ° C ± 5 ° C for coating. Example 11. Study on xanthine oxidase inhibitory activity of target compound
1. 试验材料 Test material
1.1 试剂： 黄嘌吟氧化酶、 黄嘌吟、 焦磷酸钠、 乙二胺四乙酸二钠。 1.1 Reagents: xanthine oxidase, astragalus, sodium pyrophosphate, disodium edetate.
1.2 仪器： 电子分析天平 （AR1140型）， 电热恒温水浴锅 （DK-98-1型）， 台式离心机 (TDL80-2B型）， 紫外可见分光光度计 （WFZ UV-2000型）
1.3 受试样品 （代号） ： 阳性药 FBST, WSJ-00545 WSJ-00573 1.2 Instruments: Electronic analytical balance (AR1140 type), electrothermal constant temperature water bath (Model DK-98-1), bench top centrifuge (TDL80-2B type), UV-visible spectrophotometer (WFZ UV-2000 type) 1.3 Test sample (code): Positive drug FBST, WSJ-00545 WSJ-00573
2. 实验方法： 2. Experimental method:
2.1 药物配制方法 2.1 Drug preparation method
化合物用 10% KOH溶液溶解成 10mM母液， 临用时以反应稀释液稀释，现配现用。 酶活力检测方法 The compound was dissolved in 10 mM mother liquor with 10% KOH solution and diluted with the reaction diluent at the time of use. Enzyme activity detection method
配制反应稀释液： O. lmol/L焦磷酸钠， 0.3mmol/L EDTA二钠， 11值8.3. Prepare the reaction diluent: O. lmol / L sodium pyrophosphate, 0.3mmol / L EDTA disodium, 11 value 8.3.
黄嘌吟氧化酶购至 Sigma, 临用时用反应稀释液稀释， 反应体系中黄嘌吟氧化酶 25U/L, 黄嘌吟 200μιηΟ1/ί。 反应时依次加入黄嘌吟氧化酶、 受试药物 （阳性药物采用 非布索坦 FBST-OO 25°C孵育 15min后加入黄嘌吟、 25°C孵育 2h后于 295nm处检测吸光 度， 空白组采用相应的药物溶剂作为对照。 Xanthine oxidase was purchased from Sigma and diluted with the reaction diluent at the time of use. In the reaction system, xanthine oxidase 25 U/L, Astragalus 200 μιη Ο 1/ί. In the reaction, xanthine oxidase and test drug were added in sequence (the positive drug was incubated with febuxostat FBST-OO at 25 ° C for 15 min, then added to xanthine, and incubated at 25 ° C for 2 h, and the absorbance was measured at 295 nm. The corresponding drug solvent served as a control.
2.2 统计学方法 2.2 Statistical methods
全部数据采用 SPSS ( 17.0) 统计软件包进行检验分析。 结果用平均值 ±标准误差 表示， 组间均数比较进行方差齐性分析， 并进行 Dunnett's test分析方法进行组间比较 All data were analyzed using the SPSS ( 17.0) statistical software package. The results were expressed as mean ± standard error, and the mean between groups were compared for homogeneity analysis of variance, and Dunnett's test analysis method was used for comparison between groups.
3. 实验结果： 3. Experimental results:
实验结果表明， 所合成的 29个目标化合物大部分显示出较强的黄嘌吟氧化酶抑 制活性 （实验数据见表 1 )。 The experimental results showed that most of the 29 target compounds synthesized showed strong xanthine oxidase inhibitory activity (see Table 1 for experimental data).
表 1 29种样品 10μ§/ιη1对黄嘌吟氧化酶活性的影响 （M+SE) 药物编号 溶剂对照 0.21±0.32 Table 1 Effect of 29 samples of 10μ § /ιη1 on xanthine oxidase activity (M+SE) Drug number solvent control 0.21±0.32
阳性药 FBST 90.89±0.16*** Positive drug FBST 90.89±0.16***
CSL-MI-1 10.68±0.09*** CSL-MI-1 10.68±0.09***
CSL-MI-2 18.34±0.63*** CSL-MI-2 18.34±0.63***
CSL-MI-3 32.91±0.98*** CSL-MI-3 32.91±0.98***
CSL-MI-4 41.19±2.00*** CSL-MI-4 41.19±2.00***
CSL-MI-5 83.13±0.70*** CSL-MI-5 83.13±0.70***
CSL-MI-6 31.91±0.97*** CSL-MI-6 31.91±0.97***
CSL-MI-7 59.55±0.84*** CSL-MI-7 59.55±0.84***
CSL-MI-8 80.34±1.26*** CSL-MI-8 80.34±1.26***
CSL-MI-9 26.80±1.97***
CSL-MI-10 19.00±0.75*** CSL-MI-9 26.80±1.97*** CSL-MI-10 19.00±0.75***
CSL-MI-11 86.72±1.59*** CSL-MI-11 86.72±1.59***
CSL-HI-1 90.14±2.01*** CSL-HI-1 90.14±2.01***
CSL-HI-2 89.77±1.19*** CSL-HI-2 89.77±1.19***
CSL-HI-3 91.04±0.23*** CSL-HI-3 91.04±0.23***
CSL-HI-4 89.57±0.54*** CSL-HI-4 89.57±0.54***
CSL-HI-5 88.33±1.44*** CSL-HI-5 88.33±1.44***
CSL-HI-6 94.08±0.89*** CSL-HI-6 94.08±0.89***
CSL-HI-7 91.25±0.73*** CSL-HI-7 91.25±0.73***
CSL-HI-8 92.51±0.71 *** CSL-HI-8 92.51±0.71 ***
CSL-HI-9 89.93±1.37*** CSL-HI-9 89.93±1.37***
CSL-HI-10 88.17±0.11*** CSL-HI-10 88.17±0.11***
CSL-HI-11 91.65±0.88*** CSL-HI-11 91.65±0.88***
CSL-I-1 82.83±1.38*** CSL-I-1 82.83±1.38***
CSL-I-2 87.14±1.24*** CSL-I-2 87.14±1.24***
CSL-I-3 87.18±0.69*** CSL-I-3 87.18±0.69***
CSL-I-4 88.85±0.97*** CSL-I-4 88.85±0.97***
CSL-I-5 81.47±3.04*** CSL-I-5 81.47±3.04***
CSL-I-6 29.76±4.6** CSL-I-6 29.76±4.6**
CSL-I-7 9.57±2.00** CSL-I-7 9.57±2.00**
与溶剂对照组比较， P<0.05; ** , 与溶剂对照组比较， P<0.01 ; ***， 与溶剂对 照组比较， P<0.001。
P < 0.05; ** compared with the vehicle control group, P < 0.01; ***, compared with the solvent control group, P < 0.001.
Claims
1、 具有黄嘌吟氧化酶抑制活性的化合物或其药学上可接受的盐， 其特征在于: 所述化合物的结构通式如式 I、 II、 ΠΙ所示： 1. A compound with xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof, characterized in that: the general structural formula of the compound is as shown in formula I, II, II:
I II I II
其中： R为甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 异戊基、 正己基、 正庚基、 正辛基或 4-甲基苄基。 Where: R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isopentyl, n-hexyl, n-heptyl, n-octyl or 4-methylbenzyl base.
2、 按照权利要求 1所述的具有黄嘌呤氧化酶抑制活性的化合物或其药学上可接 受的盐， 其特征在于： 所述化合物是下述化合物 （1 ) ~ (29) 中的任一个： 2. The compound with xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: the compound is any one of the following compounds (1) to (29):
( 1 ) 2-(3-氰基 -4-乙氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-1 )、 (1) 2-(3-cyano-4-ethoxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-1),
(2) 2-(3-氰基 -4-正丙氧基〕苯基- 1 -甲氧基 -4-甲基- 1H-咪唑 -5-甲酸 （ CSL-MI-2 )、(2) 2-(3-cyano-4-n-propoxy]phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-2),
(3 ) 2-(3-氰基 -4-异丙氧基〕苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-MI-3 )、(3) 2-(3-cyano-4-isopropoxy]phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-3),
(4) 2-(3-氰基 -4-正丁氧基〕苯基- 1 -甲氧基 -4-甲基- 1H-咪唑 -5-甲酸 （ CSL-MI-4 )、(4) 2-(3-cyano-4-n-butoxy]phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-4),
( 5 ) 2-(3-氰基 -4-异丁氧基〕苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 （ CSL-MI-5 )、(5) 2-(3-cyano-4-isobutoxy]phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-5),
(6) 2-(3-氰基 -4-仲丁氧基〕苯基- 1 -甲氧基 -4-甲基- 1H-咪唑 -5-甲酸 （ CSL-MI-6 )、(6) 2-(3-cyano-4-sec-butoxy]phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-6),
(7) 2-(3-氰基 -4-异戊氧基〕苯基- 1 -甲氧基 -4-甲基- 1H-咪唑 -5-甲酸 （ CSL-MI-7 )、(7) 2-(3-cyano-4-isoamyloxy]phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-7),
( 8 ) 2-(3-氰基 -4-正己氧基)苯基 - 1 -甲氧基 -4-甲基- 1H-咪唑 -5-甲酸 （ CSL-MI-8 )、(8) 2-(3-cyano-4-n-hexyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-8),
(9) 2-(3-氰基 -4-正庚氧基)苯基- 1 -甲氧基 -4-甲基- 1H-咪唑 -5-甲酸 （ CSL-MI-9 )、(9) 2-(3-cyano-4-n-heptyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-9),
( 10) 2-(3-氰基 -4-正辛氧基:苯基 - 1 -甲氧基 -4-甲基 - 1H-咪唑 -5-甲酸（ CSL-MI- 10)、(10) 2-(3-cyano-4-n-octyloxy:phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-MI-10),
( 11 ) 2-(3-氰基 -4-甲基苄氧基)苯基 -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸 (11) 2-(3-cyano-4-methylbenzyloxy)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylic acid
(CSL-MI-11 )、 (CSL-MI-11),
( 12) 2-(3-氰基 -4-甲氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-1 )、 (12) 2-(3-cyano-4-methoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-1),
( 13 ) 2-(3-氰基 -4-正丙氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-2)、(13) 2-(3-cyano-4-n-propoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-2),
( 14) 2-(3-氰基 -4-异丙氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-3 )、(14) 2-(3-cyano-4-isopropoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-3),
( 15 ) 2-(3-氰基 -4-正丁氧基)苯基小羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-4)、(15) 2-(3-cyano-4-n-butoxy)phenyl small hydroxyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-4),
( 16) 2-(3-氰基 -4-仲丁氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-5 )、
(16) 2-(3-cyano-4-sec-butoxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-5),
( 17) 2-(3-氰基 -4-异丁氧基)苯基小羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-6)、(17) 2-(3-cyano-4-isobutoxy)phenyl small hydroxyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-6),
( 18) 2-(3-氰基 -4-异戊氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-7)、(18) 2-(3-cyano-4-isoamyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-7),
( 19) 2-(3-氰基 -4-正己氧基)苯基小羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-8)、(19) 2-(3-cyano-4-n-hexyloxy)phenyl small hydroxyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-8),
(20) 2-(3-氰基 -4-正庚氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-9)、(20) 2-(3-cyano-4-n-heptyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-9),
(21 ) 2-(3-氰基 -4-正辛氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-HI-10)、(21) 2-(3-cyano-4-n-octyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-10),
(22) 2-(3-氰基 -4-甲基苄氧基)苯基 -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸（CSL-HI-11 )、(22) 2-(3-cyano-4-methylbenzyloxy)phenyl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acid (CSL-HI-11),
(23 ) 2-(3-氰基 -4-正丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-1 )、 (23) 2-(3-cyano-4-n-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-1),
(24) 2-(3-氰基 -4-异丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-2)、 (24) 2-(3-cyano-4-isobutoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-2),
(25 ) 2-(3-氰基 -4-仲丁氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-3 )、 (25) 2-(3-cyano-4-sec-butoxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-3),
(26) 2-(3-氰基 -4-异戊氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-4)、 (26) 2-(3-cyano-4-isopentyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-4),
(27) 2-(3-氰基 -4-正己氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-5 )、 (27) 2-(3-cyano-4-n-hexyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-5),
(28) 2-(3-氰基 -4-正庚氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-6)、 (28) 2-(3-cyano-4-n-heptyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-6),
(29) 2-(3-氰基 -4-正辛氧基)苯基 -4-甲基 -1H-咪唑 -5-甲酸 （CSL-I-7)。 (29) 2-(3-cyano-4-n-octyloxy)phenyl-4-methyl-1H-imidazole-5-carboxylic acid (CSL-I-7).
3、 一种用于制备权利要求 1或 2所述的具有黄嘌吟氧化酶抑制活性的化合物或 其药学上可接受的盐的中间体， 所述中间体包括 2-(3-氰基 -4-烷氧基；)苯基 -1-甲氧基 -4- 甲基- 1H-咪唑 -5-甲酸酯、 2-(3 -氰基 -4-垸氧基；)苯基- 1 -羟基基 -4-甲基- 1H-咪唑 -5-甲酸酯 和 2-(3 -氰基 -4-烷氧基)苯基 -4-甲基- 1H-咪唑 -5-甲酸酯。 3. An intermediate for preparing the compound having xanthine oxidase inhibitory activity or a pharmaceutically acceptable salt thereof according to claim 1 or 2, the intermediate comprising 2-(3-cyano- 4-alkoxy;)phenyl-1-methoxy-4-methyl-1H-imidazole-5-carboxylate, 2-(3-cyano-4-alkyloxy;)phenyl-1 -Hydroxy-4-methyl-1H-imidazole-5-carboxylate and 2-(3-cyano-4-alkoxy)phenyl-4-methyl-1H-imidazole-5-carboxylate .
4、 按照权利要求 3所述的中间体， 其特征在于： 所述酯为甲酯、 乙酯、 丙酯、 叔丁酯、 苄酯或对甲基苄酯。 4. The intermediate according to claim 3, characterized in that: the ester is methyl ester, ethyl ester, propyl ester, tert-butyl ester, benzyl ester or p-methylbenzyl ester.
5、 一种用于权利要求 1或 2所述的咪具有黄嘌吟氧化酶抑制活性的化合物或药 学上可接受的盐的制备方法， 其特征在于： 5. A method for preparing the compound or pharmaceutically acceptable salt of imidazole having xanthine oxidase inhibitory activity according to claim 1 or 2, characterized in that:
1 ) 以 4-羟基苯甲醛为起始原料， 经溴代得到 3-溴 -4-羟基苯甲醛， 与溴代烃进行 烃化反应得到 3-溴 4-烃氧基苯甲醛， 再与氰化亚铜反应得到 3-氰基 -4-烃氧基苯甲醛， 然后再与 2- (羟基亚胺基 )-3-氧代丁酸酯环化， 得到 2-(3-氰基 -4-烃氧苯基) -1-羟基 -4-甲 基 咪唑 -5-甲酸酯； 1) Use 4-hydroxybenzaldehyde as the starting material, undergo bromination to obtain 3-bromo-4-hydroxybenzaldehyde, perform an alkylation reaction with brominated hydrocarbons to obtain 3-bromo-4-alkoxybenzaldehyde, and then react with cyanide The cuprous reaction reacts to obtain 3-cyano-4-alkoxybenzaldehyde, which is then cyclized with 2-(hydroxyimino)-3-oxobutyrate to obtain 2-(3-cyano-4 -Hydroxyphenyl)-1-hydroxy-4-methylimidazole-5-carboxylate;
2) 2-(3-氰基 -4-烃氧苯基) -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸酯经水解反应，制得通式 I所示的化合物； 2) 2-(3-cyano-4-alkoxyphenyl)-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate undergoes hydrolysis reaction to prepare the compound represented by general formula I;
3 ) 2-(3-氰基 -4-烃氧苯基;) -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸酯用硫酸二甲酯甲基化， 制得 2-(3-氰基 -4-烃氧苯基) -1-甲氧基 -4-甲基 -1H-咪唑 -5-甲酸酯， 经水解反应， 制得通 式 Π所示的化合物；
4)2-(3-氰基 -4-烃氧苯基) -1-羟基 -4-甲基 -1H-咪唑 -5-甲酸酯用三甲基卤硅烷与碘化 盐脱羟基制得 2-(3-氰基 -4-烃氧苯基； ) -4-甲基 -1H-咪唑 -5-甲酸酯， 经水解反应， 制得通 式 III所示的化合物。 3) 2-(3-cyano-4-alkoxyphenyl;)-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate is methylated with dimethyl sulfate to prepare 2- (3-cyano-4-alkoxyphenyl)-1-methoxy-4-methyl-1H-imidazole-5-carboxylate, through hydrolysis reaction, prepare the compound represented by the general formula Π; 4) 2-(3-cyano-4-alkoxyphenyl)-1-hydroxy-4-methyl-1H-imidazole-5-carboxylate is prepared by dehydroxylation of trimethylhalosilane and iodide salt 2-(3-cyano-4-alkoxyphenyl; )-4-methyl-1H-imidazole-5-carboxylate is hydrolyzed to prepare the compound represented by the general formula III.
6、 一种药物组合物， 其包含如权利要求 1或 2中所述的具有黄嘌吟氧化酶抑制 活性的化合物或其药学上可接受的盐， 以及药学上可接受的辅料、 稀释剂和载体。 6. A pharmaceutical composition comprising the compound with xanthine oxidase inhibitory activity as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, as well as pharmaceutically acceptable excipients, diluents and carrier.
7、 按照权利要求 6所述的药物组合物， 其特征在于： 所述组合物中具有黄嘌吟 氧化酶抑制活性的化合物或其药学上可接受的盐的重量百分比为 5%-20%， 余量为所 述可接受的辅料、 稀释剂和载体。 7. The pharmaceutical composition according to claim 6, characterized in that: the weight percentage of the compound with xanthine oxidase inhibitory activity or its pharmaceutically acceptable salt in the composition is 5%-20%, The balance is the acceptable excipients, diluents and carriers.
8、 一种治疗或预防高尿酸血症或痛风病药物， 其包含如权利要求 1或 2中所述 的具有黄嘌吟氧化酶抑制活性的化合物或其药学上可接受的盐。 8. A drug for treating or preventing hyperuricemia or gout, which contains a compound with xanthine oxidase inhibitory activity as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof.
9、 如权利要求 1或 2中所述的具有黄嘌吟氧化酶抑制活性的化合物或其药学上 可接受的盐、 或如权利要求 6或 7所述的药物组合物在制备用于治疗或预防高尿酸血 症或痛风病的药物中的用途。
9. The compound having xanthine oxidase inhibitory activity as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 6 or 7 in preparation for treatment or Use in medicines to prevent hyperuricemia or gout.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210279511.2A CN102766099B (en) | 2012-08-07 | 2012-08-07 | There is compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity |
| CN201210279511.2 | 2012-08-07 |
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| WO2014023104A1 true WO2014023104A1 (en) | 2014-02-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/CN2013/073327 WO2014023104A1 (en) | 2012-08-07 | 2013-03-28 | Compound with xanthine oxidase inhibitory activity and salt thereof, preparation method and usage for the same |
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| CN (1) | CN102766099B (en) |
| WO (1) | WO2014023104A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022041821A (en) * | 2020-08-31 | 2022-03-11 | 沈陽海諾威医薬科技有限公司 | Platelet aggregation inhibitor and preparation and uses thereof |
| CN115120579A (en) * | 2022-08-10 | 2022-09-30 | 中国科学院华南植物园 | Application of folium Cajani extract and its monomer component in preparing xanthine oxidase inhibiting medicine |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766099B (en) * | 2012-08-07 | 2015-09-23 | 沈阳药科大学 | There is compound and salt, preparation method and the purposes of xanthine oxidase inhibitory activity |
| CN106282136A (en) * | 2015-06-01 | 2017-01-04 | 中国药科大学 | Xanthine oxidase B cell epi-position and the antigenic peptides comprising this epi-position and application thereof |
| CN106892871A (en) * | 2015-12-18 | 2017-06-27 | 中国科学院上海药物研究所 | One class 4,5- disubstituted imidazole derivatives and its production and use |
| CN106674098B (en) * | 2016-12-23 | 2019-07-02 | 中国医科大学 | N- (3- cyano -4- alkoxyl phenyl) pyridine carboxamides and application thereof |
| CN108072712B (en) * | 2017-01-22 | 2020-10-02 | 中国医科大学附属第一医院 | Quantitative analysis method for blood concentration of new compound WSJ-557 in SD rat plasma |
| 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 |
| CN108929275B (en) * | 2018-06-14 | 2021-08-24 | 沈阳药科大学 | 6- (3, 4-substituted phenyl) -3-oxo-2, 3-dihydropyridazine-4-hydrazide compound and application thereof |
| CN108484494B (en) * | 2018-06-15 | 2021-07-30 | 沈阳药科大学 | 2-oxo-1, 2-dihydropyridine-4-carboxylic acid compounds |
| CN110204494B (en) * | 2019-07-01 | 2023-03-24 | 华南理工大学 | Oxygen-substituted phenylimidazole XOR/URAT1 dual inhibitor and preparation and application thereof |
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| JP2022041821A (en) * | 2020-08-31 | 2022-03-11 | 沈陽海諾威医薬科技有限公司 | Platelet aggregation inhibitor and preparation and uses thereof |
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| CN115120579A (en) * | 2022-08-10 | 2022-09-30 | 中国科学院华南植物园 | Application of folium Cajani extract and its monomer component in preparing xanthine oxidase inhibiting medicine |
| CN115120579B (en) * | 2022-08-10 | 2023-10-03 | 中国科学院华南植物园 | Application of cajan leaf extract and monomer components thereof in preparation of xanthine oxidase inhibition drugs |
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| Publication number | Publication date |
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| CN102766099A (en) | 2012-11-07 |
| CN102766099B (en) | 2015-09-23 |
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