WO2023143034A1 - 一种吡啶并咪唑类衍生物及其制备方法与应用 - Google Patents
一种吡啶并咪唑类衍生物及其制备方法与应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- 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
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Definitions
- the invention relates to the field of related medicines for treating hyperuricemia and gout.
- the present invention relates to a pyridoimidazole compound used for treating hyperuricemia and gout, a preparation method thereof or a pharmaceutical combination containing them, and its use in medicine.
- Hyperuricemia refers to the level of fasting blood uric acid twice on different days under normal purine diet: male blood uric acid > 420 ⁇ mol/L, female blood uric acid > 360 ⁇ mol/L.
- Gout refers to crystal-associated arthropathy caused by the deposition of monosodium urate (MSU) with a blood uric acid concentration exceeding 6.8 mg/dL.
- MSU monosodium urate
- Both gout and hyperuricemia are related to the level of uric acid in the body.
- Uric acid transporter 1 Uric acid transporter 1 (URAT1) is located on the brush border of human renal proximal tubular epithelial cells, and mainly mediates the reabsorption of uric acid in the kidney. The increased activity or gene expression of URAT1 caused by its gene mutation is the cause of hyperuricemia.
- the present invention provides a pyridoimidazole derivative and a preparation method thereof.
- the present invention also provides the activity screening result of the above-mentioned compound as a uric acid-lowering drug and its application.
- pyridoimidazole derivatives of the present invention have the structure shown in the following general formula I or II:
- Ar is 1-cyclopropyl-4-naphthalene or 1-bromo-4-naphthalene; when X is a nitrogen atom, Y is a carbon atom or when X is a carbon atom, Y is a nitrogen atom; R is an alkane or a substituted alkane , the substituent is a C1-C10 alkane.
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- pyridoimidazole derivatives are one of the following:
- the preparation method of pyridoimidazole derivatives of the present invention is one of the following methods:
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- Reagents and conditions (i-a) 2-nitro-3-pyridyl triflate, triethylamine, acetonitrile, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol , 60°C; (ii) stannous chloride, ethanol, nitrogen, room temperature; (iii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N , N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- Reagents and conditions (i-a) 2-nitro-3-pyridyl triflate, palladium acetate, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, cesium carbonate, Nitrogen, 1,4-dioxane, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (ii) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (iii) N,N'-carbonyldiimidazole (CDI), triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (v) lithium hydroxide , tetrahydrofuran, ethanol, room temperature.
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- the room temperature mentioned in the present invention refers to 20-30°C.
- the invention discloses the screening results of the blood uric acid-lowering activity of pyridoimidazole derivatives and the first application for preparing uric acid-lowering drugs. It is proved by experiments that the pyridoimidazole derivatives of the present invention can be used as drugs for lowering blood uric acid. Specifically, it can be used as a blood uric acid-lowering compound to prepare uric acid-lowering drugs. The present invention also provides the application of the above compound in the preparation of uric acid-lowering medicine.
- the pyridoimidazole derivatives of the present invention are a series of novel compounds with blood uric acid-lowering activity, which can be used as candidate drugs for reducing uric acid and used to prepare uric acid-lowering drugs.
- a pharmaceutical composition for reducing uric acid comprising the pyridoimidazole derivatives of the present invention and one or more pharmaceutically acceptable carriers or excipients.
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- Reagents and conditions (i-a) 2-nitro-3-pyridyl triflate, triethylamine, acetonitrile, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol , 60°C; (ii) stannous chloride, ethanol, nitrogen, room temperature; (iii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N , N-dimethylformamide, room temperature; (v) lithium hydroxide, tetrahydrofuran, ethanol, room temperature.
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- Reagents and conditions (i-a) 2-nitro-3-pyridyl triflate, palladium acetate, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, cesium carbonate, Nitrogen, 1,4-dioxane, 90°C; (i-b) 4-chloro-3-nitropyridine, sodium bicarbonate, ethanol, 60°C; (ii) 10% palladium on carbon, hydrogen, tetrahydrofuran, room temperature; (iii) 1,1'-thiocarbonyldiimidazole, triethylamine, acetonitrile, 90°C; (iv) ester, potassium carbonate, N,N-dimethylformamide, room temperature; (v) lithium hydroxide, THF, ethanol, room temperature.
- R is methylene, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl.
- Example 17 In vivo uric acid-lowering activity test of the target compound
- Modeling drugs hypoxanthine, potassium oxonate.
- Test method 0.2mL hypoxanthine, 0.2mL subcutaneous injection of potassium oxonate, and 0.2mL drug were administered to each group and the timing was started. After 4 hours of administration, the eyeballs were removed to take blood, centrifuged after 30 minutes of coagulation , take the supernatant serum. The concentration of uric acid in serum was detected with a uric acid meter.
Abstract
本发明涉及一种吡啶并咪唑类衍生物及其制备方法和应用。所述化合物具有式(I)或(II)所示的结构。本发明还涉及含有式(I)或式(II)结构化合物的制备方法以及药物组合物。本发明还提供上述化合物在制备降尿酸的药物中的应用。
Description
本发明涉及治疗高尿酸血症和痛风的相关药物领域。具体而言,本发明涉及一种用于治疗高尿酸血症和痛风的吡啶并咪唑类化合物及其制备方法或含有它们的药物组合,以及其在医药上的用途。
高尿酸血症(HUA)是指正常嘌呤饮食状态下,非同日两次空腹血尿酸水平:男性血尿酸>420μmol/L,女性血尿酸>360μmol/L。痛风是指血尿酸浓度超过6.8mg/dL,由单钠尿酸盐(MSU)沉积所致的晶体相关性关节病,与嘌呤代谢紊乱或尿酸排泄减少所致的高尿酸血症直接相关,特指急性特征性关节炎和慢性痛风石疾病。痛风与高尿酸血症都与人体内的尿酸水平有关。正常成年人每日约产生尿酸750mg,其中1/3经肠道分解代谢,2/3经肾脏排泄,从而维持体内尿酸水平的稳定。目前治疗痛风的药物主要有两类:一类是抑制尿酸生成的黄嘌呤氧化酶抑制剂,另一类是促进尿酸排泄的URAT1抑制剂。尿酸转运蛋白1(URAT1)位于人肾近端小管上皮细胞的刷状缘上,主要介导尿酸在肾脏的重吸收,其基因突变所导致的URAT1活性增加或基因表达增加是高尿酸血症的重要发病机制之一。Lesinurad是一种用于治疗高尿酸血症和痛风的URAT1抑制剂,因其治疗剂量大且具有严重的毒副作用而被撤市。因此,对其进行进一步地结构修饰,有望获得具有更优活性及安全性且具有自主知识产权的新型降尿酸药物。
发明内容
针对现有技术的不足,本发明提供了一种吡啶并咪唑类衍生物及其制备方法,本发明还提供了上述化合物作为降尿酸药物的活性筛选结果及其应用。
本发明的技术方案如下:
一、吡啶并咪唑类衍生物
本发明的吡啶并咪唑类衍生物,或其药学上可接受的盐,具有如下通式I或Ⅱ所示的结构:
其中,Ar为1-环丙基-4-萘或1-溴-4-萘;X为氮原子时,Y为碳原子或X为碳原子时,Y为氮原子;R为烷烃或取代烷烃,所述取代基为C1-C10的烷烃。
根据本发明优选的,R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
根据本发明进一步优选的,吡啶并咪唑类衍生物是下列之一:
表1.化合物9-44的结构式
二、吡啶并咪唑类衍生物的制备方法
本发明吡啶并咪唑类衍生物的制备方法为如下方法之一:
(1)化合物9-20的合成:
在过氧化苯甲酰(BPO)的存在下,将1a用N-溴代琥珀酰亚胺(NBS)在正己烷中处理得到中间体2a,将其与邻苯二甲酰亚胺钾反应得到3a;3a与80%水合肼通过Gabriel合成得到4a,然后在25:1v/v的甲苯/水混合物中进行Suzuki偶联反应,将4a转化为5a;5a和2-硝基-3-吡啶基三氟甲磺酸酯(1b)或4-氯-3-硝基吡啶(1c)通过偶联反应获得中间体6a或6b;在Pd/C存在下,氢化还原得到7a或7b,然后用1,1'-硫代羰基二咪唑(TCDI)环化得到关键中间体8a或8b;通过亲核取代反应和氢氧化锂水解得到化合物9-14;化合物15-20的制备方法与化合物9-14相似,不同之处在于步骤V,以4-氯-3-硝基吡啶(1c)为起始原料;
路线一:
试剂及条件:(i)N-溴代琥珀酰亚胺,过氧化苯甲酰,氮气
,正己烷,70℃;(ii)邻苯二甲酰亚胺钾,N,N-二甲基甲酰胺,100℃,氮气
;(iii)80%水合肼,乙醇,80℃;(iv)环丙基硼酸,磷酸钾
,四(三苯基膦)钯
,甲苯,水,氮气,100℃;(v-a)2-硝基-3-吡啶基三氟甲磺酸酯,三乙胺,乙腈,90℃;(v-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(vi)10%钯碳,氢气,四氢呋喃,室温;(vii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(viii)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(ix)氢氧化锂,四氢呋喃,乙醇,室温。
R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
(2)化合物21-32的合成
4a用2-硝基-3-吡啶基三氟甲磺酸酯(1b)或4-氯-3-硝基吡啶(1c)处理,通过偶联反应得到5b或5c;然后,在氯化亚锡存在下氢化还原得到6c或6d,将其与1,1'-硫代羰基二咪唑(TCDI)环化得到关键中间体7c或7d,然后进行亲核取代和水解反应得到目标化合物21-26;化合物27-32的制备方法与化合物21-26类似,不同之处在于步骤I的起始原料为4-氯-3-硝基吡啶(1c);
路线二:
试剂及条件:(i-a)2-硝基-3-吡啶基三氟甲磺酸酯,三乙胺,乙腈,90℃;(i-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(ii)氯化亚锡,乙醇,氮气,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温。
R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
(3)化合物33-44的合成
起始原料4-环丙基-1-萘氨(1d)用2-硝基-3-吡啶基三氟甲磺酸酯(1b)或4-氯-3-硝基吡啶(1c)处理,通过偶联反应得到中间体2b或2c;然后,在钯碳存在下氢化还原得到3b或3c,将其与N,N'-羰基二咪唑(CDI)环化得到4b或4c,然后进行亲核取代和水解得到化合物33-38;化合物39-44的制备方法与化合物33-38类似,不同之处在于起始原料为4-氯-3-硝基吡啶(1c);
路线三:
试剂及条件:(i-a)2-硝基-3-吡啶基三氟甲磺酸酯,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,氮气,1,4-二氧六环,90℃;(i-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(ii)10%钯碳,氢气,四氢呋喃,室温;(iii)N,N'-羰基二咪唑(CDI),三乙胺,乙 腈,90℃;(iv)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温。
R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
本发明所述的室温是指20-30℃。
三、吡啶并咪唑类衍生物的应用
本发明公开了吡啶并咪唑类衍生物降血尿酸活性筛选结果及其用于制备降尿酸药物的首次应用。通过实验证明本发明的吡啶并咪唑类衍生物可作为降血尿酸药物应用。具体地说,可作为降血尿酸化合物用于制备降尿酸药物。本发明还提供上述化合物在制备降尿酸药物中的应用。
目标化合物的降尿酸活性:
对按照上述方法合成的36个化合物(化合物的结构式见表1),并对其进行了降尿酸活性筛选,它们的降尿酸活性数据列于表2中,以Lesinurad为阳性药物。
由表2和表3可以看出有29种化合物均呈现出较好的抗降尿酸活性,降尿酸活性均强于阳性对照药物Lesinurad。其中代表化合物13、23、33、35、36、38和39,在动物体内活性测试中,血尿酸下降率均超过80%,显示出优异的降尿酸活性,可作为制备降尿酸的药物。
因此,本发明的吡啶并咪唑类衍生物是一系列结构新颖的具有降血尿酸活性的化合物,可作为降尿酸的候选药物加以利用,用于制备降尿酸的药物。
一种降尿酸药物组合物,包括本发明的吡啶并咪唑类衍生物和一种或多种药学上可接受的载体或赋形剂。
通过下述实例有助于理解本发明,但是不能限制本发明的内容,在下列实例中,所有目标化合物的编号与表1相同。
化合物9-20的合成路线:
试剂及条件:(i)N-溴代琥珀酰亚胺,过氧化苯甲酰,氮气
,正己烷,70℃;(ii)邻苯二甲酰亚胺钾,N,N-二甲基甲酰胺,100℃,氮气
;(iii)80%水合肼,乙醇,80℃;(iv)环丙基硼酸,磷酸钾,四(三苯基膦)钯,甲苯,水,氮气,100℃;(v-a)2-硝基-3-吡啶基三氟甲磺酸酯,三乙胺,乙腈,90℃;(v-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(vi)10%钯碳,氢气,四氢呋喃,室温;(vii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(viii)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(ix)氢氧化锂,四氢呋喃,乙醇,室温。
R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
化合物2a的制备
将市售的化合物1a(2g,9.05mmol)、BPO(44.11mg,0.18mmol)和NBS(1.93g,10.86mmol)加入正己烷(50mL)中,在氮气下回流36h(通过TLC监测)。在搅拌下将反应混合物冷却至室温,并通过真空过滤收集沉淀物。将沉淀物依次用饱和碳酸氢钠水溶液(100mL×2)、水(100mL×2)和正己烷(100mL)洗涤,得到粗产物2a,白色固体。产率:75.0%。熔点:103-105℃。ESI-MS:m/z 300.88[M+H]
+.C
11H
8Br
2(Exact Mass:297.90)。
化合物3a的制备
将化合物2a(1g,3.36mmol)和邻苯二甲酰亚胺钾(0.62g,3.33mmol)溶解在DMF(10mL)中,将混合物在氮气氛下于100℃搅拌直至TLC监测反应完成。冷却至室温后,将反应混合物倒入冰水(50mL)中,用二氯甲烷(20mL×3)萃取。合并的有机溶液用饱和氯化钠水溶液(20mL×3)洗涤,用无水硫酸钠干燥。过滤后,减压蒸发有机相,得到粗产物,将其从乙醇中重结晶,得到化合物3a,白色固体。产率:66.6%。熔点:165-168℃。ESI-MS:m/z 367.74[M+H]
+.C
19H
12BrNO
2(Exact Mass:365.00)。
化合物4a的制备
将化合物3a(1g,2.73mmol)和80%水合肼(0.34g,5.46mmol)溶解在乙醇(25mL)中,在80℃回流12小时(通过TLC监测)。冷却约10分钟,将1M氢氧化钠水溶液(10mL)加入反应 混合物中,然后将混合物减压浓缩至其原始体积的一半。将其倒入冰水(100mL)中并用二氯甲烷(3×20mL)萃取。合并的有机层用5%氢氧化钠(10mL×2)和5%盐水(20mL)洗涤,用无水硫酸钠干燥,在旋转蒸发仪上蒸发得到残余物,将其通过柱色谱纯化得到化合物4a,黄色油状物。产率:84.0%。ESI-MS:m/z 236.38[M+H]
+.C
11H
10BrN(Exact Mass:234.99)。
化合物5a的制备
将化合物4a(2.0g,9.0mmol)、环丙基硼酸(1g,11.60mmol)、磷酸钾(6.40g,30.0mmol)和四(三苯基膦)钯(0.70g,0.6mmol)的混合物加入到甲苯(50mL)和水(2mL)的混合溶剂,然后将反应体系在氮气氛围下于100℃反应12h,TLC监测反应完成。当反应混合物冷却至室温时,将反应混合物倒入100mL水中,并用乙酸乙酯(20mL×3)萃取。有机相用无水硫酸钠干燥并过滤。过滤后,减压蒸发有机相,得到粗产物5a,棕色油状物。产率:52.4%。ESI-MS:m/z 198.62[M+H]
+.C
14H
15N(Exact Mass:197.12)。
化合物6a的制备
将化合物5a(2g,10.14mmol)溶解在50mL乙腈中,然后将2-硝基-3-吡啶基三氟甲磺酸酯(1b)(3.3g,12.12mmol)和三乙胺(0.5g,5.07mmol)加入溶液中,将混合物在氮气氛围下,于50℃搅拌过夜(通过TLC监测),然后过滤。滤渣用乙酸乙酯重结晶,得到化合物6a,黄色固体。产率:73.2%。熔点:141-143℃。ESI-MS:m/z 320.56[M+H]
+.C
19H
17N
3O
2(Exact Mass:319.13)。
化合物7a的制备
将化合物6a(1g,3.13mmol)溶解在30mL四氢呋喃中,并将10%钯碳(0.2g)添加到溶液中。将混合物在氢气氛围下,室温搅拌6小时,然后过滤。减压浓缩滤液。通过快速柱层析纯化,得到化合物7a,淡黄色固体。产率:76.2%。熔点:162-164℃。ESI-MS:m/z 290.02[M+H]
+.C
19H
19N
3(Exact Mass:289.16).
化合物8a的制备
将化合物7a(1g,3.46mmol)、1,1'-硫代羰基二咪唑(1g,5.53mmol)和三乙胺(0.1mL)溶解在50mL乙腈中。溶液在90℃反应5小时,然后冷却至室温,过滤。固体用乙酸乙酯重结晶,得到化合物8a,白色固体。产率:47.6%。熔点:156-159℃。ESI-MS:m/z 330.09[M–H]
–.C
19H
17N
3O
2(Exact Mass:331.11)。
化合物9a-14a的制备
将化合物8a(0.20g,0.60mmol)溶解在DMF(10mL)中,加入碳酸钾(0.13g,0.90mmol),然后加入适当的取代酯(1.1倍当量)并将混合物在室温下搅拌4小时(TLC监测)。减压蒸发DMF并用乙酸乙酯(30mL×3)萃取。有机溶液用饱和氯化钠水溶液(3×10mL)洗涤,用无水硫酸钠干燥,过滤。滤液通过柱色谱纯化,得到化合物9a-14a。化合物9a,白色固体,产 率:79.8%,熔点:130-133℃,ESI-MS:m/z 404.11[M+H]
+.C
23H
21N
3O
2S(Exact Mass:403.14)。化合物10a,白色固体,产率:79.8%,熔点:139-142℃,ESI-MS:m/z 418.29[M+H]
+.C
24H
23N
3O
2S(Exact Mass:417.15)。化合物11a,白色固体,产率:68.0%,熔点:151-152℃,ESI-MS:m/z 432.03[M+H]
+.C
25H
25N
3O
2S(Exact Mass:431.17)。化合物12a,白色固体,产率:75.5%,熔点:177-179℃,ESI-MS:m/z 418.17[M+H]
+.C
24H
23N
3O
2S(Exact Mass:417.15)。化合物13a,淡黄色油状物,产率:60.0%,熔点:150-153℃,ESI-MS:m/z 432.01[M+H]
+.C
25H
25N
3O
2S(Exact Mass:431.17)。化合物14a,白色固体,产率:79.8%,熔点:130-133℃,ESI-MS:m/z 458.19[M+H]
+.C
27H
27N
3O
2S(Exact Mass:457.18)。
化合物9-14的制备
将化合物9a-14a溶解在5mL四氢呋喃和5mL乙醇的混合物中。将氢氧化锂(0.1g,4.13mmol)溶解在少量水中并滴加到上述溶液中,然后将混合物在室温下搅拌2h。反应完成后,通过减压旋转蒸发除去溶剂。向残余物中加入10mL水,并滴加1M HCl溶液将pH调节至3-4。过滤收集产物,用乙醇重结晶,得到目标化合物9-14。
实施例1.化合物9的制备
从乙酸乙酯中重结晶为黄色固体,产率82.6%,熔点:60-63℃。化合物9的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.49(t,1H,Pyr-H),8.39(d,J=4.9Hz,1H,Pyr-H),8.21(t,1H,Naph-H),7.87(d,J=8.1Hz,1H,Naph-H),7.70(d,J=6.6Hz,1H,Pyr-H),7.67(t,J=3.8Hz,1H,Naph-H),7.21(q,J=5.0Hz,1H,Naph-H),7.11(d,J=7.5Hz,1H,Naph-H),6.52(d,J=7.5Hz,1H,Naph-H),5.95(s,2H,CH
2),2.43–2.33(m,1H,CH),1.63(d,J=7.3Hz,2H,CH
2),CH
2,1.06–1.00(m,2H,CH
2),0.69–0.64(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ172.66,155.83,154.79,142.97,139.61,133.63,130.62,129.82,129.42,126.90,126.74,125.47,123.99,123.19,123.13,119.39,117.99,45.89,45.24,18.73,13.29,7.10.HR-MS:m/z 388.1127[M-H]
-.C
22H
19N
3O
2S(Exact Mass:389.12)。
实施例2.化合物10的制备
从乙酸乙酯中重结晶为白色固体,产率:86.1%,熔点:80-83℃。化合物10的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.49(q,1H,Pyr-H),8.32(d,J=3.3Hz,1H,Pyr-H),8.24–8.17(m,1H,Naph-H),7.75(d,J=8.1Hz,1H,Pyr-H),7.69(d,J=7.0Hz,1H,Naph-H),7.66(t,J=3.8Hz,1H,Naph-H),7.13(d,J=4.6Hz,1H,Naph-H),7.11(d,J=4.8Hz,1H,Naph-H),6.57(d,J=7.5Hz,1H,Naph-H),5.93(s,2H,CH
2),4.22(s,3H,CH
3),3.44(q,J=7.0Hz,1H,CH),2.41–2.34(m,1H,CH),1.05–0.99(m,2H,CH
2),0.68(q,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ169.68,163.63,156.07,155.77,143.87,139.60,133.63,130.72,129.53,129.50,126.89,126.68,125.47,124.03,123.49,123.14,118.07,117.67,45.75,35.23,19.03,13.29,7.10.HR-MS:m/z 402.1282[M-H]
-.C
23H
21N
3O
2S(Exact Mass:403.14)。
实施例3.化合物11的制备
从乙酸乙酯中重结晶为白色固体,产率:80%,熔点:60-63℃。化合物11的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.49(t,1H,Pyr-H),8.40(d,J=4.8Hz,1H,Pyr-H),8.22(t,1H,Naph-H),7.85(d,J=7.9Hz,1H,Naph-H),7.70(s,1H,Pyr-H),7.68(d,J=5.0Hz,1H,Naph-H),7.21(q,J=4.8Hz,1H,Naph-H),7.09(d,J=7.5Hz,1H,Naph-H),6.39(d,J=7.5Hz,1H,Naph-H),5.98(s,2H,CH
2),2.42–2.33(m,1H,CH),1.72(s,6H,CH
3×2),1.03(q,2H,CH
2),0.66(q,J=4.8Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.33,155.06,153.95,143.69,139.47,133.60,130.53,129.85,128.97,126.89,126.89,126.74,126.74,125.47,123.97,123.13,122.77,119.43,118.30,54.32,45.90,26.79,13.26,7.08.HR-MS:m/z 416.1438[M-H]
-.C
24H
23N
3O
2S(Exact Mass:417.15)。
实施例4.化合物12的制备
从乙酸乙酯中重结晶为白色固体,产率:83.1%,熔点:145-148℃。化合物12的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.47(t,1H,Pyr-H),8.29(t,J=10.4Hz,1H,Pyr-H),8.15(q,1H,Naph-H),7.67(d,J=5.1Hz,1H,Naph-H),7.65(d,J=4.9Hz,1H,Pyr-H),7.44(q,1H,Naph-H),7.17(q,1H,Naph-H),7.08(q,1H,Naph-H),6.83(q,1H,Naph-H),5.97(d,2H,CH
2),4.81(s,4H,CH
2×2),2.41–2.34(m,1H,CH),1.03(d,J=8.6Hz,2H,CH
2),0.67(d,J=5.5Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ172.39,170.92,145.63,144.92,143.44,139.36,133.67,130.99,129.42,129.19,126.77,126.58,126.48,125.43,124.31,124.28,123.12,118.49,117.41,45.38,32.24,13.29,7.08.HR-MS:m/z 438.1048[M+Cl]
-.C
23H
21N
3O
2S(Exact Mass:403.14).
实施例5.化合物13的制备
从乙酸乙酯中重结晶为黄色固体,产率:79%,熔点:60-63℃。化合物13的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.48(q,J=5.8Hz,1H,Pyr-H),8.36(t,1H,Pyr-H),8.26–8.17(m,1H,Naph-H),7.93(d,J=8.1Hz,1H,Naph-H),7.68(d,J=3.8Hz,1H,Pyr-H),7.66(t,1H,Naph-H),7.27–7.16(m,1H,Naph-H),7.12(q,J=7.4Hz,1H,Naph-H),6.61(q,1H,Naph-H),6.00(d,2H,CH
2),3.70(s,2H,CH
2),2.39(s,1H,CH),2.35(q,2H,CH
2),2.15–1.95(m,2H,CH
2),1.05–1.00(m,2H,CH
2),0.66(d,J=3.4Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.20,171.00,145.21,143.38,141.82,139.59,133.63,130.64,130.45,129.37,126.87,126.72,125.49,123.96,123.13,119.85,119.10,117.80,45.87,32.83,31.75,24.87,13.27,7.11.HR-MS:m/z 452.1205[M-H]
-.C
24H
23N
3O
2S(Exact Mass:417.15)。
实施例6.化合物14的制备
从乙酸乙酯中重结晶为白色固体,产率:67%,熔点:230-235℃。化合物14的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.47(t,1H,Pyr-H),8.30(t,1H,Pyr-H),8.15(d,J=5.0Hz,1H,Naph-H),7.67(d,J=6.0Hz,1H,Naph-H),7.64(t,J=3.8Hz,1H,Pyr-H),7.40(d,J=8.1Hz,1H,Naph-H),7.15(d,J=7.3Hz,1H,Naph-H),7.07(q,J=5.0Hz,1H,Naph-H),6.85(d,J=7.3Hz,1H,Naph-H),5.97(s,2H,CH
2),3.38(s,6H,CH
2×3),2.37(t,J=5.3Hz,1H,CH),1.05–1.00(m,2H,CH
2),0.68(q,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ170.97,145.75,144.06,143.45,139.35,133.68,131.00,129.46,126.76,126.56,126.48,125.43,124.33,124.28,123.13,123.13,118.44,117.34,45.79,45.39,33.03,29.72,16.94,13.29,7.08.HR-MS:m/z 428.1438[M-H]
-.C
25H
23N
3O
2S(Exact Mass:429.15)。
化合物6b的制备
将4-氯-3-硝基吡啶(1c)(1g,6.33mmol)、化合物5a(1.5g,7.6mmol)和碳酸氢钠(1.6g,18.9mmol)溶解在50mL乙醇中,并将该溶液在60℃回流10小时,然后冷却至室温。加入二氯甲烷(30ml),混合物用饱和氯化钠(3×10mL)洗涤。有机层用无水硫酸钠干燥,过滤并减压浓缩。通过快速柱层析得到化合物6b,黄色固体,产率:73.0%,熔点::143-146℃。ESI-MS:m/z 320.54[M+H]
+.C
19H
17N
3O
2(Exact Mass:319.13)。
化合物7b的制备
化合物7b的合成方法与化合物7a的合成方法相似。白色固体,产率:76.2%,熔点:192-195℃。ESI-MS:m/z 290.13[M+H]
+.C
19H
19N
3(Exact Mass:289.16)。
化合物8b的制备
化合物8b的合成方法与化合物8a的合成方法相似。黄色固体,产率:52.6%,熔点:130-134℃。ESI-MS:m/z 330.77[M+H]
+.C
19H
17N
3O
2(Exact Mass:331.11)。
化合物9b-14b的制备
除了是化合物8b与合适的取代酯反应外,化合物9b-14b的合成方法与化合物9a-14a的合成方法相似。化合物9b,白色固体,产率:80.0%,熔点:142-145℃,ESI-MS:m/z 404.96[M+H]
+.C
23H
21N
3O
2S(Exact Mass:403.14)。化合物10b,白色固体,产率:79.0%,熔点:120-122℃,ESI-MS:m/z 419.11[M+H]
+.C
24H
23N
3O
2S(Exact Mass:417.15)。化合物 11b,白色固体,产率:83.0%,熔点:130-133℃。ESI-MS:m/z 432.81[M+H]
+.C
25H
25N
3O
2S(Exact Mass:431.17)。化合物12b,无色油状物,产率67.5%,熔点:147-150℃,ESI-MS:m/z 418.98[M+H]
+.C
24H
23N
3O
2S(Exact Mass:417.15)。化合物13b,无色油状物,产率84.0%,熔点:160-163℃,ESI-MS:m/z 432.55[M+H]
+.C
25H
25N
3O
2S(Exact Mass:431.17)。化合物14b,无色油状物,产率59.0%,熔点:130-133℃,ESI-MS:m/z 458.65[M+H]
+.C
27H
27N
3O
2S(Exact Mass:457.18)。
化合物15-20的制备
化合物15-20的合成方法与化合物9-14的制备所描述的合成方法相似。
实施例7.化合物15的制备
从乙酸乙酯中重结晶为白色固体,产率:80%,熔点:95-100℃。化合物15的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.88(s,1H,Pyr-H),8.48(d,J=7.5Hz,1H,Pyr-H),8.23(s,1H,Naph-H),8.21(s,1H,Naph-H),7.68(s,1H,Pyr-H),7.67(d,J=3.7Hz,1H,Naph-H),7.42(d,J=5.7Hz,1H,Naph-H),7.12(d,J=7.5Hz,1H,Naph-H),6.57–6.47(m,1H,Naph-H),5.93(s,2H,CH
2),4.21(s,2H,CH
2),2.38(s,1H,CH),1.03(d,J=10.3Hz,2H,CH
2),0.67(d,J=5.5Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ169.71,154.91,141.91,141.79,140.58,140.16,139.65,133.64,130.71,129.38,126.90,126.71,125.48,124.01,123.45,123.13,123.09,105.93,45.66,35.10,13.29,7.11.HR-MS:m/z 388.1125[M-H]
-.C
22H
19N
3O
2S(Exact Mass:389.12)。
实施例8.化合物16的制备
从乙酸乙酯中重结晶为黄色固体,产率:78%,熔点:60-63℃。化合物16的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.92(s,1H,Pyr-H),8.49(q,1H,Pyr-H),8.24(d,J=5.5Hz,1H,Naph-H),8.21(q,1H,Naph-H),7.69(t,1H,Pyr-H),7.67(t,J=2.1Hz,1H,Naph-H),7.43(d,J=5.6Hz,1H,Naph-H),7.11(d,J=7.5Hz,1H,Naph-H),6.46(d,J=7.3Hz,1H,Naph-H),5.93(s, 2H,CH
2),4.67(q,J=7.2Hz,1H,CH),2.40–2.35(m,1H,CH),1.61(d,J=7.2Hz,3H,CH
3),1.02(q,J=2.0Hz,2H,CH
2),0.67(q,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ172.75,153.95,141.87,141.65,140.66,140.33,139.59,133.63,130.63,129.47,126.89,126.72,125.48,123.97,123.14,123.10,123.10,106.07,45.67,45.43,18.85,13.28,7.09.HR-MS:m/z 402.1282[M-H]
-.C
23H
21N
3O
2S(Exact Mass:403.14)。
实施例9.化合物17的制备
从乙酸乙酯中重结晶为白色固体,产率:84%,熔点:65-68℃。化合物17的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.96(s,1H,Pyr-H),8.49(t,1H,Pyr-H),8.26(d,J=5.6Hz,1H,Naph-H),8.22(t,1H,Naph-H),7.70(s,1H,Pyr-H),7.68(d,J=5.0Hz,1H,Naph-H),7.45(d,J=5.6Hz,1H,Naph-H),7.09(d,J=7.5Hz,1H,Naph-H),6.34(d,J=7.5Hz,1H,Naph-H),5.97(s,2H,CH
2),2.41–2.33(m,1H,CH),1.69(s,6H,CH
3×2),1.02(q,J=6.1Hz,2H,CH
2),0.66(q,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.40,152.33,141.98,140.96,140.90,140.72,140.72,139.48,133.60,130.52,129.83,126.90,126.75,125.47,123.95,123.13,122.69,106.40,54.28,45.78,26.75,26.49,13.26,7.08.HR-MS:m/z 416.1438[M-H]
-.C
24H
23N
3O
2S(Exact Mass:417.15)。
实施例10.化合物18的制备
从乙酸乙酯中重结晶为白色固体,产率:80%,熔点:248-251℃。化合物18的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ9.28(s,1H,Pyr-H),8.54(d,J=6.4Hz,1H,Pyr-H),8.49(t,1H,Naph-H),8.25(t,1H,Naph-H),7.73(d,J=6.4Hz,1H,Pyr-H),7.70(d,J=3.3Hz,1H,Naph-H),7.68(d,J=3.3Hz,1H,Naph-H),7.09(d,J=7.5Hz,1H,Naph-H),6.71(d,J=7.6Hz,1H,Naph-H),6.09(s,2H,CH
2),4.64(t,J=7.0Hz,2H,CH
2),2.92(t,J=7.0Hz,2H,CH
2),2.40–2.35(m,1H,CH),1.03(t,2H,CH
2),0.67(d,J=3.5Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ173.79,172.55,142.15,139.48,137.57,133.67,131.00,130.73,128.32,126.89,126.72,125.83, 125.47,124.14,123.25,123.11,123.03,106.88,46.71,42.01,31.71,13.29,7.09.HR-MS:m/z402.1284[M-H]
-.C
23H
21N
3O
2S(Exact Mass:403.14)。
实施例11.化合物19的制备
从乙酸乙酯中重结晶为白色固体,产率:80%,熔点:180-183℃。化合物19的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.91(s,1H,Pyr-H),8.49(q,1H,Pyr-H),8.22(d,J=5.5Hz,1H,Naph-H),8.19(s,1H,Naph-H),7.68(d,J=3.9Hz,1H,Pyr-H),7.66(d,J=6.6Hz,1H,Naph-H),7.41(d,J=5.5Hz,1H,Naph-H),7.11(d,J=7.5Hz,1H,Naph-H),6.43(d,J=7.5Hz,1H,Naph-H),5.91(d,2H,CH
2),3.40(d,J=7.1Hz,2H,CH
2),2.37(t,J=3.8Hz,1H,CH),2.34(d,J=7.3Hz,2H,CH
2),2.01–1.92(m,2H,CH
2),1.05–1.00(m,2H,CH
2),0.67(q,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.31,155.09,141.81,140.75,140.18,139.54,133.64,130.66,129.53,129.20,126.85,126.71,126.71,125.49,123.95,123.15,123.00,105.89,45.54,32.86,31.65,24.84,13.27,7.10.HR-MS:m/z 416.1437[M-H]
-.C
24H
23N
3O
2S(Exact Mass:417.15)。
实施例12.化合物20的制备
从乙酸乙酯中重结晶为白色固体,产率:61%,熔点:60-63℃。化合物20的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.88(s,1H,Pyr-H),8.49(d,J=9.8Hz,1H,Pyr-H),8.22(s,1H,Naph-H),8.21(s,1H,Naph-H),7.68(d,J=4.0Hz,1H,Pyr-H),7.67(s,1H,Naph-H),7.39(d,J=5.5Hz,1H,Naph-H),7.11(d,1H,Naph-H),6.46(d,1H,Naph-H),5.94(s,2H,CH
2),3.41(s,6H,CH
2×3),2.39(d,J=5.3Hz,1H,CH),1.03(d,J=10.5Hz,2H,CH
2),0.67(d,J=3.8Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ153.48,141.93,141.02,140.83,140.75,139.51,133.62,130.60,129.77,129.76,126.88,126.72,125.47,123.99,123.14,123.06,123.02,106.16,45.81,32.74,2 1.56,16.90,13.28,7.08,7.08.HR-MS:m/z 428.1438[M-H]
-.C
25H
23N
3O
2S(Exact Mass:429.15)。
化合物21-32的合成路线:
试剂及条件:(i-a)2-硝基-3-吡啶基三氟甲磺酸酯,三乙胺,乙腈,90℃;(i-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(ii)氯化亚锡,乙醇,氮气,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温。
R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
化合物5b的制备
化合物5b的合成方法与化合物6a中描述的相似。除了使原料化合物4a与2-硝基-3-吡啶基三氟甲磺酸酯(1b)反应。黄色固体,产率:60.6%,熔点:144-147℃。ESI-MS:m/z358.1950[M+H]
+.C
16H
12BrN
3O
2(Exact Mass:357.01)。
化合物6c的制备
将化合物5b(1g,2.80mmol)溶解在乙醇(30mL)中并将氯化亚锡(3.16g)添加到溶液中。将混合物在室温下搅拌过夜,TLC监测反应完成。加入氢氧化钠调节pH至9-10,继续搅拌1小时。然后减压过滤,用乙酸乙酯萃取,浓缩。残余物用EA重结晶,得到化合物6c,白色固体,产率:76.0%,熔点:192-193℃。ESI-MS:m/z 328.21[M+H]
+.C
16H
14BrN
3(Exact Mass:327.03).
化合物7c的制备
化合物7c的合成方法与化合物8a中描述的方法相似。化合物7c,黄色固体,产率:70.9%,熔点:246-248℃。ESI-MS:m/z 370.26[M+H]
+.C
17H
12BrN
3S(Exact Mass:368.99)。
化合物8c-13c的制备
化合物8c-13c的合成方法与化合物9a-14a中描述的合成方法相似。化合物8c,白色固体,产率:84.8%,熔点:132-135℃,ESI-MS:m/z 442.96[M+H]
+.C
20H
16BrN
3O
2S(Exact Mass:441.01)。化合物9c,白色固体,产率:76.6%,熔点:124-127℃,ESI-MS:m/z 456.36[M+H]
+.C
21H
18BrN
3O
2S(Exact Mass:455.03)。化合物10c,白色固体,产率: 81.6%,熔点:130-132℃,ESI-MS:m/z 470.39[M+H]
+.C
22H
20BrN
3O
2S(Exact Mass:469.05)。化合物11c,白色固体,产率:80.0%,熔点:135-138℃,ESI-MS:m/z 456.36[M+H]
+.C
21H
18BrN
3O
2S(Exact Mass:455.03)。化合物12c,白色固体,产率:77.7%,熔点:140-143℃,ESI-MS:m/z 471.01[M+H]
+.C
22H
20BrN
3O
2S(Exact Mass:469.05)。化合物13c,白色固体,产率:62.1%,熔点:139-141℃,ESI-MS:m/z 496.43[M+H]
+.C
24H
22BrN
3O
2S(Exact Mass:495.06)。
化合物21-26的制备
化合物21-26的合成方法与化合物9-14的制备所描述的合成方法相似。
实施例13.化合物21的制备
从乙酸乙酯中重结晶为黄色固体,产率80.1%,熔点:71-74℃。化合物21的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.34(d,J=4.9Hz,1H,Pyr-H),8.31(t,1H,Pyr-H),8.25(t,1H,Naph-H),7.81(s,1H,Naph-H),7.80(s,1H,Naph-H),7.78(s,1H,Naph-H),7.76(d,J=4.0Hz,1H,Naph-H),7.15(q,J=4.8Hz,1H,Pyr-H),6.57(d,J=7.7Hz,1H,Naph-H),5.98(s,2H,CH
2),4.22(s,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ169.61,156.12,155.80,143.98,132.20,132.20,131.88,131.66,130.12,129.44,128.64,128.21,127.69,124.47,122.35,118.06,117.76,45.45,35.49.HR-MS:m/z 425.9917[M-H]
-.C
19H
14BrN
3O
2S(Exact Mass:427.00)。
实施例14.化合物22的制备
从乙酸乙酯中重结晶为白色固体,产率:77.1%,熔点:62-65℃。化合物22的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.37(d,J=4.8Hz,1H,Pyr-H),8.29(t,1H,Pyr-H),8.25(t,1H,Naph-H),7.83(d,J=9.8Hz,1H,Naph-H),7.80(d,J=2.2Hz,1H,Naph-H),7.78(d,J=5.4Hz,1H,Naph-H),7.75(s,1H,Naph-H),7.17(dd,J=8.1,4.8Hz,1H,Pyr-H),6.49(d,J=7.8Hz,1H,Naph-H),5.98(s,2H,CH
2),4.70(q,J=7.2Hz,1H,CH),1.63(d,J=7.2Hz,3H,CH
3).
13C N MR(100MHz,DMSO-d
6)δ172.74,155.77,154.97,144.21,132.27,131.79,131.65,130.13,129.19,128.67,128.19,127.69,124.43,124.14,122.29,118.30,117.99,45.52,45.47,18.88.HR-MS:m/z 440.0074[M-H]
-.C
20H
16BrN
3O
2S(Exact Mass:441.01)。
实施例15.化合物23的制备
从乙酸乙酯中重结晶为白色固体,产率84.0%,熔点:79-82℃。化合物23的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.40(d,J=4.8Hz,1H,Pyr-H),8.30(q,J=3.3Hz,1H,Pyr-H),8.25(q,1H,Naph-H),7.84(d,J=8.1Hz,1H,Naph-H),7.81(t,J=2.2Hz,1H,Naph-H),7.79(t,J=3.7Hz,1H,Naph-H),7.74(d,J=7.7Hz,1H,Naph-H),7.19(q,J=4.8Hz,1H,Pyr-H),6.38(d,J=7.8Hz,1H,Naph-H),6.02(s,2H,CH
2),1.72(s,6H,CH
3×2).
13C NMR(100MHz,DMSO-d
6)δ174.40,155.74,153.33,144.58,132.62,131.69,131.62,130.11,128.67,128.53,128.19,127.69,124.40,123.78,122.18,118.70,118.37,54.60,45.53,26.84,26.84.HR-MS:m/z 454.0231[M-H]
-.C
21H
18BrN
3O
2S(Exact Mass:455.03)。
实施例16.化合物24的制备
从乙酸乙酯中重结晶为白色固体,产率:83.0%,熔点:225-228℃。化合物24的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.37(t,1H,Pyr-H),8.24(t,1H,Pyr-H),8.17(t,J=4.9Hz,1H,Naph-H),7.80(d,J=6.1Hz,1H,Naph-H),7.78(s,1H,Naph-H),7.76(d,J=5.7Hz,1H,Naph-H),7.51–7.27(m,1H,Naph-H),7.18–7.07(m,1H,Pyr-H),6.88–6.47(m,1H,Naph-H),5.97(d,2H,CH
2),3.18(s,2H,CH
2),1.23(s,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ171.09,145.98,143.54,132.17,132.10,131.70,130.07,128.52,128.08,127.68,126.47,125.14,124.66,122.09,119.23,118.46,117.27,45.06,34.68,32.57.HR-MS:m/z 440.0074[M-H]
-.C
20H
16BrN
3O
2S(Exact Mass:441.01)。
实施例17.化合物25的制备
从乙酸乙酯中重结晶为黄色固体,产率:79.0%,熔点:60-63℃。化合物25的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.36(d,J=4.6Hz,1H,Pyr-H),8.29(d,J=9.7Hz,1H,Pyr-H),8.25(t,1H,Naph-H),7.84(d,J=6.4Hz,1H,Naph-H),7.79(d,J=6.8Hz,1H,Naph-H),7.77(d,J=3.7Hz,1H,Naph-H),7.75(d,J=3.7Hz,1H,Naph-H),7.22–7.13(m,1H,Pyr-H),6.58(q,1H,Naph-H),6.01(d,2H,CH
2),3.41(t,J=7.2Hz,2H,CH
2),2.36(q,J=7.6Hz,2H,CH
2),2.15–1.95(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ173.25,170.98,145.70,143.60,132.16,132.04,131.70,130.07,128.52,128.10,127.68,126.42,125.13,124.64,122.11,118.58,117.37,54.41,46.01,45.06,32.69.HR-MS:m/z 454.0234[M-H]
-.C
21H
18BrN
3O
2S(Exact Mass:455.03)。
实施例18.化合物26的制备
从乙酸乙酯中重结晶为白色固体,产率:67.0%,熔点:230-233℃。化合物26的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ13.67(s,1H,COOH),8.38(q,J=3.4Hz,1H,Pyr-H),8.23(q,1H,Pyr-H),8.18(d,J=5.0Hz,1H,Naph-H),7.80(s,1H,Naph-H),7.78(s,1H,Naph-H),7.76(d,J=3.4Hz,1H,Naph-H),7.49(d,J=7.9Hz,1H,Naph-H),7.11(q,J=5.0Hz,1H,Pyr-H),6.83(d,J=7.8Hz,1H,Naph-H),6.00(s,2H,CH
2),3.67(s,6H,CH
2×3).
13C NMR(100MHz,DMSO-d
6)δ173.20,170.97,145.70,143.60,132.16,132.04,131.70,130.07,128.52,128.10,127.68,126.42,125.13,124.64,122.11,118.59,117.38,54.46,47.24,45.06,32.69,17.13.HR-MS:m/z466.0230[M-H]
-.C
22H
18BrN
3O
2S(Exact Mass:467.03)。
化合物5c的制备
化合物5c的合成方法与化合物6b中描述的相似。化合物5c,黄色固体,产率:69.8%,熔点:116-118℃。ESI-MS:m/z 358.19[M+H]
+.C
16H
12BrN
3O
2(Exact Mass:357.01)。
化合物6d的制备
化合物6d的合成方法与化合物6c中描述的相似。化合物6d,白色固体,产率:73.5%,熔点:144-147℃。ESI-MS:m/z 328.21[M+H]
+.C
16H
14BrN
3(Exact Mass:327.03).
化合物7d的制备
化合物7d的合成方法与化合物8a中描述的方法相似。化合物7d,黄色固体,产率:69.9%,熔点:143-144℃。ESI-MS:m/z 370.26[M+H]
+.C
17H
12BrN
3S(Exact Mass:368.99)。
化合物8d-13d的制备
化合物8d-13d的合成方法与化合物9a-14a中描述的合成方法相似。化合物8d,白色固体,产率:80.7%,熔点:135-138℃,ESI-MS:m/z 444.03[M+H]
+.C
20H
16BrN
3O
2S(Exact Mass:441.01)。化合物9d,白色固体,产率:63.8%,熔点:134-137℃,ESI-MS:m/z 458.11[M+H]
+.C
21H
18BrN
3O
2S(Exact Mass:455.03)。化合物10d,白色固体,产率:82.7%,熔点:130-131℃,ESI-MS:m/z 472.21[M+H]
+.C
22H
20BrN
3O
2S(Exact Mass:469.05)。化合物11d,白色固体,产率:61.7%,熔点:154-156℃,ESI-MS:m/z 456.87[M+H]
+.C
21H
18BrN
3O
2S(Exact Mass:455.03)。化合物12d,白色固体,产率:50.5%,熔点:177-179℃,ESI-MS:m/z 470.88[M+H]
+.C
22H
20BrN
3O
2S(Exact Mass:469.05)。化合物13d,白色固体,产率:64.0%,熔点:165-168℃,ESI-MS:m/z 496.8221[M+H]
+.C
24H
22BrN
3O
2S(Exact Mass:495.06)。
化合物27-32的制备
化合物27-32的合成方法与化合物9-14的制备所描述的合成方法相似。
实施例19.化合物27的制备
从乙酸乙酯中重结晶为白色固体,产率:83.0%,熔点:128-131℃。化合物27的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.88(s,1H,Pyr-H),8.31(d,J=9.8Hz,1H,Pyr-H),8.25(d,J=2.6Hz,1H,Naph-H),8.23(s,1H,Naph-H),7.78(s,2H,Naph-H),7.76(s,1H,Pyr-H),7.46(d,J=5.6Hz,1H,Naph-H),6.53(d,J=7.8Hz,1H,Naph-H),5.98(s,2H,CH
2),4.16(s,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ169.49,155.37,141.84,141.80,140.66,140.14,132.12,131.86,131.66,130.11,128.65,128.22,127.70,124.45,124.34,122.35,105.83,45.32,36.44.HR-MS:m/z 425.9917[M-H]
-.C
19H
14BrN
3O
2S(Exact Mass:427.00)。
实施例20.化合物28的制备
从乙酸乙酯中重结晶为黄色固体,产率:87.4%,熔点:115-118℃。化合物28的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.93(s,1H,Pyr-H),8.30(s,1H,Pyr-H),8.27(d,J=5.7Hz,1H,Naph-H),8.24(s,1H,Naph-H),7.80(d,J=5.6Hz,1H,Naph-H),7.77(s,1H,Naph-H),7.75(s,1H,Pyr-H),7.50(d,J=5.5Hz,1H,Naph-H),6.46(d,J=7.7Hz,1H,Naph-H),5.98(s,2H,CH
2),4.67(q,J=7.2Hz,1H,CH),1.61(d,J=7.3Hz,3H,CH
3).
13C NMR(100MHz,DMSO-d
6)δ172.69,153.83,142.02,141.60,140.65,140.41,132.13,131.79,131.66,130.12,128.69,128.22,127.71,124.42,124.08,122.35,106.04,45.44,45.38,18.81.HR-MS:m/z 440.0074[M-H]
-.C
20H
16BrN
3O
2S(Exact Mass:441.01)。
实施例21.化合物29的制备
从乙酸乙酯中重结晶为黄色固体,产率:86.2%,熔点:135-138℃。化合物29的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.95(s,1H,Pyr-H),8.31(t,1H,Pyr-H),8.26(s,1H,Naph-H),8.25(s,1H,Naph-H),7.80(d,J=3.9Hz,1H,Naph-H),7.78(t,1H,Naph-H),7.74(s,1H,Pyr-H),7.73(s,1H,Naph-H),6.33(d,J=7.8Hz,1H,Naph-H),6.01(s,2H,CH
2),1.70(s,6H,CH
3×2).
13C NMR(100MHz,DMSO-d
6)δ174.57,163.94,153.46,142.08,140.96,140.80,140.73,132.62,131.67,131.60,130.06,128.67,128.20,127.68,124.39,123.66,122.15,106.19,45.44,27.17,27.16.HR-MS:m/z 454.0234[M-H]
-.C
21H
18BrN
3O
2S(Exact Mass:455.03)。
实施例22.化合物30的制备
从乙酸乙酯中重结晶为黄色固体,产率:81.1%,熔点:78-81℃。化合物30的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.93(s,1H,Pyr-H),8.30(s,1H,Pyr-H),8.28(s,1H,Naph-H),8.25(d,J=8.9Hz,1H,Naph-H),7.80(d,J=6.7Hz,1H,Naph-H),7.77(s,1H,Naph-H),7.75(s,1H,Pyr-H),7.50(d,J=5.5Hz,1H,Naph-H),6.47(d,J=8.1Hz,1H,Naph-H),5.98(s,2H,CH
2),4.72–4.42(m,2H,CH
2),1.61(d,J=7.2Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ172.71,153.85,142.01,141.61,140.64,140.40,132.12,131.78,131.65,130.12,128.69,128.22,127.71,124.43,124.07,122.34,106.05,45.43,45.38,18.81.HR-MS:m/z 440.0074[M-H]
-.C
20H
16BrN
3O
2S(Exact Mass:441.01)。
实施例23.化合物31的制备
从乙酸乙酯中重结晶为黄色固体,产率:77.0%,熔点:80-83℃。化合物31的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.52(s,1H,Pyr-H),8.38(q,J=3.2Hz,1H,Pyr-H),8.24(d,J=2.4Hz,1H,Naph-H),8.22(d,J=5.5Hz,1H,Naph-H),7.79(s,1H,Naph-H),7.77(s,1H,Naph-H),7.75(d,J=7.9Hz,1H,Pyr-H),7.19(d,J=5.5Hz,1H,Naph-H),6.78(d,J=7.7Hz,1H,Naph-H),5.99(s,2H,CH
2),3.37(s,6H,CH
2×3).
13C NMR(100MHz,DMSO-d
6)δ171.38,143.35,138.80,132.13,131.94,131.70,130.05,129.32,128.55,128.11,127.75,127.69,124.90,124.63,122.12,105.72,45.18,40.42,40.21,39.79,39.59.HR-MS:m/z 454.0235[M-H]
-.C
21H
18BrN
3O
2S(Exact Mass:455.03).
实施例24.化合物32的制备
从乙酸乙酯中重结晶为黄色固体,产率:67.0%,熔点:80-83℃。化合物32的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.92(s,1H,Pyr-H),8.29(q,J=6.6,3.1Hz,1H,Pyr-H),8.26(d,J=2.9Hz,1H,Naph-H),8.24(d,J=4.8Hz,1H,Naph-H),7.79(d,J=3.3Hz,1H,Naph-H),7.77(d,J=4.0Hz,1H,Naph-H),7.75(d,J=3.5Hz,1H,Pyr-H),7.48(d,J=5.5Hz,1H,Naph-H),6.45(d,J=7.8Hz,1H,Naph-H),5.96(s,2H,CH
2),3.39(t,J=7.2Hz,2H,CH
2),2.34(t,J=7.4Hz,2H,CH
2),1.96(q,J=7.3Hz,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.34,155.04,141.91,141.78,140.75,140.25,132.20,131.81,131.66,130.13,128.67,128.18,127.72,124.39,124.00,122.28,105.85,45.26,32.94,31.73,24.87,24.87.HR-MS:m/z 466.0235[M-H]
-.C
22H
18BrN
3O
2S(Exact Mass:467.03)。
化合物33-44的合成路线
试剂及条件:(i-a)2-硝基-3-吡啶基三氟甲磺酸酯,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,氮气,1,4-二氧六环,90℃;(i-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(ii)10%钯碳,氢气,四氢呋喃,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温。
R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
化合物2b的制备
将醋酸钯(0.007g,0.032mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.036g,0.063mmol)溶解在2mL 1,4-二氧六环中搅拌30分钟。将2-硝基-3-吡啶基三氟甲磺酸酯(1b)(0.17g,0.63mmol)、4-环丙基-1-萘胺(1d)(0.13g,0.76mmol)和碳酸铯(0.41g,1.26mmol)溶解在10mL 1,4-二氧六环中。将两种溶液混合,并在氮气氛围下,90℃,回流12小时。TLC监测反应结束,冷却至室温后,加入30mL二氯甲烷和饱和氯化钠水溶液(3×10mL)萃取。分离有机 层,用无水硫酸钠干燥并过滤。产物通过快速柱层析纯化,得到化合物2b。黄色固体,产率:69.5%,熔点:76-79℃。ESI-MS:m/z 306.4[M+H]
+.C
18H
15N
3O
2(Exact Mass:305.12)。
化合物3b的制备
化合物3b的合成方法与化合物7a的合成方法相似,除了原料是化合物2b。化合物3b,淡黄色固体,收率:73.0%,熔点:143-146℃。ESI-MS:m/z 276.44[M+H]
+.C
19H
17N
3O
2(Exact Mass:275.14)。
化合物4b的制备
化合物3b(1g,3.60mmol)、N,N'-羰基二咪唑(CDI)(0.94g,5.80mmol)和三乙胺(0.4mL)溶解在30mL乙腈中。将该溶液在90℃回流10小时,然后冷却至室温,减压蒸发溶剂。用30mL二氯甲烷和饱和氯化钠水溶液(3×10mL)洗涤,分离有机层,用无水硫酸钠干燥,过滤,浓缩。通过快速柱层析纯化,得到化合物4b。白色固体,产率:57.2%,熔点:149-150℃。ESI-MS:m/z 300.28[M–H]
–.C
19H
15N
3O(Exact Mass:301.12)。
化合物5e-10e的制备
化合物5e-10e的合成方法与化合物9a-14a中描述的合成方法相似。化合物5e,白色固体,产率:87.5%,熔点:184-185℃,ESI-MS:m/z 374.24[M+H]
+.C
22H
19N
3O
3(Exact Mass:373.14)。化合物6e,白色固体,产率:81.6%,熔点:173-176℃,ESI-MS:m/z 388.41[M+H]
+.C
23H
21N
3O
3(Exact Mass:387.16)。化合物7e,白色固体,产率:88.4%,熔点:152-155℃,ESI-MS:m/z 402.1[M+H]
+.C
24H
23N
3O
3(Exact Mass:401.17)。化合物8e,透明油状,产率:64.8%,熔点:154-156℃,ESI-MS:m/z 388.6[M+H]
+.C
23H
21N
3O
3(Exact Mass:387.16)。化合物9e,透明油状,产率:60.6%,熔点:177-179℃,ESI-MS:m/z 402.8[M+H]
+.C
24H
23N
3O
3(Exact Mass:401.17)。化合物10e,白色固体,产率:47.5%,熔点:188-190℃,ESI-MS:m/z 428.3[M+H]
+.C
26H
25N
3O
3(Exact Mass:427.19)。
化合物33-38的制备
化合物33-38的合成方法与化合物9-14的制备所描述的合成方法相似。
实施例25.化合物33的制备
从乙酸乙酯中重结晶为白色固体,产率:77.8%,熔点:190-193℃。化合物33的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.56(t,J=8.4Hz,1H,Pyr-H),8.05(t,J=5.1Hz,1H,N aph-H),7.70(t,1H,Naph-H),7.59(d,J=7.6Hz,1H,Pyr-H),7.54(d,J=6.5Hz,1H,Naph-H),7.52(s,1H,Naph-H),7.43(d,J=7.6Hz,1H,Naph-H),7.00(q,1H,Pyr-H),6.93(t,J=8.5Hz,1H,Naph-H),4.65–4.56(m,2H,CH
2),2.57–2.51(m,1H,CH),1.14(d,J=8.4Hz,2H,CH
2),0.90–0.75(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ169.73,153.33,143.85,141.52,141.15,134.37,130.01,128.47,127.51,127.22,126.97,126.46,125.66,125.45,123.52,118.05,114.96,42.28,13.40,7.60,7.32.HR-MS:m/z 358.1197[M-H]
-.C
21H
17N
3O
3(Exact Mass:359.13)。
实施例26.化合物34的制备
从乙酸乙酯中重结晶为红色固体,产率:60.0%,熔点:100-103℃。化合物34的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.58(d,J=5.7Hz,1H,Pyr-H),8.55(d,J=7.7Hz,1H,Naph-H),8.16(d,J=5.3Hz,1H,Naph-H),7.70(t,J=7.6Hz,1H,Pyr-H),7.60(d,J=7.6Hz,1H,Naph-H),7.55(t,1H,Naph-H),7.45(t,1H,Naph-H),7.38(t,1H,Pyr-H),6.64(d,J=5.3Hz,1H,Naph-H),5.31(t,J=7.2Hz,1H,CH),2.58–2.52(m,1H,CH),1.77(q,J=3.6Hz,3H,CH
3),1.15(d,J=8.7Hz,2H,CH
2),0.88–0.81(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ171.76,148.14,141.12,135.66,131.74,129.94,128.83,128.35,126.79,126.21,125.28,124.12,123.49,119.46,118.10,115.24,113.33,13.40,13.22,13.03,7.02,6.49.HR-MS:m/z 372.1354[M-H]
-.C
22H
19N
3O
3(Exact Mass:373.14)。
实施例27.化合物35的制备
从乙酸乙酯中重结晶为黄色固体,产率:78.8%,熔点:180-183℃。化合物35的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.55(d,J=8.6Hz,1H,Pyr-H),7.99(d,J=3.9Hz,1H,Naph-H),7.69(d,J=7.7Hz,1H,Naph-H),7.57(s,1H,Pyr-H),7.54(d,J=6.7Hz,1H,Naph-H),7.49(d,J=8.3Hz,1H,Naph-H),7.41(d,J=7.6Hz,1H,Naph-H),6.92(q,J=5.0Hz,1H,Pyr-H),6.79(d,J=9.1Hz,1H,Naph-H),3.38(s,6H,CH
3×2),2.51(s,1H,CH),1.14(d,J=8.4Hz,2H, CH
2),0.89–0.76(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ154.12,144.82,141.18,141.03,134.31,130.13,129.80,129.00,128.77,127.42,127.11,127.00,126.57,125.41,123.52,123.05,117.28,114.44,13.38,7.59,7.59,7.28,7.27.HR-MS:m/z 386.1509[M-H]
-.C
23H
21N
3O
3(Exact Mass:387.16)。
实施例28.化合物36的制备
从乙酸乙酯中重结晶为黄色固体,产率57.2%,熔点:68-71℃。化合物36的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.55(d,J=8.4Hz,1H,Pyr-H),8.08(t,J=5.0Hz,1H,Naph-H),7.69(t,1H,Naph-H),7.57(t,1H,Pyr-H),7.55(d,J=4.2Hz,1H,Naph-H),7.53(s,1H,Naph-H),7.42(d,J=7.6Hz,1H,Naph-H),7.04–6.95(m,1H,Pyr-H),6.86(t,1H,Naph-H),4.23(t,2H,CH
2),3.45(q,J=7.2Hz,1H,CH),2.85(t,J=7.6Hz,2H,CH
2),1.14(t,J=8.6Hz,2H,CH
2),0.89–0.77(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ172.91,153.78,152.91,144.32,143.65,141.45,141.09,134.31,130.08,128.52,127.49,127.20,127.01,125.41,123.49,117.87,114.94,36.55,33.05,13.39,7.59,7.33.HR-MS:m/z 372.1354[M-H]
-.C
22H
19N
3O
3(Exact Mass:373.14)。
实施例29.化合物37的制备
从乙酸乙酯中重结晶为黄色固体,产率:65.5%,熔点:58-61℃。化合物37的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.56(d,J=8.6Hz,1H,Pyr-H),8.07(d,J=5.0Hz,1H,Naph-H),7.72–7.69(m,1H,Naph-H),7.60(d,J=7.6Hz,1H,Pyr-H),7.55(s,1H,Naph-H),7.54(s,1H,Naph-H),7.42(d,J=7.6Hz,1H,Naph-H),6.99(q,J=5.3Hz,1H,Pyr-H),6.88(d,J=7.8Hz,1H,Naph-H),4.05(t,J=6.9Hz,2H,CH
2),3.37(s,1H,CH),2.39(t,J=7.3Hz,2H,CH
2),2.07(t,J=7.0Hz,2H,CH
2),1.14(q,2H,CH
2),0.89–0.78(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.37,153.19,143.88,141.41,141.06,134.30,130.10,129.00,128.59,127.50,127.17,12 7.08,126.43,125.41,123.57,123.50,117.80,114.90,31.50,23.82,13.40,7.59,7.32.HR-MS:m/z 386.1509[M-H]
-.C
23H
21N
3O
3(Exact Mass:387.16)。
实施例30.化合物38的制备
从乙酸乙酯中重结晶为白色固体,产率:46.0%,熔点:180-183℃。化合物38的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ11.94(s,1H,COOH),8.55(d,J=8.6Hz,1H,Pyr-H),8.00(d,J=5.0Hz,1H,Naph-H),7.69(d,J=6.5Hz,1H,Naph-H),7.56(d,J=7.5Hz,1H,Pyr-H),7.52(d,J=7.7Hz,1H,Naph-H),7.49(d,J=8.1Hz,1H,Naph-H),7.41(d,J=7.6Hz,1H,Naph-H),6.93(q,J=5.3Hz,1H,Pyr-H),6.81(d,J=6.5Hz,1H,Naph-H),3.35(s,6H,CH
2×3),2.58–2.51(m,1H,CH),1.18–1.10(m,2H,CH
2),0.90–0.76(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ153.82,144.38,141.26,141.09,134.31,130.12,129.88,129.01,128.64,127.75,127.46,127.13,127.03,126.48,125.42,123.50,123.00,117.47,114.61,13.38,7.60,7.60,7.28,7.28.HR-MS:m/z 398.1514[M-H]
-.C
23H
21N
3O
3(Exact Mass:399.16)。
化合物2c的制备
化合物2c的合成方法与化合物6b的合成方法相似,除了原料是化合物1d。化合物2c,黄色固体,产率:56.6%,熔点:116-118℃。ESI-MS:m/z 306.4[M+H]
+.C
18H
15N
3O
2(Exact Mass:305.11)。
化合物3c的制备
化合物3c的合成方法与化合物7a的合成方法相似,除了原料是化合物2c。化合物3c,黄色固体,收率:76.2%,熔点:192-193℃。ESI-MS:m/z 276.4[M+H]
+.C
18H
17N
3(Exact Mass:275.14)。
化合物4c的制备
化合物4c的合成方法与化合物4b的合成方法相似,白色固体,产率:60.9%,熔点:159-161℃。ESI-MS:m/z 300.88[M–H]
–.C
19H
15N
3O(Exact Mass:301.12)。
化合物5f-10f的制备
化合物5f-10f的合成方法与化合物9a-14a中描述的合成方法相似。化合物5f,白色固体,产率:82.2%,熔点:123-125℃,Melting point:123-125℃.ESI-MS:m/z 374.7[M+H]
+.C
22H
19N
3O
3(Exact Mass:373.14)。化合物6f,白色固体,产率:84.5%,熔点:136-137℃, ESI-MS:m/z 388.3[M+H]
+.C
23H
21N
3O
3(Exact Mass:387.16)。化合物7f,淡黄色油状,产率:88.2%,熔点:142-145℃,ESI-MS:m/z 402.6[M+H]
+.C
24H
23N
3O
3(Exact Mass:401.17)。化合物8f,淡黄色油状,产率:70.0%,熔点:151-154℃,ESI-MS:m/z 388.1[M+H]
+.C
23H
21N
3O
3(Exact Mass:387.16)。化合物9f,白色固体,产率:53.9%,熔点:152-155℃,ESI-MS:m/z 402.4[M+H]
+.C
24H
23N
3O
3(Exact Mass:401.17)。化合物10f,白色固体,产率:55.0%,熔点:164-167℃,ESI-MS:m/z 428.4[M+H]
+.C
26H
25N
3O
3(Exact Mass:427.19)。
化合物39-44的制备
化合物39-44的合成方法与化合物9-14的制备所描述的合成方法相似。
实施例31.化合物39的制备
从乙酸乙酯中重结晶为黄色固体,产率:72.5%,熔点:120-123℃。化合物39的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ11.54(d,1H,COOH),8.54(s,1H,Pyr-H),8.37(d,J=4.9Hz,1H,Pyr-H),8.15(d,J=5.3Hz,1H,Naph-H),8.10(d,J=5.3Hz,1H,Naph-H),7.70(d,J=6.8Hz,1H,Naph-H),7.67(s,1H,Naph-H),7.57(s,1H,Pyr-H),7.55(s,1H,Naph-H),7.45(s,1H,Naph-H),6.59(q,2H,CH
2),4.74(d,J=8.6Hz,2H,CH
2),2.54(q,1H,CH),1.14(d,J=8.3Hz,2H,CH
2),0.88–0.83(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ169.71,154.02,143.42,142.95,141.77,141.50,138.17,136.92,134.29,130.23,127.54,127.19,126.99,125.46,123.49,123.31,104.21,43.60,13.39,7.62,7.31.HR-MS:m/z 358.1197[M-H]
-.C
21H
17N
3O
3(Exact Mass:359.13)。
实施例32.化合物40的制备
从乙酸乙酯中重结晶为黄色固体,产率:76.9%,熔点:245-248℃。化合物40的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.58(s,1H,Pyr-H),8.56(t,1H,Pyr-H),8.16(d,J=5.3 Hz,1H,Naph-H),7.70(t,J=7.9Hz,1H,Naph-H),7.60(d,J=7.6Hz,1H,Naph-H),7.55(t,1H,Naph-H),7.45(t,1H,Pyr-H),7.38(t,1H,Naph-H),6.64(d,J=5.3Hz,1H,Naph-H),5.31(t,J=7.2Hz,1H,CH),2.60–2.52(m,1H,CH),1.78(q,J=3.7Hz,3H,CH
3),1.14(d,J=8.8Hz,2H,CH
2),0.87–0.79(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ171.87,152.86,143.30,141.83,137.05,134.34,130.42,129.80,128.17,127.59,127.28,127.06,125.50,123.48,123.29,122.94,104.36,51.19,15.66,13.40,7.60,7.39.HR-MS:m/z 372.1354[M-H]
-.C
22H
19N
3O
3(Exact Mass:373.14)。
实施例33.化合物41的制备
从乙酸乙酯中重结晶为黄色固体,产率92.0%,熔点:110-113℃。化合物41的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ11.57(s,1H,COOH),8.56(d,J=8.4Hz,1H,Pyr-H),8.37(d,1H,Pyr-H),8.10(t,J=5.3Hz,1H,Naph-H),7.69(t,J=7.1Hz,1H,Naph-H),7.57(s,1H,Naph-H),7.54(d,J=7.9Hz,1H,Naph-H),7.45(d,J=8.2Hz,1H,Pyr-H),7.42(d,J=7.6Hz,1H,CH,Naph-H),6.55(d,J=5.3Hz,1H,Naph-H),3.39(s,6H,CH
3×2),2.54(t,J=8.2Hz,1H,CH),1.14(t,2H,CH
2),0.88–0.79(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ154.02,142.95,141.49,138.15,134.29,130.25,129.97,128.47,127.54,127.19,126.99,126.82,125.46,125.37,123.49,123.39,123.31,104.21,13.39,7.62,7.62,7.31,7.31.HR-MS:m/z 386.1507[M-H]
-.C
23H
21N
3O
3(Exact Mass:387.16)。
实施例34.化合物42的制备
从乙酸乙酯中重结晶为白色固体,产率88.4%,熔点:105-108℃。化合物42的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ8.64(s,1H,Pyr-H),8.56(d,J=8.4Hz,1H,Pyr-H),8.14(d, J=5.3Hz,1H,Naph-H),7.69(t,J=7.2Hz,1H,Naph-H),7.57(d,J=7.7Hz,1H,Naph-H),7.54(d,J=7.0Hz,1H,Naph-H),7.45(d,J=8.3Hz,1H,Pyr-H),7.43(d,J=7.6Hz,1H,Naph-H),6.59(d,J=5.3Hz,1H,Naph-H),4.24(t,J=7.0Hz,2H,CH
2),2.82(t,J=6.9Hz,2H,CH
2),2.55(q,1H,CH),1.14(d,J=8.4Hz,2H,CH
2),0.88–0.80(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ172.88,153.06,143.22,141.69,136.93,134.30,130.13,129.91,128.37,127.58,127.25,127.25,126.99,125.46,123.47,123.37,104.16,37.93,33.04,13.40,7.61,7.36.HR-MS:m/z 372.1354[M-H]
-.C
22H
19N
3O
3(Exact Mass:373.14)。
实施例35.化合物43的制备
从乙酸乙酯中重结晶为黄色固体,产率66.1%,熔点:150-153℃。化合物43的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ12.18(s,1H,COOH),8.61(s,1H,Pyr-H),8.56(d,J=8.6Hz,1H,Pyr-H),8.15(d,J=5.3Hz,1H,Naph-H),7.69(t,J=7.7Hz,1H,Naph-H),7.59(d,J=7.5Hz,1H,Naph-H),7.54(d,J=7.0Hz,1H,Naph-H),7.47(d,J=8.6Hz,1H,Pyr-H),7.43(d,J=7.7Hz,1H,Naph-H),6.60(d,J=5.3Hz,1H,Naph-H),4.04(q,J=7.0Hz,2H,CH
2),2.54(t,J=5.3Hz,1H,CH),2.41(t,J=7.3Hz,2H,CH
2),2.03(t,2H,CH
2),1.14(d,J=8.4Hz,2H,CH
2),0.88–0.79(m,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ174.39,153.22,143.28,141.64,136.97,134.28,129.94,129.63,128.45,127.59,127.46,127.22,127.04,125.46,123.48,123.37,104.22,31.22,23.77,13.40,7.62,7.62,7.35.HR-MS:m/z 386.1507[M-H]
-.C
23H
21N
3O
3(Exact Mass:387.16)。
实施例36.化合物44的制备
从乙酸乙酯中重结晶为黄色固体,产率77.0%,熔点:70-73℃。化合物44的波谱数据:
1H NMR(400MHz,DMSO-d
6)δ11.54(d,1H,COOH),8.56(d,J=8.6Hz,1H,Pyr-H),8.37(s,1H,Pyr-H),8.10(d,J=5.3Hz,1H,Naph-H),7.70(d,J=8.3Hz,1H,Naph-H),7.67(s,1H,Naph-H),7.58(s,1H,Naph-H),7.56(s,1H,Pyr-H),7.44(d,J=4.0Hz,1H,Naph-H),6.56(t,J=5.4Hz,1H,Naph-H),3.50(q,2H,CH
2),2.54(t,1H,CH),1.15(d,2H,CH
2),1.13(t,2H,CH
2),0.92–0.84(m,2H,CH
2),0.80(q,2H,CH
2).
13C NMR(100MHz,DMSO-d
6)δ154.00,142.82,141.52,138.28,134.29,130.04,129.95,128.43,127.55,127.19,127.09,127.00,126.83,125.46,123.49,123.39,123.31,104.24,37.24,34.68,13.40,7.63,7.62,7.31.HR-MS:m/z 398.1509[M-H]
-.C
24H
21N
3O
3(Exact Mass:399.16)。
实施例17.目标化合物的体内降尿酸活性试验
测试材料和方法:
(1)实验动物:雄性昆明小鼠,由山东大学实验动物中心提供。
(2)样品处理:待测化合物临用前,用DMSO和CMC-Na配成适当的浓度。
(3)造模药物:次黄嘌呤、氧嗪酸钾。
(4)阳性对照药:Lesinurad。
(5)测试方法:每组灌胃次黄嘌呤0.2mL,皮下注射氧嗪酸钾0.2mL,灌胃药物0.2mL并开始计时,在给药4小时后摘眼球取血,30分钟凝血后离心,取上清液血清。用尿酸仪检测血清中的尿酸浓度。
表2.化合物9~32的结构及降尿酸的活性
表3.化合物33~44的结构及降尿酸的活性
结论:由表2和表3可以看出,有29种化合物呈现出降尿酸活性,降尿酸活性均优于或相当于阳性对照药物Lesinurad,其中代表化合物13、23、33、35、36、38和39,在动物体内活性测试中,血尿酸下降率均超过80%,显示出优异的降尿酸活性,可作为降尿酸候选药物。
Claims (6)
- 如权利要求1所述的吡啶并咪唑类衍生物,其特征在于,R为甲基,乙基,丙基,异丙基,叔丁基,环丁基。
- 如权利要求3所述的吡啶并咪唑类衍生物的制备方法,其特征在于,为如下方法之一:(1)化合物9-20的合成:在过氧化苯甲酰(BPO)的存在下,将1a用N-溴代琥珀酰亚胺(NBS)在正己烷中处理得到中间体2a,将其与邻苯二甲酰亚胺钾反应得到3a;3a与80%水合肼通过Gabriel合成得到4a,然后在25:1v/v的甲苯/水混合物中进行Suzuki偶联反应,将4a转化为5a;5a和2-硝基-3-吡啶基三氟甲磺酸酯(1b)或4-氯-3-硝基吡啶(1c)通过偶联反应获得中间体6a或6b;在Pd/C存在下,氢化还原得到7a或7b,然后用1,1'-硫代羰基二咪唑(TCDI)环化得到关键中间体8a或8b;通过亲核取代反应和氢氧化锂水解得到化合物9-14;化合物15-20的制备方法与化合物9-14相似,不同之处在于步骤V,以4-氯-3-硝基吡啶(1c)为起始原料;路线一:试剂及条件:(i)N-溴代琥珀酰亚胺,过氧化苯甲酰,氮气 ,正己烷,70℃;(ii)邻苯二甲酰亚胺钾,N,N-二甲基甲酰胺,100℃,氮气 ;(iii)80%水合肼,乙醇,80℃;(iv)环丙基硼酸,磷酸钾 ,四(三苯基膦)钯 ,甲苯,水,氮气,100℃;(v-a)2-硝基-3-吡啶基三氟甲磺酸 酯,三乙胺,乙腈,90℃;(v-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(vi)10%钯碳,氢气,四氢呋喃,室温;(vii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(viii)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(ix)氢氧化锂,四氢呋喃,乙醇,室温;R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基;(2)化合物21-32的合成4a用2-硝基-3-吡啶基三氟甲磺酸酯(1b)或4-氯-3-硝基吡啶(1c)处理,通过偶联反应得到5b或5c;然后,在氯化亚锡存在下氢化还原得到6c或6d,将其与1,1'-硫代羰基二咪唑(TCDI)环化得到关键中间体7c或7d,然后进行亲核取代和水解反应得到目标化合物21-26;化合物27-32的制备方法与化合物21-26类似,不同之处在于步骤I的起始原料为4-氯-3-硝基吡啶(1c);路线二:试剂及条件:(i-a)2-硝基-3-吡啶基三氟甲磺酸酯,三乙胺,乙腈,90℃;(i-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(ii)氯化亚锡,乙醇,氮气,室温;(iii)1,1'-硫代羰基二咪唑,三乙胺,乙腈,90℃;(iv)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温;R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基;(3)化合物33-44的合成起始原料4-环丙基-1-萘氨(1d)用2-硝基-3-吡啶基三氟甲磺酸酯(1b)或4-氯-3-硝基吡啶(1c)处理,通过偶联反应得到中间体2b或2c;然后,在钯碳存在下氢化还原得到3b或3c,将其与N,N'-羰基二咪唑(CDI)环化得到4b或4c,然后进行亲核取代和水解以得到化合物33-38;化合物39-44的制备方法与化合物33-38类似,不同之处在于起始原料为4-氯-3-硝基吡啶(1c);路线三:试剂及条件:(i-a)2-硝基-3-吡啶基三氟甲磺酸酯,醋酸钯,4,5-双二苯基膦-9,9-二甲基氧杂蒽,碳酸铯,氮气,1,4-二氧六环,90℃;(i-b)4-氯-3-硝基吡啶,碳酸氢钠,乙醇,60℃;(ii)10%钯碳,氢气,四氢呋喃,室温;(iii)N,N'-羰基二咪唑(CDI),三乙胺,乙腈,90℃;(iv)酯,碳酸钾,N,N-二甲基甲酰胺,室温;(v)氢氧化锂,四氢呋喃,乙醇,室温;R为亚甲基、乙基、丙基、异丙基、叔丁基、环丁基。
- 权利要求1-3任一项所述的吡啶并咪唑类衍生物在制备降尿酸的药物中的应用。
- 一种降尿酸药物组合物,包含权利要求1-3任一项所述的吡啶并咪唑类衍生物和一种或多种药学上可接受载体或赋形剂。
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