WO2018033019A1 - 一类噁唑并吡啶季铵盐类化合物、其制备方法及用途 - Google Patents

一类噁唑并吡啶季铵盐类化合物、其制备方法及用途 Download PDF

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WO2018033019A1
WO2018033019A1 PCT/CN2017/096975 CN2017096975W WO2018033019A1 WO 2018033019 A1 WO2018033019 A1 WO 2018033019A1 CN 2017096975 W CN2017096975 W CN 2017096975W WO 2018033019 A1 WO2018033019 A1 WO 2018033019A1
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朱维良
李波
薛溯塑
李小龙
刘鹏
张勇
徐志建
蔡婷婷
陈凯先
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中国科学院上海药物研究所
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of organic chemistry and medicinal chemistry, in particular to an oxozolopyridine quaternary ammonium salt compound which can be used as an organic synthesis intermediate and for treating tumor or cancer, diabetes, cardiovascular disease, central nervous system disease, antibacterial anti-inflammatory, etc., preparation Methods and their use as synthetic intermediates for transformation.
  • the quaternary ammonium salt is a compound formed by substituting four hydrogen atoms in the ammonium ion with a hydrocarbon group.
  • the four hydrocarbon groups may be the same or different; the anions are mostly halogen anions (F, Cl, Br, I) or acid groups (such as HSO 4 - , RCOO - etc.).
  • Quaternary ammonium salts have been widely used in medicine, chemical industry, etc., such as fungicides, disinfectants, soft antistatic agents, flocculant demulsifiers, drilling fluids, VES fracturing fluids, drag reducing agents, and Thickeners, anionic synergists, phase transfer catalysts, and the like.
  • oxazole quaternary ammonium salt is an important organic synthesis reagent, which can undergo 1,3-dipolar cycloaddition reaction (Albert Padwa, Edward M. Burgess, Henry L. Gingrich, David M. Roush. On The problem of regioselectivity in the 1,3-dipolar cycloaddition reaction of munchnones and sydnones with acetylenic dipolarophiles. J. Org. Chem.
  • Chem Commun (Camb)., 2012, 48, 9625–9627), can be used as a preparation drug Active molecule intermediate (Pandey PS, Srinivasa Rao T. An efficient synthesis of N-3,4-diphenyl-5-(4-fluorophenyl)-2-isopropyl-1H-3-pyrrolecarboxamide, a key intermediate for atorvastatin synthesis. Bioorg Med Chem Lett. 2004 Jan 5; 14(1): 129-31) and the like.
  • Pyridine quaternary ammonium salt is a very important organic synthesis reagent, which can undergo nucleophilic addition, Michael addition, 1,3-dipole addition, nucleophilic substitution and ⁇ -migration rearrangement (Osyanin VA , Osipov DV, Klimochkin YN.
  • berberine hydrochloride is an isoquinoline alkaloid with a quaternary quaternary ammonium salt in the molecular structure, which is widely used in the treatment of enteritis bacilli, and modern research shows that it also has anti-tumor, diabetes, Pharmacological effects such as cardiovascular disease, central nervous system disease, etc.
  • Shanh IP, Mahajan S. Berberine and its derivatives a patent review (2009-2012). Expert Opin Ther Pat. 2013, 23(2): 215-231).
  • Oxazopyridine quaternary ammonium salt compounds have rarely been reported in the literature.
  • the only literatures are mainly pyridine oxazolone compounds. These compounds can be used as intermediates to generate 1,3-dipolar cycloaddition reactions.
  • Preparation of heterocyclic compounds Kazhkenov ZG1, Bush AA, Babaev EV. Dakin-West trick in the design of novel 2-alkyl(aralkyl) derivatives of oxazolo[3,2-a]pyridines. Molecules.2005Sep 1;10(9):1109-18).
  • the method of the present application adopts another strategy of preparing an oxygen-substituted pyridine compound by reacting an alcohol compound with a 2-position halogenated pyridine compound as a raw material, and obtaining an object by an intramolecular ring-closing reaction under acidic conditions.
  • the product has higher reaction selectivity and less by-products, thereby increasing the overall yield.
  • An object of the present invention is to provide a oxazolopyridine quaternary ammonium salt compound of the formula 1;
  • Another object of the present invention is to provide a method for preparing an oxazolopyridine quaternary ammonium salt compound of the formula 1;
  • Still another object of the present invention is to provide a conversion application of the oxazolopyridine quaternary ammonium salt compound of the formula 1 as a synthetic intermediate.
  • the oxazolopyridine quaternary ammonium salt compound of the invention can be used as an organic synthesis intermediate and a drug molecular structural unit, and has potential development and application value.
  • Q, U each independently represent oxygen, sulfur or nitrogen
  • R 1 is 1-4 identical or different substituents on the pyridine ring, each substituent being independently selected from the group consisting of hydrogen, hydroxy, amino, fluorenyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryl ether, C6-C12 arylamino, C6-C12 arylthio, nitro, amide, benzodioxole a metal or a halogen; or when R1 is 2 or more substituents on the pyridine ring, wherein two adjacent substituents may be bonded to each other and form a substituted or unsubstituted aryl group with a carbon atom on the pyridine ring Or containing 0-3 5-7 membered cycloalkyl groups independently selected from O, S or N atoms;
  • R 2 and R 3 each independently represent hydrogen, hydroxy, amino, fluorenyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkane Thio group, C6-C12 aryl ether group, C6-C12 arylamino group, C6-C12 arylthio group or halogen; When it is a double bond, R 3 does not exist;
  • R 4 represents hydrogen, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group
  • Y is an acid anion selected from the group consisting of inorganic acid ions, organic acid ions and halogen ions, including but not limited to nitrate ions, sulfate ions, phosphate ions, mesylate ions, benzenesulfonate ions, acetate ions, tartrate Ions, citrate ions, maleate ions, succinate ions, citrate ions, salicylate ions, glycerate ions, ascorbate ions, fluoride ions, chloride ions, bromide ions or iodide ions.
  • inorganic acid ions organic acid ions and halogen ions
  • halogen ions including but not limited to nitrate ions, sulfate ions, phosphate ions, mesylate ions, benzenesulfonate ions, acetate ions, tartrate Ions, citrate ions, maleate ions, succinate ions, citrate
  • the substituted or unsubstituted alkyl group includes a substituted or unsubstituted saturated, unsaturated, linear, branched, all-carbon C1-C6 alkyl group or a C1-C6 alkyl group containing a hetero atom such as oxygen, nitrogen or sulfur;
  • substituted in “substituted or unsubstituted” means substituted with one or more substituents selected from the group consisting of halogen, aryl, and C1-C6 alkyl.
  • the substituted or unsubstituted aryl group includes a substituted or unsubstituted phenyl group or an aryl group containing a hetero atom such as oxygen, nitrogen, sulfur or the like; wherein "substituted" in the "substituted or unsubstituted” means selected Substituted from one or more substituents of C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, benzyl (BnO), hydroxy, cyano, C1-C3 alkoxycarbonyl.
  • the halogen means fluorine, chlorine, bromine or iodine.
  • U and Q each independently represent oxygen or sulfur
  • R 4 represents a substituted or unsubstituted alkyl group
  • R 2 and R 3 each independently represent hydrogen, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group;
  • R 1 is 1-4 identical or different substituents on the pyridine ring, each substituent being independently selected from the group consisting of hydrogen, alkyl, aryl, C1-C6 alkoxy, nitro, amide, a benzodioxan group; or when R 1 is 2 or more substituents on the pyridine ring, two of the adjacent substituents and together with the carbon atom on the pyridine ring form an aryl group.
  • the oxazolopyridine quaternary ammonium salt compound is preferably:
  • the invention also provides a preparation method of the oxazolopyridine quaternary ammonium salt compound:
  • the compound S is dissolved in a solvent, added with acid NY, reacted at a certain temperature for a period of time, and the solvent is distilled off to obtain the compound I;
  • R 1 , R 2 , R 3 , R 4 , U, Q, and Y are as defined above.
  • the solvent includes, but not limited to, toluene, acetone, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, xylene, chlorobenzene, dimethyl sulfoxide, dimethylformamide, dimethyl
  • One or more combination solvents such as acetamide, water, etc.; the solvent is preferably one or more of toluene, acetone, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, water, or the like. Combine the solvents.
  • the acid NY is selected from the group consisting of inorganic acids, organic acids, and hydrohalic acids. Including but not limited to nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, tartaric acid, citric acid, maleic acid, succinic acid, citric acid, salicylic acid, glyceric acid, ascorbic acid, hydrofluoric acid, hydrochloric acid One or more combination acids such as hydrobromic acid or hydroiodic acid; the acid NY is preferably methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, phosphoric acid, etc. One or more combinations of acids.
  • the certain temperature is any temperature from minus 80 degrees Celsius to 200 degrees Celsius; preferably any temperature from 0 degrees Celsius to 100 degrees Celsius.
  • the invention also provides the conversion application of the oxazolopyridine quaternary ammonium salt compound as a synthetic intermediate:
  • R 1 , R 2 , R 3 , R 4 , U, Q, and Y are as defined above.
  • W and Z are each independently O, R 7 N or S, etc.;
  • A is hydrogen or a metal atom such as lithium, sodium, magnesium, copper, tin;
  • R 5 is hydrogen, substituted or unsubstituted aryl or C1-C6 alkane
  • substituted in the "substituted or unsubstituted aryl group" means substituted by a C1-C3 alkoxy group, a nitro group or a halogen; and R 6 is a hydrogen, substituted or unsubstituted aryl group.
  • a C1-C6 alkyl group in the "substituted or unsubstituted aryl group", "substituted” means being substituted with C1-C3 alkoxy, trifluoromethyl or halo;
  • R 7 is hydrogen, a substituted or unsubstituted Substituted C1-C6 alkyl, said "substituted or unsubstituted” means substituted by C1-C3 alkyl, C1-C3 alkoxy, nitro, trifluoromethyl or halogen.
  • the compound I (the compound I can be prepared from the compound S, the product is purified or not purified or not isolated) is dissolved in a solvent, and the nucleophilic reagent is R 5 -WA, R 6 - ZA or an inorganic base, reacted at a temperature of minus 80 degrees Celsius to 200 degrees Celsius, evaporating the solvent, and conventionally separating and purifying, thereby obtaining an N-substituted pyridone compound P or a 2-substituted pyridine compound T, when the nucleophile is inorganic
  • W is O and R 5 is hydrogen.
  • the inorganic base is selected from the group consisting of sodium hydrogencarbonate, sodium hydroxide and the like.
  • the solvent includes, but not limited to, toluene, acetone, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, xylene, chlorobenzene, dimethyl sulfoxide, dimethylformamide, dimethyl
  • One or more combination solvents such as acetamide and water;
  • the preparation method of the oxazolopyridine quaternary ammonium salt compound according to the invention has mild conditions, easy availability of reagents, high product yield, convenient post-treatment, etc., and has good popularization and application value; and the oxazole synthesized according to the method
  • the pyridine quaternary ammonium salt compounds have potential organic synthesis and medicinal chemical applications, and the compounds can be further conveniently reacted with different nucleophiles to be converted into N-substituted pyridone compounds and 2-substituted compounds commonly found in drug molecules.
  • Pyridine compounds have potential development and application value as organic synthesis intermediates and molecular structural units of drugs.
  • the preparation of the starting materials S-1 to S-20 is carried out by a commercial 2-chloropyridine compound or a 2-hydroxypyridine compound, and is obtained by the method of Tetrahedron, 2004, 60, 6113.
  • the reagents used were purchased from Sinopharm Group unless otherwise stated.
  • the nucleophilic reagent was m-methoxyaniline, and the oily product P-16 (32% yield) was obtained.
  • the nucleophilic reagent was p-methoxyaniline, and the oily product P-17 (53% yield) was obtained.
  • the nucleophilic reagent was m-nitroaniline, and the oily product P-18 (11% yield) was obtained.
  • the nucleophilic reagent was m-chloroaniline, and the oily product P-19 (36% yield) was obtained.
  • the nucleophilic reagent was p-bromoaniline, and the product P-20 (65% yield) was obtained.
  • the nucleophilic reagent was sodium phenolate to obtain the oily product P-21 (14% yield).
  • the nucleophilic reagent was sodium thiophenolate to obtain the oily product P-22 (98% yield).
  • the nucleophilic reagent was methylamine according to the preparation method of Example 35 to give the product P-23 (yield: 73%).
  • the nucleophilic reagent was propylamine according to the preparation method of Example 35 to give the oil product P-24 (75% yield).
  • the nucleophilic reagent was isopropylamine according to the preparation method of Example 35 to give the product P-25 (95% yield).
  • the nucleophilic reagent was dipropylamine, and the product P-26 (33% yield) was obtained.
  • the compound S-1 was replaced with the compound S-8 according to the preparation method of Example 35, and the nucleophilic reagent was sodium thiophenol to obtain the oily product P-27 (43% yield).
  • the compound S-7 was replaced with the compound S-7 according to the preparation method of Example 35, and the nucleophilic reagent was sodium thiophenol to obtain the oily product P-28 (39% yield).
  • the compound S-7 was replaced by the compound S-7 and the nucleophilic reagent was isopropylamine to give the oily product P-29 (45% yield).
  • the preparation method was the same as the preparation of P-15.
  • the nucleophilic reagent was benzylamine to give the oily product T-1 (75% yield).
  • the nucleophilic reagent was m-methoxybenzylamine to give the oily product T-2 (68% yield).
  • the nucleophilic reagent was p-methoxybenzylamine to give the oily product T-3 (54% yield).
  • the nucleophilic reagent was m-trifluoromethylbenzylamine to give the oily product T-4 (yield 39%).
  • the nucleophilic reagent was p-chlorobenzylamine to give the oily product T-5 (40% yield).
  • the nucleophilic reagent was m-bromobenzylamine to give the oil product T-6 (85% yield).
  • the nucleophilic reagent was phenethylamine according to the preparation method of Example 35 to give the oily product T-7 (67% yield).
  • the nucleophilic reagent was amphetamine, and the oily product T-8 (77% yield) was obtained.
  • the oxazolopyridine quaternary ammonium salt compound claimed in the present invention can be conveniently converted into an N-substituted pyridone compound and a 2-substituted pyridine compound, and has potential value in the field of pharmaceutical application, such as Compound P. -1 to P-29 can further synthesize azacitidine (cytosine nucleoside) analogs; compounds T-1 to T-8 can be used as intermediates to further synthesize pyridylamine (antihistamines) And their analogues for the discovery and synthesis of innovative drugs.
  • azacitidine cytosine nucleoside
  • compounds T-1 to T-8 can be used as intermediates to further synthesize pyridylamine (antihistamines) And their analogues for the discovery and synthesis of innovative drugs.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

涉及一种如式1所示的噁唑并吡啶季铵盐类化合物、制备方法及其作为合成中间体的转化应用。提供的式1所示的噁唑并吡啶季铵盐类化合物的制备方法主要包括由2-氧乙缩醛(或缩酮)基-(取代)吡啶类化合物在酸的作用下发生分子内环化反应制得；提供的式1所示的噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用主要包括其与不同的亲核试剂反应获得N-取代吡啶酮类化合物或者2-取代吡啶类化合物。

Description

一类噁唑并吡啶季铵盐类化合物、其制备方法及用途 技术领域
本发明涉及有机化学及药物化学领域，具体涉及可作为有机合成中间体及治疗肿瘤或癌症、糖尿病、心血管病、中枢神经系统疾病、抗菌消炎等的噁唑并吡啶季铵盐类化合物、制备方法及其作为合成中间体的转化应用。
背景技术
季铵盐(四级铵盐)为铵离子中的四个氢原子都被烃基取代而生成的化合物。其中四个烃基可以相同，也可以不同；阴离子多是卤素负离子(F、Cl、Br、I)，也可是酸根(如HSO4 -、RCOO-等)。季铵盐类化合物在医药、化工等领域都有着极其广泛的应用，如用于杀菌剂、消毒剂、柔软抗静电剂、絮凝剂破乳剂、钻井液、VES压裂液、减阻剂、增稠剂、阴离子增效剂、相转移催化剂等。
其中，噁唑季铵盐是一种很重要的有机合成试剂，它可以发生1,3-偶极环加成反应(Albert Padwa,Edward M.Burgess,Henry L.Gingrich,David M.Roush.On the problem of regioselectivity in the 1,3-dipolar cycloaddition reaction of munchnones and sydnones with acetylenic dipolarophiles.J.Org.Chem.1982,47)、可以用来制备氮杂卡宾化合物(Ung G,Mendoza-Espinosa D,Bertrand G.Ynamides:stable ligand equivalents of unstable oxazol-4-ylidenes(novel mesoionic carbenes).Chem Commun(Camb).,2012,48,7088–7090)、(Zhang J,Fu J,Su X,Qin X,Zhao M,Shi M.Chem.Abnormal oxazol-4-ylidene and thiazol-4-ylidene rhodium complexes:synthesis,structure,and properties.Chem Commun(Camb).,2012,48,9625–9627)、可以用作制备药物活性分子中间体(Pandey PS,Srinivasa Rao T.An efficient synthesis of  N-3,4-diphenyl-5-(4-fluorophenyl)-2-isopropyl-1H-3-pyrrolecarboxamide,a key intermediate for atorvastatin synthesis.Bioorg Med Chem Lett.2004Jan5；14(1):129-31)等。吡啶季铵盐除了本身是一种很重要的有机合成试剂，可以发生亲核加成、Michael加成、1,3-偶极加成、亲核取代和σ-迁移重排等反应(Osyanin VA,Osipov DV,Klimochkin YN.Reactions of o-quinone methides with pyridinium methylides:a diastereoselective synthesis of1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans.J Org Chem.2013Jun 7；78(11):5505-20)外，该类化合物还具有不同的生理活性，如甲基丙烯酰氧十二烷基溴吡啶(12-methacryloyloxydodecylpyridinium bromide,MDPB)和氯化十六烷吡啶(Cetylpyridinium chloride,CPC)可以用于口腔消毒剂(Sreenivasan P1,Gaffar A.Antiplaque biocides and bacterial resistance:a review.J Clin Periodontol.2002Nov；29(11):965-74)；来自于海洋生物的3-烷基吡啶季铵盐多聚物具有抗肺癌活性(Zovko A1,Viktorsson K,Lewensohn R,
Figure PCTCN2017096975-appb-000001
K,
Figure PCTCN2017096975-appb-000002
M,Xing H,Kem WR,Paleari L,Turk T.APS8,a polymeric alkylpyridinium salt blocksα7nAChR and induces apoptosis in non-small cell lung carcinoma.Mar Drugs.2013Jul 16；11(7):2574-94)；来源于传统中药活性成分的盐酸小檗碱，为异喹啉类生物碱，分子结构中具有吡啶季铵盐片段，临床广泛用于治疗肠炎菌痢等，现代研究表明，其还具有抗肿瘤、糖尿病、心血管病、中枢神经系统疾病等药理作用(Singh IP,Mahajan S.Berberine and its derivatives:a patent review(2009-2012).Expert Opin Ther Pat.2013,23(2):215-231)。
噁唑并吡啶季铵盐类化合物鲜有文献报道，仅有的几篇文献以吡啶噁唑酮类化合物为主，该类化合物作为中间体可以发生1,3-偶极环加成反应用以制备杂环化合物(Kazhkenov ZG1,Bush AA,Babaev EV.Dakin-West trick in the design of novel 2-alkyl(aralkyl)derivatives of oxazolo[3,2-a]pyridines. Molecules.2005Sep 1；10(9):1109-18)。这些方法在制备吡啶并噁唑季铵盐类化合物时需要先制备氮取代吡啶酮类化合物，再经过分子内关环获得。其中前一步制备氮取代吡啶酮类原料化合物时需要用到卤代烷烃类化合物与吡啶酮类化合物反应，此种方法的缺点在于卤代烷烃类化合物与吡啶酮类化合物的反应存在反应位点的竞争性，既可生成氮取代吡啶酮类化合物产物，又可生成氧取代吡啶类化合物副产物，从而造成产率不高。本申请的方法则采取另外一种策略，即通过醇类化合物与2位卤代吡啶类化合物反应制备氧取代吡啶类化合物，以此为原料，再通过酸性条件下的分子内关环反应获得目标产物，反应选择性较高，副产物少，从而提高总收率。
发明内容
本发明的一个目的是提供一种式1所示噁唑并吡啶季铵盐类化合物；
本发明的另一个目的是提供式1所述噁唑并吡啶季铵盐类化合物的制备方法；
本发明的再一个目的是提供式1所述噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用。
本发明所涉及的噁唑并吡啶季铵盐类化合物可以作为有机合成中间体及药物分子结构单元，具有潜在的开发应用价值。
一种如式1所示的噁唑并吡啶季铵盐类化合物：
Figure PCTCN2017096975-appb-000003
其中，
Figure PCTCN2017096975-appb-000004
代表双键或单键；
Q、U各自独立地代表氧、硫或氮；
R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、羟基、氨基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳氨基、C6-C12芳硫基、硝基、酰胺基、苯并二噁茂基或卤素；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基可彼此连接并且与吡啶环上的碳原子共同形成取代或未取代的芳基或含有0-3个独立选自O、S或N原子的5-7元环烷基；
R2、R3各自独立地代表氢、羟基、氨基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳氨基、C6-C12芳硫基或卤素；且当
Figure PCTCN2017096975-appb-000005
为双键时，R3不存在；
R4代表氢、取代或未取代的烷基或取代或未取代的芳基；
Y为酸根阴离子，选自无机酸根离子、有机酸根离子和卤素离子，包括但不限于硝酸根离子、硫酸根离子、磷酸根离子、甲磺酸根离子、苯磺酸根离子、醋酸根离子、酒石酸根离子、枸橼酸根离子、马来酸根离子、琥珀酸根离子、柠檬酸根离子、水杨酸根离子、甘油酸根离子、抗坏血酸根离子、氟离子、氯离子、溴离子或碘离子。
所述取代或未取代的烷基包括取代或未取代的饱和、不饱和、直链、支链的全碳C1-C6烷基或含氧、氮或硫等杂原子的C1-C6烷基；其中，“所述取代或未取代”中的“取代”是指被选自卤素、芳基、C1-C6烷基中的一种或多种取代基所取代。
所述取代或未取代的芳基包括取代或未取代的苯基或含氧、氮、硫等杂原子的芳基；其中，“所述取代或未取代”中的“取代”是指被选自C1-C6烷氧基、卤素取代的C1-C6烷氧基、苄基(BnO)、羟基、氰基、C1-C3烷氧基羰基中的一种或多种取代基所取代。
所述的卤素是指氟、氯、溴或碘。
优选的，
Figure PCTCN2017096975-appb-000006
代表单键；
优选的，U和Q各自独立地代表氧或硫；
优选的，R4代表取代或未取代的烷基；
优选的，R2、R3各自独立地代表氢、取代或未取代的烷基或取代或未取代的芳基；
优选的，R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、烷基、芳基、C1-C6烷氧基、硝基、酰胺基、苯并二噁茂基；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基并且与吡啶环上的碳原子共同形成芳基。
所述的噁唑并吡啶季铵盐类化合物优选为：
Figure PCTCN2017096975-appb-000007
本发明还提供了所述的噁唑并吡啶季铵盐类化合物的制备方法：
Figure PCTCN2017096975-appb-000009
化合物S溶于溶剂中，加入酸NY，在一定温度下反应一段时间，蒸除溶剂，既得化合物I；
其中，R1、R2、R3、R4、U、Q、Y的定义同前所述。
所述的溶剂包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水等一种或一种以上组合溶剂；所述的溶剂优选为甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、水等一种或一种以上的组合溶剂。
所述的酸NY选自无机酸、有机酸和氢卤酸。包括但不限于硝酸、硫酸、磷酸、甲磺酸、苯磺酸、醋酸、酒石酸、枸橼酸、马来酸、琥珀酸、柠檬酸、水杨酸、甘油酸、抗坏血酸、氢氟酸、盐酸、氢溴酸或氢碘酸等一种或一种以上组合酸；所述的酸NY优选为甲磺酸、对甲苯磺酸、三氟甲磺酸、乙酸、三氟乙酸、盐酸、磷酸等一种或一种以上组合酸。
所述的一定温度为从零下80摄氏度至200摄氏度的任何温度；优选为从0摄氏度到100摄氏度的任何温度。
本发明还提供了所述的噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用：
Figure PCTCN2017096975-appb-000010
其中，R1、R2、R3、R4、U、Q、Y的定义同前所述。
W、Z各自独立的为O，R7N或S等；A为氢或锂、钠、镁、铜、锡等金属原子；R5为氢、取代或未取代的芳基或C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、硝基或卤素所取代；R6为氢、被取代或未取代的芳基所取代的C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、三氟甲基或卤素所取代；R7为氢、取代或未取代的C1-C6烷基，所述“取代或未取代”是指被C1-C3烷基、C1-C3烷氧基、硝基、三氟甲基或卤素所取代。
所述化合物I(化合物I可以从化合物S制备得到，产物经纯化或未经纯化或不经分离)溶于溶剂中，加入亲核试剂，所述亲核试剂为R5-WA、R6-ZA或无机碱，在零下80摄氏度至200摄氏度的温度下反应，蒸除溶剂，常规分离纯化处理，即获得N取代吡啶酮类化合物P或者2-取代吡啶类化合物T，当亲核试剂为无机碱时，W为O，R5为氢。
所述无机碱选自碳酸氢钠、氢氧化钠等。
所述的溶剂包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水等一种或一种以上组合溶剂；
有益效果
根据本发明的噁唑并吡啶季铵盐类化合物的制备方法条件温和、试剂易得、产物收率高、后处理方便等，具有较好的推广应用价值；并且根据所述方法合成的噁唑并吡啶季铵盐类化合物具有潜在的有机合成和药物化学用途，该类化合物可以进一步很方便的与不同亲核试剂反应，从而转化为药物分子中常见的N取代吡啶酮类化合物及2-取代吡啶类化合物，具有潜在的作为有机合成中间体及药物分子结构单元的开发应用价值。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但不限制本发明。
制备实施实例
本发明式1所述化合物的合成：
原料S-1到S-20的制备由商业化的2-氯吡啶类化合物或2-羟基吡啶类化合物为原料，参考文献Tetrahedron,2004,60,6113的方法制得。所用试剂如无特殊说明，均购自国药集团。
实施例1 化合物I-1的制备
Figure PCTCN2017096975-appb-000011
将化合物S-1溶于干燥的甲苯中，向其中加入过量的三氟乙酸，加热至50℃，保持干燥，反应过夜，将过量的酸和溶剂旋干，乙醚洗得到纯净的化合物I-1，收率为86％.1H NMR(400MHz,氯仿-d)δ7.62(dd,J＝7.0,2.0Hz,1H),7.52(ddt,J＝8.7,6.6,2.7Hz,1H),6.75(d,J＝9.1Hz,1H),6.47(q,J＝7.1Hz,1H),6.08–5.97(m,1H),3.78(q,J＝11.5,9.8Hz,2H),3.37(s,3H).13C  NMR(125MHz,CDCl3)δ159.91,149.11,137.12,119.27,110.64,93.01,75.74,58.15.MS(EI)：265.
实施例2 化合物I-2的制备
Figure PCTCN2017096975-appb-000012
将化合物S-2溶于干燥的无水乙醚中，向其中加入过量的浓盐酸，立即有大量的黄色固体析出，搅拌3h后，过滤，无水乙醚洗得到纯净的化合物I-2，收率为92％。1H NMR(400MHz,氯仿-d)δ7.66(d,J＝7.3Hz,1H),6.88(dd,J＝1.9,1.0Hz,1H),6.43(dd,J＝7.3,2.0Hz,1H),6.07(dd,J＝4.8,3.6Hz,1H),3.87–3.70(m,2H),3.45(s,3H).13C NMR(125MHz,CDCl3)δ160.93,141.24,140.97,133.41,122.63,120.45,117.99,100.85,84.91,57.37,43.98.MS(EI)255.
实施例3 化合物I-3的制备
Figure PCTCN2017096975-appb-000013
制备方法同实施例2，将化合物S-2替换为化合物S-3得化合物I-3，收率为99％。1H NMR(400MHz,氯仿-d)δ9.28(s,1H),8.60(dd,J＝7.2,2.2Hz,1H),7.77(dd,J＝6.8,1.9Hz,1H),6.56(t,J＝6.9Hz,1H),6.22–6.09(m,1H),5.97(s,1H),3.93–3.69(m,2H),3.46(s,3H).13C NMR(125MHz,CDCl3)δ164.76,161.45,144.37,135.61,120.97,106.16,85.37,57.49,44.09.MS(ESI)195.
实施例4 化合物I-4的制备
Figure PCTCN2017096975-appb-000014
制备方法同实施例2，将化合物S-2替换为化合物S-4得化合物I-4，收率为82％。1H NMR(400MHz,氯仿-d)δ8.83–8.72(m,1H),8.17(ddd,J＝10.1,3.2,1.2Hz,1H),6.61(d,J＝10.1Hz,1H),6.11–5.98(m,1H),3.83(qdd,J＝12.1,4.0,1.1Hz,2H),3.51(d,J＝1.2Hz,3H).13C NMR(125MHz,CDCl3)δ161.38,134.60,133.67,131.41,119.88,86.11,58.29,44.34.MS(ESI)197.
实施例5 化合物I-5的制备
Figure PCTCN2017096975-appb-000015
制备方法同实施例2，将化合物S-2替换为化合物S-5得化合物I-5，收率为80％。1H NMR(400MHz,氯仿-d)δ7.12(dd,J＝7.2,1.7Hz,1H),6.66(dd,J＝7.4,1.6Hz,1H),6.28–6.14(m,2H),3.86(s,3H),3.78–3.70(m,2H),3.41(s,3H).13C NMR(125MHz,CDCl3)δ158.08,149.87,122.41,112.25,105.13,85.08,57.53,55.90,44.60.MS(ESI)182.
实施例6 化合物I-6的制备
Figure PCTCN2017096975-appb-000016
制备方法同实施例2，将化合物S-2替换为化合物S-6得化合物I-6，收率为77％。1H NMR(400MHz,氯仿-d)δ7.36(d,J＝7.1Hz,1H),6.38(s,1H),6.13(d,J＝8.2Hz,1H),6.08(d,J＝5.1Hz,1H),3.83–3.65(m,2H),3.40(s,3H),2.21(s,3H).13C NMR(125MHz,CDCl3)δ162.61,151.76,130.80,119.14,108.97,84.66,57.49,44.85,21.35.HRMS(ESI)计算值(计算值)C9H12O2NCl202.0629[M+H]+,实测值(found)202.0635.
实施例7 化合物I-7的制备
Figure PCTCN2017096975-appb-000017
制备方法同实施例2，将化合物S-2替换为化合物S-7得化合物I-7，收率为86％。1H NMR(400MHz,氯仿-d)δ8.48–8.41(m,1H),7.70(ddd,J＝8.3,7.0,1.3Hz,1H),7.60–7.49(m,2H),7.28(d,J＝7.6Hz,1H),6.62(d,J＝7.6Hz,1H),6.26(t,J＝5.2Hz,1H),3.78(d,J＝5.2Hz,2H),3.43(s,3H).13C NMR(125MHz,CDCl3)δ161.99,136.33,132.38,127.52,126.69,125.63,125.41,124.76,106.37,84.25,56.88,44.19.HRMS(ESI)m/z:计算值C12H12O2N+202.0863,实测值202.0868.
实施例8 化合物I-8的制备
Figure PCTCN2017096975-appb-000018
制备方法同实施例2，将化合物S-2替换为化合物S-8得化合物I-8，收率为98％。1H NMR(400MHz,甲醇-d4)δ9.10(d,J＝9.3Hz,1H),8.33(d,J＝8.1Hz,1H),8.26–8.16(m,2H),7.91(ddd,J＝8.2,5.4,2.6Hz,1H),7.69(d,J＝9.2Hz,1H),7.16(dd,J＝6.6,2.5Hz,1H),5.43(dd,J＝11.5,2.5Hz,1H),5.29(dd,J＝11.5,6.6Hz,1H),3.52(d,J＝1.0Hz,3H).13C NMR(125MHz,MeOD4)δ162.43,151.61,135.22,133.58,130.40,128.10,125.05,116.94,108.39,89.66,75.23,53.39.LRMS(ESI):202.
实施例9 化合物I-9的制备
Figure PCTCN2017096975-appb-000019
制备方法同实施例2，将化合物S-2替换为化合物S-9得化合物I-9，收率为96％。1H NMR(400MHz,丙酮-d6)δ8.17(s,1H),8.04(s,1H),7.82(s,1H),7.34(s,2H),7.14(s,1H),6.94(s,1H),6.19(s,2H),5.52(s,1H),5.43(s,1H),4.12(d,J＝19.5Hz,6H),3.17(s,3H).13C NMR(125MHz,丙酮)δ161.60,153.19,149.69,148.48,146.87,136.49,134.49,129.66,125.51,124.32,123.91,119.06,110.75,109.36,108.83,102.23,91.20,61.47,56.51,55.76.HRMS(ESI)计算值C21H20O6N 382.1291[M+H]+,实测值382.1286.
实施例10 化合物I-10的制备
Figure PCTCN2017096975-appb-000020
制备方法同实施例2，将化合物S-2替换为化合物S-10得化合物I-10，收率为88％。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝9.0Hz,1H),8.03(d,J＝8.9Hz,1H),7.92(s,1H),7.52–7.32(m,7H),7.29(s,2H),6.78(s,1H),5.34(s,2H),5.22(s,2H),4.05(s,3H),3.98(s,3H),3.88(s,3H),2.93(s,3H).13C NMR(125MHz,DMSO)δ161.07,152.95,149.70,146.15,137.12,136.55,134.49,128.93,128.46,128.36,126.11,124.97,124.76,122.35,119.07,114.07,113.14,110.53,91.16,76.57,70.40,62.28,57.43,56.48,55.86.ESI-LR:474.
实施例11 化合物I-11的制备
Figure PCTCN2017096975-appb-000021
制备方法同实施例2，将化合物S-2替换为化合物S-11得化合物I-11，收率为92％。1H NMR(400MHz,氯仿-d)δ7.80(d,J＝8.9Hz,1H),7.74(d,J＝9.0Hz,1H),7.54(s,1H),7.19(s,2H),7.12(s,1H),6.12(s,1H),4.96(d,J＝7.7Hz,1H),4.09–3.87(m,15H),2.97(s,3H).
实施例12 化合物I-12的制备
Figure PCTCN2017096975-appb-000022
制备方法同实施例2，将化合物S-2替换为化合物S-12得化合物I-12，收率为99％。1H NMR(DMSO-d6,400MHz)δ8.54(1H,d,J＝7.7Hz),8.32(2H,d,J＝3.6Hz),8.24(2H,d,J＝8.5Hz),8.16(1H,s),7.96(2H,d,J＝7.7Hz),6.81(1H,d,J＝6.4Hz),5.45(1H,dd,J＝11.1,2.1Hz),5.30(1H,dd,11.1,6.4Hz),3.94(3H,s),3.88-3.91(1H,m),2.94(3H,s).HRMS(ESI):计算值C20H18O4N+336.1230,实测值336.1239.
实施例13 化合物I-13的制备
Figure PCTCN2017096975-appb-000023
制备方法同实施例2，将化合物S-2替换为化合物S-13得化合物I-13，收率为94％。1H NMR(DMSO-d6,400MHz)δ8.50(d,J＝8.0Hz，1H),8.29(d,J＝3.9Hz，2H),8.04(s，1H),7.41(d,J＝2.0Hz，1H),7.37–7.33(m，1H),7.24(d,J＝8.3Hz，1H),6.88(d,J＝5.9Hz，1H),5.41(d,J＝11.1Hz，1H),5.31(dd,J＝11.1,6.1Hz，1H),3.88(d,J＝1.3Hz，6H),3.80-3.84(m，1H),2.97(d,J＝1.1Hz，3H).HRMS(ESI)m/z:计算值C20H20O4N+338.1387,实测值338.1391.
实施例14 化合物I-14的制备
Figure PCTCN2017096975-appb-000024
制备方法同实施例2，将化合物S-2替换为化合物S-14得化合物I-14，收率为99％。1H NMR(DMSO-d6,500MHz)δ8.43(d,J＝8.9Hz，1H),8.23(d,J＝4.9Hz，2H),8.10(d,J＝8.2Hz，1H),7.94(s，1H),7.88(d,J＝8.2Hz，1H),7.83(s，1H),7.70(d,J＝7.0Hz，1H),7.55(s，1H),6.77(dd,J＝6.0,1.8Hz，1H),5.36(dd,J＝11.0,1.8Hz，1H),5.26(dd,11.0,6.0Hz，1H),3.09-3.12(m，1H),2.94(s，3H).HRMS(ESI)m/z:计算值C18H16O3N+294.1125,实测值294.1122.
实施例15 化合物I-15的制备
Figure PCTCN2017096975-appb-000025
制备方法同实施例2，将化合物S-2替换为化合物S-15得化合物I-15，收率为91％。1H NMR(DMSO-d6,400MHz)δ8.54(d,J＝8.2Hz，1H),8.32-8.33(m，2H),8.16(s，1H),7.82-7.89(m，2H),7.69-7.77(m，1H),7.58-7.62(m，1H),6.79(dd,J＝6.3,2.2Hz，1H),5.44(dd,J＝11.1,2.2Hz，1H),5.33(dd,J＝11.1,6.3Hz，1H),4.21–3.94(m，1H),2.96(s，3H).HRMS(ESI)m/z:计算值C19H15O3F3N+362.0999,实测值362.1008.
实施例16 化合物I-16的制备
Figure PCTCN2017096975-appb-000026
制备方法同实施例2，将化合物S-2替换为化合物S-16得化合物I-16，收率为96％。1H NMR(DMSO-d6,400MHz)δ8.55(d,J＝8.1Hz，1H),8.33(d,J＝5.3Hz，2H),8.20(d,J＝8.3Hz，2H),8.16(s，1H),8.01(d,J＝8.2Hz，2H),6.80(dd,J＝6.3,2.2Hz，1H),5.48(dd,J＝11.1,2.2Hz，1H),5.30(dd,J＝11.1,6.5Hz，1H),3.44–3.35(m，1H),2.96(s，3H).HRMS(ESI)m/z:计算值C19H15O2N2 +303.1128,实测值303.1126.
实施例17 化合物I-17的制备
Figure PCTCN2017096975-appb-000027
制备方法同实施例2，将化合物S-2替换为化合物S-17得化合物I-17，收率为92％。1H NMR(DMSO-d6,400MHz)δ8.49(d,J＝8.3Hz，1H),8.28(d,J＝3.8Hz，2H),8.01(s，1H),7.73(d,J＝8.1Hz，2H),7.21(d,J＝8.7Hz，2H),6.80(dd,J＝5.5,1.8Hz，1H),5.41(dd,J＝10.4,1.8Hz，1H),5.31(dd,10.4,5.5Hz，1H),4.16(q,J＝6.8Hz，2H),4.09-4.12(m，1H),2.96(s，3H),1.39(t,J＝7.1Hz，3H).HRMS(ESI)m/z:计算值C20H20O3N[M]+322.1438,实测值322.1440.
实施例18 化合物I-18的制备
Figure PCTCN2017096975-appb-000028
制备方法同实施例2，将化合物S-2替换为化合物S-18得化合物I-18，收率为99％。1H NMR(DMSO-d6,400MHz)δ8.50(d,J＝8.1Hz，1H),8.29(dd,J＝4.0,1.3Hz，2H),8.09–8.08(m，1H),7.15(d,J＝2.0Hz，2H),6.95(dd,J＝6.0,2.1Hz，1H),5.41(dd,J＝11.0,2.0Hz，1H),5.36(dd,J＝11.0,6.1Hz，1H),3.89(s，6H),3.77(s，3H),3.70-3.73(m，1H),3.00(s，3H).HRMS(ESI)m/z:计算值C21H22O5N+368.1492,实测值368.1487.
实施例19 化合物I-19的制备
Figure PCTCN2017096975-appb-000029
制备方法同实施例2，将化合物S-2替换为化合物S-19得化合物I-19，收率为97％。1H NMR(DMSO-d6,400MHz)δ8.50(d,J＝8.2Hz，1H),8.30(d,J＝3.7Hz，2H),8.05(s，1H),7.75(d,J＝8.1Hz，2H),7.61(d,J＝8.2Hz，2H),6.82(dd,J＝6.1,1.8Hz，1H),5.42(dd,J＝11.1,1.8Hz，1H),5.30(dd,J＝11.1,6.2Hz，1H),4.64(s，2H),4.20(s，1H),3.10-3.13(m，1H),2.93(s，3H).HRMS(ESI)m/z:计算值C19H18O3N+308.1281,实测值308.1280.
实施例20 化合物I-20的制备
Figure PCTCN2017096975-appb-000030
制备方法同实施例2，将化合物S-2替换为化合物S-20得化合物I-20，收率为85％。1H NMR(DMSO-d6,400MHz)δ8.51(d,J＝8.2Hz，1H),8.30(d,J＝4.3Hz，2H),8.09(s，1H),7.64–7.58(m，1H),7.40–7.34(m，2H),7.24(s，1H),6.85(dd,J＝6.2,2.1Hz，1H),5.42(dd,J＝11.1,2.1Hz，1H),5.31(dd,11.1,6.2Hz，1H),3.88(s，3H),3.80-3.82(m，1H),2.95(s，3H).HRMS(ESI)m/z:计算值C19H18O3N+308.1281,实测值308.1290.
本发明式1所述噁唑并吡啶季铵盐类化合物作为合成中间体转化为N取代吡啶酮类化合物和2-取代吡啶类化合物的应用实施例：
实施例21 化合物P-1的制备
Figure PCTCN2017096975-appb-000031
以化合物S-1为原料，将化合物S-1(1mmol)溶于甲苯(5ml)，加入三氟乙酸(3mmol)搅拌，升温至50℃反应。反应完毕后，反应液用冰水降温，加入饱和碳酸氢钠溶液搅拌。减压蒸干溶剂，残余物通过硅胶柱分离纯化得到产物，得到油状产物P-1(84％收率)。
1H NMR(400MHz,氯仿-d)δ7.50(dd,J＝7.0,2.1Hz,1H),7.37(ddd,J＝8.9,6.5,2.0Hz,1H),6.57(ddd,J＝9.2,1.4,0.7Hz,1H),6.33–6.26(m,1H),6.02(dd,J＝5.5,4.4Hz,1H),3.77(p,J＝11.7,10.9Hz,2H),3.37(d,J＝0.6Hz,4H).13C NMR(125MHz,氯仿-d)δ162.71,139.34,131.71,120.23,106.04,85.76,63.59,56.75.HRMS(EI)计算值C8H11NO3[M]+:169.0739,实测值:169.0743.
实施例22 化合物P-2的制备
Figure PCTCN2017096975-appb-000032
2-(2,2-二甲氧基乙氧基)-3-甲基吡啶(以购买的2-氯-3-甲基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-3-甲基吡啶，得到油状产物P-2(55％收率)。
1H NMR(400MHz,氯仿-d)δ7.37(dt,J＝7.2,1.3Hz,1H),7.26(ddd,J＝6.7,2.1,1.1Hz,1H),6.23(t,J＝6.8Hz,1H),6.08(dd,J＝5.6,4.4Hz,1H),3.79(qd,J＝11.7,5.0Hz,2H),3.39(s,3H),2.18(t,J＝0.9Hz,3H).13C NMR(125MHz,氯仿-d)δ163.00,136.66,129.17,128.87,105.84,86.07,63.78,56.75,16.57.HRMS(ESI)计算值C9H13NO3[M+Na]+:206.0793,实测值206.0791.
实施例23 化合物P-3的制备
Figure PCTCN2017096975-appb-000033
以化合物S-5为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-5，得到油状产物P-3(76％收率)。
1H NMR(400MHz,氯仿-d)δ7.10(dd,J＝7.1,1.6Hz,1H),6.63(dd,J＝7.4,1.6Hz,1H),6.21(t,J＝7.2Hz,1H),6.07(t,J＝5.1Hz,1H),3.81(s,3H),3.78–3.70(m,2H),3.33(s,3H).13C NMR(125MHz,氯仿-d)δ157.99,149.17,122.35,111.97,104.97,86.06,63.33,56.67,55.40.HRMS(EI)计算值C9H13NO4[M]+:199.0845,实测值199.0848.
实施例24 化合物P-4的制备
Figure PCTCN2017096975-appb-000034
2-(2,2-二甲氧基乙氧基)-3-硝基吡啶(以购买的2-氯-3-硝基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-3-硝基吡啶，得到油状产物P-4(26％收率)。
1H NMR(400MHz,氯仿-d)δ8.40(dd,J＝7.6,2.1Hz,1H),7.92(dd,J＝6.8,2.1Hz,1H),6.45(t,J＝7.2Hz,1H),6.11(t,J＝3.9Hz,1H),3.95(dd,J＝12.2,3.5Hz,1H),3.81(dd,J＝12.2,4.2Hz,1H),3.45(s,3H).13C NMR(125MHz,Acetone)δ153.88,139.82,137.59,102.57,87.06,61.93,56.22.HRMS(EI)计算值C8H10N2O5[M]+:214.0590,实测值214.0595.
实施例25 化合物P-5的制备
Figure PCTCN2017096975-appb-000035
2-(2,2-二甲氧基乙氧基)-3-(三氟甲基)吡啶(以购买的2-氯-3-三氟甲基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-3-(三氟甲基)吡啶，得到油状产物P-5(61％收率)。
1H NMR(400MHz,氯仿-d)δ7.85–7.77(m,1H),7.74(dd,J＝7.0,2.0Hz,1H),6.38(t,J＝7.0Hz,1H),6.03(dd,J＝5.0,4.0Hz,1H),3.87–3.80(m,1H),3.75(dd,J＝12.1,4.9Hz,1H),3.39(s,3H),3.28–3.17(m,1H).13C NMR(125MHz,氯仿-d)δ158.47,138.79,138.75,136.37,123.21,121.06,119.93,119.68,104.15,86.37,86.28,62.89,57.06,56.98.HRMS(ESI)计算值C9H10NO3F3[M+Na]+:260.0510,实测值260.0509.
实施例26 化合物P-6的制备
Figure PCTCN2017096975-appb-000036
以化合物S-3为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-3，得到油状产物P-6(59％收率)。
1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝4.2Hz,1H),8.36(dd,J＝7.2,2.2Hz,1H),7.88(dd,J＝6.7,2.2Hz,1H),7.65(d,J＝4.2Hz,1H),6.58(t,J＝6.9Hz,1H),5.94(t,J＝4.6Hz,1H),5.21(t,J＝6.1Hz,1H),3.60(ddd,J＝6.7, 4.7,2.3Hz,2H),3.25(s,3H).13C NMR(125MHz,DMSO-d6)δ164.56,161.69,143.78,138.11,106.30,86.67,61.60,56.60,38.81,38.60.HRMS(EI)计算值C9H12N2O4[M]+:212.0797,实测值212.0799.
实施例27 化合物P-7的制备
Figure PCTCN2017096975-appb-000037
以化合物S-6为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-6，得到油状产物P-7(19％收率)。
1H NMR(400MHz,氯仿-d)δ7.38(d,J＝7.1Hz,1H),6.44–6.37(m,1H),6.16(dd,J＝7.2,1.8Hz,1H),6.01(t,J＝5.0Hz,1H),3.83–3.66(m,2H),3.37(s,3H),2.28–2.17(m,3H).13C NMR(125MHz,氯仿-d)δ162.76,151.26,130.63,118.55,108.85,85.54,63.71,56.68,20.82.HRMS(ESI)计算值C9H13NO3[M+Na]+:206.0793,实测值206.0799.
实施例28 化合物P-8的制备
Figure PCTCN2017096975-appb-000038
以化合物S-2为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-2，得到油状产物P-8(51％收率)。
1H NMR(400MHz,氯仿-d)δ7.71–7.63(m,1H),6.85(dd,J＝1.9,1.0Hz,1H),6.43(dd,J＝7.3,2.0Hz,1H),5.98(t,J＝4.4Hz,1H),3.88–3.73(m, 2H),3.41(s,3H),2.97–2.89(m,1H).13C NMR(125MHz,氯仿-d)δ161.56,141.17,140.90,133.83,124.84,122.66,120.48,117.73,117.70,117.66,101.18,101.16,86.29,63.01,57.02,HRMS(ESI)计算值C9H10NO3F3[M+Na]+:260.0510,实测值260.0508.
实施例29 化合物P-9的制备
Figure PCTCN2017096975-appb-000039
2-(2,2-二甲氧基乙氧基)-5-甲基吡啶(以购买的2-氯-5-甲基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-5-甲基吡啶，得到油状产物P-9(26％收率)。
1H NMR(400MHz,氯仿-d)δ7.27–7.20(m,2H),6.57–6.51(m,1H),6.03(t,J＝5.1Hz,1H),3.77(dd,J＝5.0,1.3Hz,2H),3.37(s,3H),2.12(d,J＝1.0Hz,3H).13C NMR(125MHz,氯仿-d)δ162.07,142.15,128.91,119.78,115.33,85.73,63.57,56.76.HRMS(EI)计算值C9H13NO3[M]+:183.0895,实测值183.0892.
实施例30 化合物P-10的制备
Figure PCTCN2017096975-appb-000040
以化合物S-4为原料，按实施例21的制备方法，将化合物S-1替换为化 合物S-4，得到油状产物P-10(22％收率)。
1H NMR(400MHz,氯仿-d)δ8.78(d,J＝3.1Hz,1H),8.16(dd,J＝10.0,3.1Hz,1H),6.60(d,J＝10.0Hz,1H),5.96(t,J＝3.7Hz,1H),3.96(dd,J＝12.2,3.4Hz,1H),3.78(dd,J＝12.2,4.1Hz,1H),3.48(s,4H).13C NMR(125MHz,氯仿-d)δ161.35,134.63,133.02,130.92,129.42,129.25,119.21,86.77,62.95,57.49.HRMS(ESI)计算值C9H10N2O5[M+Na]+:237.0487,实测值237.0485.
实施例31 化合物P-11的制备
Figure PCTCN2017096975-appb-000041
2-(2,2-二甲氧基乙氧基)-5-(三氟甲基)吡啶(以购买的2-氯-5-三氟甲基吡啶和羟基乙醛缩二甲醇为原料，同Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-5-(三氟甲基)吡啶，得到油状产物P-11(78％收率)。
1H NMR(400MHz,氯仿-d)δ7.92–7.88(m,1H),7.50(dd,J＝9.6,2.7Hz,1H),6.67–6.60(m,1H),5.97(t,J＝4.3Hz,1H),3.85(dd,J＝12.1,3.9Hz,1H),3.76(dd,J＝12.0,4.8Hz,1H),3.42(s,3H),2.93(s,1H).13C NMR(125MHz,氯仿-d)δ161.98,135.01,134.99,132.02,131.97,131.93,131.89,126.05,123.90,121.76,120.74,110.28,110.00,109.72,109.45,86.36,63.02,62.90,57.13.HRMS(ESI)计算值C9H10NO3F3[M+Na]+:260.0510,实测值260.0513.
实施例32 化合物P-12的制备
Figure PCTCN2017096975-appb-000042
以化合物S-8为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-8，得到固体产物P-12(89％收率)。
1H NMR(400MHz,氯仿-d)δ8.12(d,J＝8.7Hz,1H),7.69(d,J＝9.4Hz,1H),7.55(dd,J＝7.8,1.7Hz,1H),7.51–7.46(m,1H),7.26–7.22(m,1H),6.76–6.71(m,1H),6.68(d,J＝9.4Hz,1H),4.27(dd,J＝11.8,7.2Hz,1H),4.00(dd,J＝11.8,6.0Hz,1H),3.39(s,3H).13C NMR(125MHz,氯仿-d)δ163.35,139.89,137.26,129.68,128.55,122.22,120.89,120.76,116.21,86.77,61.65,56.41.HRMS(EI)计算值C12H13NO3[M]+:219.0895,实测值219.0898.
实施例33 化合物P-13的制备
Figure PCTCN2017096975-appb-000043
2-(2,2-二甲氧基乙氧基)-4-甲基喹啉酮(以购买的2-氯-4-甲基喹啉和羟基乙醛缩二甲醇为原料，同Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-4-甲基喹啉酮，得到固体产物P-13(84％收率)。
1H NMR(400MHz,氯仿-d)δ8.14(dd,J＝8.7,1.0Hz,1H),7.70(dd,J＝8.0,1.6Hz,1H),7.49(ddd,J＝8.7,7.1,1.6Hz,1H),7.28–7.23(m,1H),6.79–6.70(m,1H),6.56(d,J＝1.4Hz,1H),4.27(dd,J＝11.7,7.2Hz,1H),3.99(dd,J＝11.8,6.0Hz,1H),3.39(s,3H),2.47(d,J＝1.1Hz,3H).13C NMR(125MHz, 氯仿-d)δ163.17,147.44,137.06,129.49,124.81,122.09,121.65,120.14,116.51,115.97,86.66,61.71,56.33,18.69.HRMS(EI)计算值C13H15NO3[M]+:233.1052,实测值233.1056.
实施例34 化合物P-14的制备
Figure PCTCN2017096975-appb-000044
以化合物S-7为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-7，得到固体产物P-14(63％收率)。
1H NMR(400MHz,DMSO-d6)δ8.28–8.21(m,1H),7.73(ddd,J＝8.2,7.0,1.3Hz,1H),7.70–7.64(m,1H),7.53(ddd,J＝8.1,7.0,1.4Hz,1H),7.35(d,J＝7.6Hz,1H),6.69(d,J＝7.6Hz,1H),5.97(t,J＝5.4Hz,1H),5.19(s,1H),4.14(s,1H),3.66(dd,J＝11.7,5.6Hz,1H),3.58(dd,J＝11.7,5.3Hz,1H),3.22(s,3H),3.17(s,3H).13C NMR(125MHz,DMSO-d6)δ161.53,136.62,132.61,127.21,126.69,126.12,125.22,105.45,85.32,85.32,61.86,55.94.HRMS(EI)计算值C12H13NO3[M]+:219.0895,实测值219.0894.
化合物P-15至P-29的制备方法：
实施例35 化合物P-15的制备
Figure PCTCN2017096975-appb-000045
以化合物S-1为原料，将化合物S-1(1mmol)溶于甲苯(5ml)，加入三氟醋酸(3mmol)搅拌反应。升温至50℃反应。反应完毕，反应液减压蒸干溶剂得到残余物。残余物再用甲苯溶解或分散，加入亲核试剂反应，搅拌过夜。反应完毕，减压蒸干溶剂得到残余物，残余物通过硅胶柱分离得到产物。亲核试剂为苯胺，得到油状产物P-15(27％收率)。
1H NMR(400MHz,氯仿-d)δ7.50(dd,J＝7.0,2.0Hz,1H),7.36(ddd,J＝8.9,6.4,2.0Hz,1H),7.19(t,J＝7.7Hz,2H),6.73(dd,J＝11.2,7.7Hz,3H),6.60(d,J＝9.2Hz,1H),6.26(t,J＝6.8Hz,1H),6.12(dd,J＝6.7,4.0Hz,1H),3.55(dd,J＝13.7,3.9Hz,1H),3.36(s,3H),3.35–3.29(m,1H).13C NMR(125MHz,氯仿-d)δ162.99,147.34,139.68,131.66,129.30,120.82,117.97,113.08,106.44,85.36,57.30,47.95.HRMS(EI)计算值C14H16N2O2[M]+:244.1212,实测值244.1218.
实施例36 化合物P-16的制备
Figure PCTCN2017096975-appb-000046
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间甲氧基苯胺，得到油状产物P-16(32％收率)。
1H NMR(400MHz,氯仿-d)δ7.49(dd,J＝7.0,2.0Hz,1H),7.37(ddd,J＝8.9,6.5,2.0Hz,1H),7.08(t,J＝8.3Hz,1H),6.60(d,J＝9.1Hz,1H),6.35–6.23(m,4H),6.12(dd,J＝6.7,4.0Hz,1H),4.21(s,1H),3.79(s,3H),3.54(dd,J＝13.5,4.0Hz,1H),3.39–3.26(m,4H).13C NMR(125MHz,氯仿-d)δ162.54,160.37,148.29,139.23,131.16,129.57,120.34,106.01,105.54,103.12,98.33, 84.86,56.85,54.67,47.51.HRMS(EI)计算值C15H18N2O3[M]+:274.1317,实测值274.1329.
实施例37 化合物P-17的制备
Figure PCTCN2017096975-appb-000047
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对甲氧基苯胺，得到油状产物P-17(53％收率)。
1H NMR(400MHz,氯仿-d)δ7.53–7.44(m,1H),7.36(ddd,J＝8.7,6.6,2.1Hz,1H),6.78(d,J＝8.5Hz,2H),6.69(d,J＝8.7Hz,2H),6.59(d,J＝9.2Hz,1H),6.26(t,J＝6.8Hz,1H),6.09(dd,J＝6.9,3.8Hz,1H),4.12(s,1H),3.74(s,3H),3.49(dd,J＝13.5,3.7Hz,1H),3.34(s,3H),3.26(dd,J＝13.5,6.8Hz,1H).13C NMR(125MHz,氯仿-d)δ162.48,152.13,140.70,139.32,131.28,120.24,114.21,106.12,84.88,56.79,55.26,48.51.HRMS(EI)计算值C15H18N2O3[M]+:274.1317,实测值274.1326.
实施例38 化合物P-18的制备
Figure PCTCN2017096975-appb-000048
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间硝基苯胺，得到油状产物P-18(11％收率)。
1H NMR(400MHz,氯仿-d)δ7.56–7.46(m,3H),7.42–7.34(m,1H),7.28(d,J＝16.2Hz,1H),7.04–6.97(m,1H),6.61(d,J＝9.1Hz,1H),6.29(t,J＝6.8Hz,1H),6.13–6.06(m,1H),4.74–4.53(m,1H),3.63–3.53(m,1H),3.42(dd,J＝13.5,6.3Hz,1H),3.38(d,J＝1.1Hz,3H).13C NMR(125MHz,氯仿-d)δ162.59,148.80,147.76,139.39,130.80,129.36,120.42,118.17,111.94,106.49,106.27,84.90,56.96,47.24.HRMS(EI)计算值C14H15N3O4[M]+:289.1063,实测值289.1058.
实施例39 化合物P-19的制备
Figure PCTCN2017096975-appb-000049
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间氯苯胺，得到油状产物P-19(36％收率)。
1H NMR(400MHz,氯仿-d)δ7.51–7.45(m,1H),7.38(ddd,J＝8.9,6.5,2.0Hz,1H),7.08(t,J＝8.2Hz,1H),6.69(dd,J＝5.1,2.6Hz,2H),6.60(t,J＝9.2Hz,2H),6.28(t,J＝6.8Hz,1H),6.09(dd,J＝6.5,4.2Hz,1H),4.26(s,1H),3.57–3.45(m,1H),3.37(s,4H).13C NMR(125MHz,氯仿-d)δ163.01,148.51,139.73,135.00,131.45,130.26,120.89,117.81,112.88,111.19,106.54,85.31,57.37,47.76.
实施例40 化合物P-20的制备
Figure PCTCN2017096975-appb-000050
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对溴苯胺，得到油状产物P-20(65％收率)。
1H NMR(400MHz,氯仿-d)δ7.47(dd,J＝6.8,1.9Hz,1H),7.42–7.33(m,1H),7.25(dd,J＝7.8,2.3Hz,2H),6.59(dd,J＝8.7,1.4Hz,3H),6.27(t,J＝6.7Hz,1H),6.07(dd,J＝6.7,4.0Hz,1H),4.20(s,1H),3.58–3.44(m,1H),3.41–3.20(m,4H).13C NMR(125MHz,氯仿-d)δ162.96,146.34,139.75,131.97,131.46,120.86,114.64,109.59,106.53,85.30,57.38,47.90.
实施例41 化合物P-21的制备
Figure PCTCN2017096975-appb-000051
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯酚钠，得到油状产物P-21(14％收率)。
1H NMR(400MHz,氯仿-d)δ7.61(dd,J＝7.0,2.1Hz,1H),7.39(ddd,J＝8.9,6.5,2.1Hz,1H),7.32–7.24(m,4H),7.02–6.91(m,3H),6.64–6.57(m,1H),6.29(dt,J＝5.8,2.6Hz,2H),4.26(dd,J＝10.6,3.1Hz,1H),4.16(dd,J＝10.6,5.4Hz,1H),3.44(d,J＝0.6Hz,3H).13C NMR(125MHz,氯仿-d)δ162.77,158.14,139.80,132.49,129.47,121.41,120.80,114.70,106.23,84.34, 68.33,57.41.
实施例42 化合物P-22的制备
Figure PCTCN2017096975-appb-000052
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯硫酚钠，得到油状产物P-22(98％收率)。
1H NMR(400MHz,氯仿-d)δ7.49(dd,J＝7.0,2.0Hz,1H),7.43(dd,J＝8.0,1.4Hz,2H),7.33(td,J＝6.6,3.2Hz,1H),7.31–7.24(m,2H),7.22–7.14(m,1H),6.57–6.51(m,1H),6.26–6.20(m,1H),6.08(dd,J＝7.1,3.9Hz,1H),3.38–3.32(m,4H),3.21(dd,J＝14.2,7.1Hz,1H).13C NMR(125MHz,氯仿-d)δ162.67,139.61,135.36,131.52,129.47,128.95,126.40,120.81,106.31,85.59,57.39,38.53.HRMS(EI)计算值C14H15NSO2[M]+:261.0823,实测值261.0828.
实施例43 化合物P-23的制备
Figure PCTCN2017096975-appb-000053
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为甲胺，得到油状产物P-23(73％收率)。
1H NMR(400MHz,氯仿-d)δ9.57(s,1H),7.99–7.91(m,1H),7.87(ddd,J＝8.8,6.9,1.6Hz,1H),6.98–6.85(m,2H),6.15(dd,J＝7.0,4.9Hz,1H),4.04 (dd,J＝12.5,4.8Hz,1H),3.60(dd,J＝12.5,6.9Hz,1H),3.34(s,3H),3.06(d,J＝4.2Hz,3H).
实施例44 化合物P-24的制备
Figure PCTCN2017096975-appb-000054
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为丙胺，得到油状产物P-24(75％收率)。
1H NMR(400MHz,氯仿-d)δ9.75(s,1H),7.95(d,J＝6.8Hz,1H),7.86–7.76(m,1H),6.94(d,J＝9.2Hz,1H),6.87(t,J＝6.9Hz,1H),6.30(dd,J＝8.3,4.5Hz,1H),4.20(dd,J＝12.5,4.4Hz,1H),3.58(dd,J＝12.5,8.1Hz,1H),3.46–3.32(m,5H),1.76(p,J＝7.4Hz,2H),1.04–0.96(m,3H).13C NMR(125MHz,氯仿-d)δ153.86,142.17,133.71,112.16,111.33,92.15,63.78,58.00,45.50,21.29,11.22.HRMS(EI)计算值C11H18N2O2[M]+:210.1368,实测值210.1374.
实施例45 化合物P-25的制备
Figure PCTCN2017096975-appb-000055
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为异丙胺，得到油状产物P-25(95％收率)。
1H NMR(400MHz,氯仿-d)δ9.16(s,1H),8.02–7.92(m,1H),7.81(t,J＝8.0Hz,1H),6.97(d,J＝9.3Hz,1H),6.87(t,J＝6.9Hz,1H),6.47(dd,J＝8.6,4.4Hz,1H),4.21(dd,J＝12.5,4.4Hz,1H),3.88(h,J＝6.6Hz,1H),3.58–3.50 (m,1H),3.41(s,3H),1.48–1.33(m,6H).13C NMR(125MHz,氯仿-d)δ153.08,142.74,134.33,112.57,111.67,92.31,63.47,57.93,46.97,21.81,21.30.HRMS(EI)计算值C11H18N2O2[M]+:210.1368,实测值210.1372.
实施例46 化合物P-26的制备
Figure PCTCN2017096975-appb-000056
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为二丙胺，得到油状产物P-26(33％收率)。
1H NMR(400MHz,氯仿-d)δ7.46(dd,J＝7.0,2.1Hz,1H),7.37–7.31(m,1H),6.55(ddt,J＝9.2,1.3,0.7Hz,1H),6.25(td,J＝6.6,6.0,1.3Hz,1H),6.06(dd,J＝6.8,3.8Hz,1H),3.32(d,J＝0.7Hz,3H),2.76–2.56(m,6H),1.01(td,J＝7.1,0.8Hz,6H).13C NMR(125MHz,氯仿-d)δ162.76,139.32,132.32,120.62,105.90,85.32,56.87,56.53,47.96,11.74.
实施例47 化合物P-27的制备
Figure PCTCN2017096975-appb-000057
以化合物S-8为原料，按照实施例35的制备方法，将化合物S-1替换为化合物S-8，亲核试剂为苯硫酚钠，得到油状产物P-27(43％收率)。
1H NMR(400MHz,氯仿-d)δ8.09(d,J＝8.6Hz,1H),7.64–7.57(m,1H),7.53–7.43(m,2H),7.42–7.34(m,2H),7.26–7.13(m,4H),6.80(t,J＝6.9Hz,1H),6.63(d,J＝9.4Hz,1H),3.73–3.53(m,2H),3.37(s,3H).13C NMR (125MHz,氯仿-d)δ163.40,140.08,137.46,134.92,130.15,130.05,129.09,128.88,126.61,122.56,121.41,121.35,116.56,85.95,77.34,77.09,76.83,56.76,36.47.
实施例48 化合物P-28的制备
Figure PCTCN2017096975-appb-000058
以化合物S-7为原料，按照实施例35的制备方法，将化合物S-1替换为化合物S-7，亲核试剂为苯硫酚钠，得到油状产物P-28(39％收率)。
1H NMR(400MHz,氯仿-d)δ8.49–8.41(m,1H),7.72–7.64(m,1H),7.56–7.49(m,2H),7.47–7.41(m,2H),7.31–7.21(m,3H),7.20–7.13(m,1H),6.56(d,J＝7.6Hz,1H),6.25(dd,J＝6.8,5.1Hz,1H),3.41–3.26(m,5H).13C NMR(125MHz,氯仿-d)δ162.41,136.76,135.32,132.60,129.90,128.94,127.97,126.98,126.52,125.97,125.95,125.13,106.81,85.08,77.29,77.24,77.03,76.78,57.07,38.69.
实施例49 化合物P-29的制备
Figure PCTCN2017096975-appb-000059
以化合物S-7为原料，按照实施例35的制备方法，将化合物S-1替换为化合物S-7，亲核试剂为异丙胺，得到油状产物P-29(45％收率)。
1H NMR(400MHz,氯仿-d)δ8.43(d,J＝8.0Hz,1H),7.72–7.61(m,1H), 7.58–7.47(m,2H),7.27(d,J＝7.6Hz,1H),6.58(d,J＝7.6Hz,1H),6.20(dd,J＝6.6,5.3Hz,1H),3.34(s,3H),3.04–2.81(m,3H),2.09(s,1H),1.08(dd,J＝6.1,1.6Hz,6H).
化合物T-1至T-8的制备方法：
制备方法同P-15的制备。
实施例50 化合物T-1的制备
Figure PCTCN2017096975-appb-000060
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苄胺，得到油状产物T-1(75％收率)。
1H NMR(400MHz,氯仿-d)δ8.17–8.08(m,1H),7.47–7.29(m,6H),6.66–6.56(m,1H),6.40(d,J＝8.4Hz,1H),4.88(s,1H),4.53(d,J＝5.8Hz,2H).13C NMR(125MHz,氯仿-d)δ158.64,148.22,139.18,137.49,128.64,127.41,127.25,113.17,106.80,46.33.HRMS(EI)计算值C12H12N2[M]+:184.1000,实测值184.0995.
实施例51 化合物T-2的制备
Figure PCTCN2017096975-appb-000061
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间甲氧基苄胺，得到油状产物T-2(68％收率)。
1H NMR(400MHz,氯仿-d)δ8.12(s,1H),7.41(s,1H),7.27(s,1H),6.98(s,2H),6.82(s,1H),6.60(s,1H),6.40(s,1H),5.08(s,1H),4.51(s,2H),3.80(s, 3H).HRMS(EI)计算值C13H14N2O[M]+:214.1106,实测值214.1105.
实施例52 化合物T-3的制备
Figure PCTCN2017096975-appb-000062
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对甲氧基苄胺，得到油状产物T-3(54％收率)。
1H NMR(400MHz,氯仿-d)δ8.13(s,1H),7.42(s,1H),7.30(s,3H),6.91(s,2H),6.59(s,1H),6.40(s,1H),4.83(s,1H),4.44(s,2H),3.82(s,3H).HRMS(EI)计算值C13H14N2O[M]+:214.1106,实测值214.1107.
实施例53 化合物T-4的制备
Figure PCTCN2017096975-appb-000063
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间三氟甲基苄胺，得到油状产物T-4(39％收率)。
1H NMR(400MHz,氯仿-d)δ8.16–8.10(m,1H),7.64(s,1H),7.56(dd,J＝11.8,7.8Hz,2H),7.50–7.40(m,2H),6.68–6.60(m,1H),6.40(d,J＝8.4Hz,1H),5.01(d,J＝8.1Hz,1H),4.62(d,J＝5.7Hz,2H).13C NMR(125MHz,氯仿-d)δ158.23,148.13,140.45,137.63,130.62,129.06,124.04,113.57,107.09,45.73.HRMS(ESI)计算值C13H12N2F3[M+H]+:253.0947,实测值253.0941.
实施例54 化合物T-5的制备
Figure PCTCN2017096975-appb-000064
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对氯苄胺，得到油状产物T-5(40％收率)。
1H NMR(400MHz,氯仿-d)δ8.12(ddd,J＝5.1,1.9,0.9Hz,1H),7.43(ddd,J＝8.4,7.2,1.9Hz,1H),7.32(s,4H),6.63(ddd,J＝7.2,5.1,1.0Hz,1H),6.37(dt,J＝8.3,0.9Hz,1H),4.92(s,1H),4.51(d,J＝5.9Hz,2H).13C NMR(125MHz,氯仿-d)δ158.37,148.19,137.55,132.90,128.74,113.40,106.92,45.56.HRMS(ESI)计算值C12H12N2Cl[M+H]+:219.0684,实测值219.0682.
实施例55 化合物T-6的制备
Figure PCTCN2017096975-appb-000065
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间溴苄胺，得到油状产物T-6(85％收率)。
1H NMR(400MHz,氯仿-d)δ8.15–8.09(m,1H),7.53(s,1H),7.46–7.39(m,2H),7.31(d,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),6.66–6.60(m,1H),6.38(d,J＝8.4Hz,1H),4.96(s,1H),4.53(d,J＝5.8Hz,2H).13C NMR(125MHz,氯仿-d)δ158.26,148.14,141.78,137.60,130.30,125.86,122.74,113.47,107.01,45.59.HRMS(ESI)计算值C12H12N2Br[M+H]+:263.0178,实测值263.0184.
实施例56 化合物T-7的制备
Figure PCTCN2017096975-appb-000066
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯乙胺，得到油状产物T-7(67％收率)。
1H NMR(400MHz,氯仿-d)δ8.10(s,1H),7.44(s,1H),7.34(s,2H),7.27(s,3H),6.59(s,1H),6.38(s,1H),4.58(s,1H),3.57(s,2H),2.95(s,2H).13C NMR(125MHz,氯仿-d)δ158.53,148.08,139.18,137.44,128.79,128.58,126.40,112.86,106.80,43.30,35.64.HRMS(EI)计算值C13H14N2[M]+:198.1157,实测值198.1158.
实施例57 化合物T-8的制备
Figure PCTCN2017096975-appb-000067
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯丙胺，得到油状产物T-8(77％收率)。
1H NMR(400MHz,氯仿-d)δ8.13–8.06(m,1H),7.43(ddd,J＝8.8,7.2,1.9Hz,1H),7.34–7.29(m,2H),7.26–7.18(m,3H),6.62–6.54(m,1H),6.36(d,J＝8.4Hz,1H),4.57(s,1H),3.37–3.26(m,2H),2.76(t,J＝7.7Hz,2H),2.03–1.93(m,2H).
综上，本发明申请保护的噁唑并吡啶季铵盐类化合物能够很方便的转化为N取代吡啶酮类化合物和2-取代吡啶类化合物，具有在药化领域应用的潜在价值，如化合物P-1到P-29可以进一步合成阿扎胞苷(胞嘧啶核苷类药物)类似物；化合物T-1到T-8可以作为中间体进一步合成吡苄明(抗组胺药) 及其类似物，用于创新药物的发现与合成研究。
Figure PCTCN2017096975-appb-000068

Claims (10)

  1. 一种如式1所示的噁唑并吡啶季铵盐类化合物：
    Figure PCTCN2017096975-appb-100001
    其中，
    Figure PCTCN2017096975-appb-100002
    代表双键或单键；
    Q、U各自独立地代表氧、硫或氮；
    R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、羟基、氨基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳氨基、C6-C12芳硫基、硝基、酰胺基、苯并二噁茂基或卤素；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基可彼此连接并且与吡啶环上的碳原子共同形成取代或未取代的芳基或含有0-3个独立选自O、S或N原子的5-7元环烷基；
    R2、R3各自独立地代表氢、羟基、氨基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳氨基、C6-C12芳硫基或卤素；且当
    Figure PCTCN2017096975-appb-100003
    为双键时，R3不存在；
    R4代表氢、取代或未取代的烷基或芳基；
    Y为酸根阴离子，选自无机酸根离子、有机酸根离子和卤素离子，包括但不限于硝酸根离子、硫酸根离子、磷酸根离子、甲磺酸根离子、苯磺酸根离子、醋酸根离子、酒石酸根离子、枸橼酸根离子、马来酸根离子、琥珀酸根离子、柠檬酸根离子、水杨酸根离子、甘油酸根离子、抗坏血酸根离子、氟离子、氯离子、溴离子或碘离子；
    所述取代或未取代的烷基包括取代或未取代的饱和、不饱和、直链、支链的全碳C1-C6烷基或含氧、氮或硫杂原子的C1-C6烷基；其中，“所述取代或未取代”中的“取代”是指被选自卤素、芳基、C1-C6烷基中的一种或多种取代基所取代；
    所述取代或未取代的芳基包括取代或未取代的苯基或含氧、氮或硫杂原子的芳基；其中，“所述取代或未取代”中的“取代”是指被选自C1-C6烷氧基、卤素取代的C1-C6烷氧基、苄基、羟基、氰基、C1-C3烷氧基羰基中的一种或多种取代基所取代；
    所述的卤素是指氟、氯、溴或碘。
  2. 根据权利要求1所述的噁唑并吡啶季铵盐类化合物，其中，
    Figure PCTCN2017096975-appb-100004
    代表单键。
  3. 根据权利要求1所述的噁唑并吡啶季铵盐类化合物，其中，U和Q各自独立地代表氧或硫。
  4. 根据权利要求1所述的噁唑并吡啶季铵盐类化合物，其中，R4代表取代或未取代的C1-C6烷基。
  5. 根据权利要求1所述的噁唑并吡啶季铵盐类化合物，其中，R2、R3各自独立地代表氢、取代或未取代的烷基或取代或未取代的芳基。
  6. 根据权利要求1所述的噁唑并吡啶季铵盐类化合物：其中，R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、硝基、酰胺基、苯并二噁茂基；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基并且与吡啶环上的碳原子共同形成芳基。
  7. 根据权利要求1～6中任一项所述的噁唑并吡啶季铵盐类化合物，所述的噁唑并吡啶季铵盐类化合物选自：
    Figure PCTCN2017096975-appb-100005
  8. 根据权利要求1-7中任一项所述的噁唑并吡啶季铵盐类化合物的制备方法：
    Figure PCTCN2017096975-appb-100006
    化合物S溶于溶剂中，加入酸NY，在一定温度下反应一段时间，蒸除溶剂，既得化合物I；其中，R1、R2、R3、R4、U、Q、Y的定义同相对应的权利要求；
    优选的，所述的溶剂包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水中的一种或一种以上组合溶剂；所述的溶剂进一步优选为甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、水一种或一种以上的组合溶剂；
    优选的，所述的一定温度包括从零下80摄氏度至200摄氏度的任何温度；进一步优选为从0摄氏度到100摄氏度的任何温度。
  9. 根据权利要求1-7中任一项所述的噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用：
    Figure PCTCN2017096975-appb-100007
    其中，R1、R2、R3、R4、U、Q、Y的定义同相对应的权利要求；
    W、Z各自独立的为O、R7N或S；
    A为氢、锂、钠、镁、铜或锡；
    R5为氢、取代或未取代的芳基或C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、硝基或卤素所取代；
    R6为氢、被取代或未取代的芳基所取代的C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、三氟甲基或卤素所取代；
    R7为氢、取代或未取代的C1-C6烷基，所述“取代或未取代”是指被C1-C3烷基、C1-C3烷氧基、硝基、三氟甲基或卤素所取代；
    所述化合物I溶于溶剂中，加入亲核试剂，所述亲核试剂为R5-WA、R6-ZA或无机碱，在零下80摄氏度至200摄氏度的温度下反应，蒸除溶剂，分离纯化，即获得N取代吡啶酮类化合物P或者2-取代吡啶类化合物T，当亲核试剂为无机碱时，W为O，R5为氢。
  10. 根据权利要求9所述的转化应用，所述的溶剂包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水中的一种或一种以上组合溶剂。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
EP3954692A4 (en) * 2019-04-08 2022-09-07 Shanghai Institute of Materia Medica, Chinese Academy of Sciences METHOD OF MODIFICATION OF AN AMINO GROUP IN THE MOLECULE WITH AN OXAZOLINE QUARTERLY AMMONIUM SALT AND USE THEREOF
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109942597B (zh) * 2017-12-20 2021-09-17 中国科学院上海药物研究所 一类芳基异喹啉并噁唑季铵盐类化合物、其制备方法及用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO143535C (no) * 1972-06-14 1981-03-04 Merck & Co Inc Analogifremgangsmaate ved fremstilling av terapeutisk aktive oxazolopyridiner
EP2520556A1 (en) * 2011-05-03 2012-11-07 Bayer Pharma Aktiengesellschaft Radiolabeled amino acids for diagnostic imaging

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BARNES, C.L. ET AL.: "Structure of 1-acetoxy-1, 2-dihydrothiazolo [3, 2-a] Quinolinium Perchlorate", ACTA CRYSTALLOGRAPHICA, SECTION C: CRYSTAL STRUCTURE COMMUNICATIONS, vol. C43, no. 9, 31 December 1987 (1987-12-31), pages 1739 - 1742, XP055470017, ISSN: 0108-2701 *
BO, LI ET AL.: "Regioselectivity and Mechanism of Synthesizing N-Substituted 2-Py-ridones and 2-Substituted Pyridines via Metal-Free C-O and C-N Bond-Cleaving of Oxazoline [3, 2-a] Pyridiniums", SCIENTIFIC REPORTS, vol. 7, no. 41287, 25 January 2017 (2017-01-25), pages 1 - 11, XP055469977, ISSN: 2045-2322 *
COX, O. ET AL.: "Synthesis and Complete 1H and 13C Assignments of Thiazolo [3, 2-a] Quinolinium Derivatives", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 36, no. 4, 31 December 1999 (1999-12-31), pages 937 - 942, XP055470002, ISSN: 0022-152X *
DATABASE CAS 24 July 2008 (2008-07-24), retrieved from STN Database accession no. 1030254-01-3 *
KIM, D.K. ET AL.: "Synthesis of Thiazolo-and Oxazolo [3, 2-a] Pyridinium Systems (review", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 27, no. 9, 30 September 1991 (1991-09-30), pages 921 - 929, XP055470004 *
POTAPOV, V.A. ET AL.: "Efficient and Selective Syntheses of Novel Unsaturated Chalcogen Chalcogencontaining Pyridine Derivatives", TETRAHEDRON LETTERS, vol. 57, 19 October 2016 (2016-10-19), pages 5341 - 5343, XP029793223, ISSN: 0040-4039 *
SYCH, E.D. ET AL.: "Synthesis and Reactions of Some Derivatives of Thiazolino [3, 2-a] Pyridinium Salt", KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII, vol. 9, 31 December 1973 (1973-12-31), pages 1254 - 1257, ISSN: 0132-6244 *
SYCH, E.D. ET AL.: "Thiazolopyridinium Salts with Active Methyl Groups and Cyanine Dyes Made Thiazolopyridinium Salts with Active Methyl Groups and Cyanine Dyes Made", KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII, vol. 10, 31 December 1974 (1974-12-31), pages 1335 - 1337, ISSN: 0132-6244 *
ULSAKER, G.A. ET AL.: "N-Quaternary Compounds. Part L. Elimination Reactions in Dihydrothiazolo [3, 2-a] Pyridinium Derivates", ACTA CHEMICA SCANDINAVICA , SERIES B: ORGANIC CHEMISTRY AND BIOCHEMISTRY, vol. B32, no. 6, 31 December 1978 (1978-12-31), pages 460 - 462, ISSN: 0302-4369 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
EP3954692A4 (en) * 2019-04-08 2022-09-07 Shanghai Institute of Materia Medica, Chinese Academy of Sciences METHOD OF MODIFICATION OF AN AMINO GROUP IN THE MOLECULE WITH AN OXAZOLINE QUARTERLY AMMONIUM SALT AND USE THEREOF

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