CN117777047B - N-substituted azaspirodecanone compounds and preparation methods and applications thereof - Google Patents
N-substituted azaspirodecanone compounds and preparation methods and applications thereof Download PDFInfo
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- CN117777047B CN117777047B CN202410208065.9A CN202410208065A CN117777047B CN 117777047 B CN117777047 B CN 117777047B CN 202410208065 A CN202410208065 A CN 202410208065A CN 117777047 B CN117777047 B CN 117777047B
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Abstract
本发明提供了N‑取代氮杂螺癸单烯酮类化合物及其制备方法和应用,属于螺癸烯酮类化合物技术领域。N‑取代氮杂螺癸单烯酮类化合物具有如式I或式II所示的结构;本发明通过亲核加成反应,实现了N‑取代氮杂螺癸单烯酮类化合物的高效构建。本发明的制备方法简单,制备的化合物结构稳定,毒副作用小,具有良好的水溶性及抗肿瘤活性,可用于制备抗肿瘤药物。The present invention provides N-substituted azaspirodecanone compounds and preparation methods and applications thereof, and belongs to the technical field of spirodecanone compounds. N-substituted azaspirodecanone compounds have a structure as shown in Formula I or Formula II; the present invention realizes efficient construction of N-substituted azaspirodecanone compounds through nucleophilic addition reaction. The preparation method of the present invention is simple, the prepared compound has a stable structure, small toxic and side effects, good water solubility and anti-tumor activity, and can be used to prepare anti-tumor drugs.
Description
技术领域Technical Field
本发明属于螺癸烯酮类化合物技术领域,具体涉及N-取代氮杂螺癸单烯酮类化合物及其制备方法和应用。The invention belongs to the technical field of spirodecanone compounds, and specifically relates to N-substituted azaspirodecanone compounds and preparation methods and applications thereof.
背景技术Background technique
恶性肿瘤是危害人类健康与生命的重大疾病,因此基于不同构效关系、不同作用靶点的毒性低疗效高的新型抗肿瘤药物的研发意义重大。螺癸烯酮是一类含有一个全取代季碳中心(螺原子,spiroatom)的衍生物,具有多种生物活性,如抗肿瘤、抗炎、抗菌、抗病毒以及抗退行性疾病等。不仅如此,螺癸烯酮还具有独特的刚性和构象结构,正因为结构的特殊性与多方面的生物活性而受到人们的广泛关注。Malignant tumors are major diseases that endanger human health and life. Therefore, the research and development of new anti-tumor drugs with low toxicity and high efficacy based on different structure-activity relationships and different targets is of great significance. Spirodecenone is a class of derivatives containing a fully substituted quaternary carbon center (spiroatom), which has multiple biological activities, such as anti-tumor, anti-inflammatory, antibacterial, antiviral and anti-degenerative diseases. In addition, spirodecanone also has a unique rigidity and conformational structure. It has attracted widespread attention because of the special structure and multi-faceted biological activities.
前期研究发现,磺酰胺具有良好氮宾反应性及稳定性,同时磺胺类化合物还可选择性地在肿瘤组织富集,具有肿瘤靶向给药载体的潜能等特点,采用磺酰胺为氮源设计合成系列磺酰胺联氮杂螺癸双烯酮H1及H2类衍生物具有一定的抗肿瘤活性,然而,该类化合物虽然能表现出在肿瘤部位富集的特征和较好的抗肿瘤活性,但存在毒性较强、水溶性不好且体外活性不高等问题,这些缺陷限制了其进一步的应用研究。磺酰胺联氮杂螺癸双烯酮H1及H2类衍生物的结构式如下所示:Previous studies have found that sulfonamide has good nitrene reactivity and stability. At the same time, sulfonamide compounds can also be selectively enriched in tumor tissues and have the potential of tumor-targeted drug delivery carriers. Using sulfonamide as a nitrogen source to design and synthesize a series of sulfonamide azaspirodecanedione H1 and H2 derivatives have certain anti-tumor activity. However, although this type of compound can show the characteristics of enrichment in tumor sites and good anti-tumor activity, it has strong toxicity, poor water solubility and low in vitro activity. These defects limit its further application research. The structural formula of sulfonamide azaspirodecanedione H1 and H2 derivatives is shown below:
。 .
发明内容Summary of the invention
本发明要解决的问题是:提供N-取代氮杂螺癸单烯酮类化合物及其制备方法和应用,以解决磺酰胺联氮杂螺癸双烯酮类衍生物存在的毒性强、水溶性不好且体外活性不高的问题。The problem to be solved by the present invention is to provide N-substituted azaspirodecanone compounds and preparation methods and applications thereof, so as to solve the problems of strong toxicity, poor water solubility and low in vitro activity of sulfonamide azaspirodecanone derivatives.
为解决其技术问题所采取的技术方案如下:提供N-取代氮杂螺癸单烯酮类化合物,该化合物具有如式I或式II所示的结构:The technical solution adopted to solve the technical problem is as follows: provide an N-substituted azaspirodecanone compound, which has a structure as shown in Formula I or Formula II:
; ;
式中:Where:
R为H、C1-20直链或支链烷基、卤素、脂肪环、芳香环、羧基、羟基、氨基、巯基、碳酰化衍生物、磷酰化衍生物、亚磷酰化衍生物或硫酰化衍生物;R is H, C 1-20 straight or branched alkyl, halogen, aliphatic ring, aromatic ring, carboxyl, hydroxyl, amino, thiol, carbonyl derivative, phosphoryl derivative, phosphitylated derivative or sulfonylated derivative;
R2为芳香磺酰基或取代的芳香磺酰基、芳香碳酰基或取代的芳香碳酰基、芳香磷酰基或取代的芳香磷酰基、芳香环或取代的芳香环、脂肪环或取代的脂肪环、杂环或取代的杂环、苄基或取代的苄基; R2 is an aromatic sulfonyl or substituted aromatic sulfonyl, an aromatic carbonyl or substituted aromatic carbonyl, an aromatic phosphoryl or substituted aromatic phosphoryl, an aromatic ring or substituted aromatic ring, an aliphatic ring or substituted aliphatic ring, a heterocyclic ring or substituted heterocyclic ring, a benzyl or substituted benzyl;
R3为C1-20直链或支链烷基、卤素、脂肪环、芳香环、杂环、羧基、羟基、氨基、巯基、碳酰化衍生物、磷酰化衍生物、亚磷酰化衍生物或硫酰化衍生物; R3 is a C1-20 straight or branched alkyl group, halogen, aliphatic ring, aromatic ring, heterocyclic ring, carboxyl, hydroxyl, amino, thiol, carbonyl derivative, phosphoryl derivative, phosphitylated derivative or sulfonylated derivative;
X为氧、硫、氮或碳元素,n为0、1、2、3、4或5。X is oxygen, sulfur, nitrogen or carbon, and n is 0, 1, 2, 3, 4 or 5.
优选的,R为H、卤素或芳香环;R2为芳香磺酰基或取代的芳香磺酰基、芳香环或取代的芳香环、杂环或取代的杂环、苄基或取代的苄基;R3为杂环、羧基、巯基或碳酰化衍生物;X为氧元素;n为1。Preferably, R is H, halogen or aromatic ring; R2 is aromatic sulfonyl or substituted aromatic sulfonyl, aromatic ring or substituted aromatic ring, heterocycle or substituted heterocycle, benzyl or substituted benzyl; R3 is heterocycle, carboxyl, thiol or carbonyl derivative; X is oxygen; and n is 1.
优选的,N-取代氮杂螺癸单烯酮类化合物的具体结构式如下:Preferably, the specific structural formula of the N-substituted azaspirodecanone compound is as follows:
。 .
上述N-取代氮杂螺癸单烯酮类化合物的制备方法,包括以下合成路径:The preparation method of the above-mentioned N-substituted azaspirodecanone compound comprises the following synthetic route:
合成路径1:将化合物A和化合物B溶于有机溶剂中,在催化剂的作用下反应制得中间化合物1,再加入氧化剂反应制得中间化合物2,再加入亲核试剂反应制得如式I所示的N-取代氮杂螺癸单烯酮类化合物;其合成路线如下:Synthesis route 1: Compound A and compound B are dissolved in an organic solvent, reacted under the action of a catalyst to obtain an intermediate compound 1, then an oxidant is added to react to obtain an intermediate compound 2, and then a nucleophilic reagent is added to react to obtain an N-substituted azaspirodecanone compound as shown in formula I; the synthesis route is as follows:
; ;
合成路径2:将化合物C及化合物D溶于有机溶剂中,在脱水剂的作用下反应制得中间化合物3,再加入氧化剂反应制得中间化合物4,再加入化合物B,在催化剂的作用下反应制得中间化合物5,再加入亲核试剂反应制得如式II所示的N-取代氮杂螺癸单烯酮类化合物;其合成路线如下:Synthesis route 2: Compound C and compound D are dissolved in an organic solvent, reacted under the action of a dehydrating agent to obtain an intermediate compound 3, then an oxidant is added to react to obtain an intermediate compound 4, then compound B is added to react under the action of a catalyst to obtain an intermediate compound 5, and then a nucleophilic reagent is added to react to obtain an N-substituted azaspirodecanone compound as shown in formula II; the synthesis route is as follows:
; ;
合成路径3:将化合物E及化合物F加入脱水剂反应制得中间化合物6,再加入氧化剂及铜盐催化剂反应制得中间化合物5,再加入亲核试剂反应制得如式II所示的N-取代氮杂螺癸单烯酮类化合物;其合成路线如下:Synthesis route 3: Compound E and compound F are added with a dehydrating agent to react to obtain intermediate compound 6, and then an oxidant and a copper salt catalyst are added to react to obtain intermediate compound 5, and then a nucleophilic reagent is added to react to obtain an N-substituted azaspirodecanone compound as shown in formula II; the synthesis route is as follows:
。 .
更优选的,化合物E为时,N-取代氮杂螺癸单烯酮类化合物的制备包括以下步骤:将3-氯苯甲醛、氨基氰及甲醇溶于N-溴代琥珀酰亚胺中,在催化剂的作用下反应制得中间化合物7,再加入苯肼及催化剂反应制得中间化合物8,再加入2-(4-甲氧基苯氧基)乙酸、碳化二亚胺及1-羟基苯并三唑反应制得中间化合物9,再加入氧化剂及铜盐催化剂反应制得中间化合物10,再加入亲核试剂反应制得如式II所示的N-取代氮杂螺癸单烯酮类化合物;其合成路线如下:More preferably, compound E is The preparation of N-substituted azaspirodecanone compounds comprises the following steps: dissolving 3-chlorobenzaldehyde, cyanamide and methanol in N-bromosuccinimide, reacting under the action of a catalyst to obtain an intermediate compound 7, then adding phenylhydrazine and a catalyst to react to obtain an intermediate compound 8, then adding 2-(4-methoxyphenoxy)acetic acid, carbodiimide and 1-hydroxybenzotriazole to react to obtain an intermediate compound 9, then adding an oxidant and a copper salt catalyst to react to obtain an intermediate compound 10, and then adding a nucleophilic reagent to react to obtain an N-substituted azaspirodecanone compound as shown in formula II; the synthesis route is as follows:
。 .
本发明采用优选的有益效果为:在进行亲核试剂加成之前的中间化合物为迈克尔受体分子,由于其具有亲电性,可与体内多种亲核性的生物活性分子发生加成反应,从而表现出生物效应,这一类的分子可与多种蛋白的亲核性氨基酸残基(如半胱氨酸、精氨酸等)、羟基或巯基共价结合,调节细胞内的信号通路如NF-κB、STAT3等,但含有亲核性氨基酸残基等基团的蛋白都有可能是迈克尔受体分子的作用靶点,容易产生由靶外效应引起的毒副作用,在临床应用中具有极大的潜在风险,通过将中间化合物与亲核试剂进行亲核加成反应,可减少迈克尔受体分子在体内的加成反应位点,即最终得到的N-取代氮杂螺癸单烯酮类化合物可有效降低毒副作用,安全性较好;同时,在螺癸烯酮结构中引入三元环、极性或亲水性基团可进一步提高其水溶性,如咪唑、三氮唑和哌嗪等多氮杂环结构,也有助于提高化合物与靶点结合力,改善脂水分配系数从而改善其药理活性。The preferred beneficial effect of the present invention is that the intermediate compound before the addition of the nucleophilic reagent is a Michael acceptor molecule, which can react with a variety of nucleophilic biologically active molecules in the body due to its electrophilicity, thereby exhibiting biological effects. This type of molecule can covalently bind to nucleophilic amino acid residues (such as cysteine, arginine, etc.), hydroxyl groups or sulfhydryl groups of a variety of proteins to regulate intracellular signaling pathways such as NF-κB, STAT3, etc. However, proteins containing nucleophilic amino acid residues and other groups may be the target of Michael acceptor molecules, which is easy to produce off-target effects. The toxic and side effects caused by the reaction have great potential risks in clinical applications. By subjecting the intermediate compound to a nucleophilic addition reaction with a nucleophilic reagent, the addition reaction sites of the Michael acceptor molecule in the body can be reduced, that is, the N-substituted azaspirodecanone compounds finally obtained can effectively reduce the toxic and side effects and have good safety. At the same time, the introduction of a three-membered ring, polar or hydrophilic group into the spirodecanone structure can further improve its water solubility. For example, polynitrogen heterocyclic structures such as imidazole, triazole and piperazine can also help to improve the binding force between the compound and the target, improve the lipid-water partition coefficient and thus improve its pharmacological activity.
更优选的,催化剂均为三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯或叔丁醇钾。More preferably, the catalyst is triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium tert-butoxide.
更优选的,氧化剂均为碘苯三氟乙酸酯或二乙酰氧基碘苯;铜盐催化剂为高氯酸四乙腈铜。More preferably, the oxidant is iodobenzene trifluoroacetate or diacetoxy iodobenzene; and the copper salt catalyst is tetraacetonitrile copper perchlorate.
更优选的,合成路径2中的脱水剂为1,3-二环己基碳二亚胺;合成路径3中的脱水剂为碳二亚胺及1-羟基苯并三唑的混合物。More preferably, the dehydrating agent in the synthesis route 2 is 1,3-dicyclohexylcarbodiimide; and the dehydrating agent in the synthesis route 3 is a mixture of carbodiimide and 1-hydroxybenzotriazole.
更优选的,亲核试剂均为乙硫醇、丙二酸二甲酯、2H-1,2,3-三唑、咪唑或1-甲基哌嗪。More preferably, the nucleophiles are ethanethiol, dimethyl malonate, 2H -1,2,3-triazole, imidazole or 1-methylpiperazine.
更优选的,有机溶剂均为二氯甲烷、乙腈、甲醇、乙醇、乙醚、1,2-二氯乙烷、三氯甲烷、甲苯或二甲苯。More preferably, the organic solvent is dichloromethane, acetonitrile, methanol, ethanol, diethyl ether, 1,2-dichloroethane, chloroform, toluene or xylene.
本发明还提供了上述N-取代氮杂螺癸单烯酮类化合物在制备抗肿瘤药物中的应用。The present invention also provides the use of the N-substituted azaspirodecanone compound in the preparation of anti-tumor drugs.
本发明具有以下有益效果:The present invention has the following beneficial effects:
(1)本发明提供的制备N-取代氮杂螺癸单烯酮类化合物的方法反应适中,制备的N-取代氮杂螺癸单烯酮类化合物不易开环,生物活性较好。(1) The method for preparing N-substituted azaspirodecanone compounds provided by the present invention has a moderate reaction, and the prepared N-substituted azaspirodecanone compounds are not easy to open the ring and have good biological activity.
(2)本发明提供的N-取代氮杂螺癸单烯酮类化合物具有良好的抗肿瘤活性,同时具有低毒性、较好的水溶性且纯度较高,且该结构为一种全新化合物。(2) The N-substituted azaspirodecanone compound provided by the present invention has good anti-tumor activity, low toxicity, good water solubility and high purity, and the structure is a completely new compound.
(3)本发明提供的N-取代氮杂螺癸单烯酮类化合物合成简单,原料易得,可大规模生成。(3) The N-substituted azaspirodecanone compounds provided by the present invention are simple to synthesize, the raw materials are readily available, and they can be produced on a large scale.
具体实施方式Detailed ways
以下所举实例只用于解释本发明,并非用于限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。The following examples are only used to explain the present invention and are not intended to limit the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.
实施例1~12的投料毫摩尔(mmol)比均一致。The millimole (mmol) ratios of the feed materials in Examples 1 to 12 are all consistent.
实施例1Example 1
10-(乙基硫基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二碳-6-烯-8-酮(I-6),具有如下式所示结构:10-(Ethylthio)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one (I-6) has the following structure:
。 .
本实施例中10-(乙基硫基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二碳-6-烯-8-酮的制备过程如下:The preparation process of 10-(ethylthio)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one in this embodiment is as follows:
S1、将2-苯氧基乙胺(1.2 mmol)溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1. Dissolve 2-phenoxyethylamine (1.2 mmol) in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺(1.5 mmol)、对甲苯磺酰氯(1 mmol)于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用聚酰胺进行分离纯化,得中间化合物1;S2, triethylamine (1.5 mmol) and p-toluenesulfonyl chloride (1 mmol) were sequentially dissolved in 2-phenoxyethylamine solution in an ice bath, and stirred at room temperature for 8 h. After the reaction, the reaction solution was washed with saturated brine, and then separated and purified with polyamide to obtain intermediate compound 1;
S3、将中间化合物1(0.4 mmol)、碘苯三氟乙酸酯(1 mmol)、二聚醋酸铑(0.04mmol)及氧化钙(4 mmol)混合加入到25 mL的二氯甲烷中,于50℃搅拌反应6 h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物2;S3, adding intermediate compound 1 (0.4 mmol), iodobenzene trifluoroacetate (1 mmol), dimerized rhodium acetate (0.04 mmol) and calcium oxide (4 mmol) to 25 mL of dichloromethane, stirring and reacting at 50°C for 6 h, separating and purifying the reaction solution after the reaction with polyamide to obtain intermediate compound 2;
S4、将中间化合物2(0.1 mmol)溶于体积分数为50%的乙醇溶液中,加入乙硫醇(0.2 mmol),室温下搅拌反应10 h,反应后用聚酰胺进行分离纯化,即得10-(乙基硫基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二碳-6-烯-8-酮(产率39%)。S4. The intermediate compound 2 (0.1 mmol) was dissolved in a 50% volume fraction ethanol solution, ethyl mercaptan (0.2 mmol) was added, and the reaction was stirred at room temperature for 10 h. After the reaction, polyamide was used for separation and purification to obtain 10-(ethylthio)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one (yield 39%).
10-(乙基硫基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二碳-6-烯-8-酮的核磁数据具体如下:The NMR data of 10-(ethylthio)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one are as follows:
1H NMR (400MHz, CDCl3)δ(ppm):7.79 (d,J= 8.3 Hz, 2H), 7.36 (d,J= 8.3Hz, 2H), 6.65 (d,J= 10.1 Hz, 1H), 6.05 (d,J= 10.1 Hz, 1H), 4.38 – 4.27 (m,1H), 4.13 – 4.00 (m, 2H), 3.81 – 3.61 (m, 2H), 2.92 – 2.85 (m, 2H), 2.78 –2.53 (m, 2H), 2.46 (s, 3H), 1.24 (t,J= 7.4 Hz, 3H); 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 10.1 Hz, 1H), 6.05 (d, J = 10.1 Hz, 1H), 4.38 – 4.27 (m,1H), 4.13 – 4.00 (m, 2H), 3.81 – 3.61 (m, 2H), 2.92 – 2.85 (m, 2H), 2.78 –2.53 (m, 2H), 2.46 (s, 3H), 1.24 (t, J = 7.4 Hz, 3H);
13C-NMR (400MHz, CDCl3)δ(ppm):196.9, 146.5, 144.3, 136.7, 130.3,129.9, 127.5, 94.2, 66.4, 49.5, 47.9, 43.9, 25.9, 21.6, 14.9; 13 C-NMR (400 MHz, CDCl 3 ) δ (ppm): 196.9, 146.5, 144.3, 136.7, 130.3,129.9, 127.5, 94.2, 66.4, 49.5, 47.9, 43.9, 25.9, 21.6, 14.9;
HRMS (ESI)m/z(%) forC17H21NNaO4S2(M+Na):Calcd. 390.0810Found. 390.0811。HRMS ( ESI ) m/z ( % ) for C17H21NNaO4S2 (M + Na): Calcd. 390.0810Found. 390.0811.
实施例2Example 2
2-(8-氧-4-甲苯磺基-1-氧-4-氮杂螺[4.5]癸-9-烯-6-基)丙二酸二甲酯(I-7),具有如下式所示结构:Dimethyl 2-(8-oxo-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dec-9-en-6-yl)malonate (I-7) has the structure shown in the following formula:
。 .
本实施例中2-(8-氧-4-甲苯磺基-1-氧-4-氮杂螺[4.5]癸-9-烯-6-基)丙二酸二甲酯的制备过程如下:The preparation process of dimethyl 2-(8-oxo-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dec-9-en-6-yl)malonate in this embodiment is as follows:
S1、将2-苯氧基乙胺溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺、对甲苯磺酰氯于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用硅胶进行分离纯化,得中间化合物1;S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution in an ice bath, stirring and reacting at room temperature for 8 h, washing the reaction solution with saturated brine, and then separating and purifying with silica gel to obtain intermediate compound 1;
S3、将中间化合物1、碘苯三氟乙酸酯、二聚醋酸铑及氧化钙混合加入到二氯甲烷中,于50℃搅拌反应8 h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物2;S3, adding the intermediate compound 1, iodobenzene trifluoroacetate, dimerized rhodium acetate and calcium oxide into dichloromethane, stirring and reacting at 50° C. for 8 h, and separating and purifying the reaction solution after the reaction with silica gel to obtain the intermediate compound 2;
S4、将中间化合物2溶于乙腈中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU),再加入丙二酸二甲酯,室温下搅拌反应7 h,反应后用硅胶进行分离纯化,即得2-(8-氧-4-甲苯磺基-1-氧-4-氮杂螺[4.5]癸-9-烯-6-基)丙二酸二甲酯(产率67%)。S4. The intermediate compound 2 was dissolved in acetonitrile, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added, and then dimethyl malonate was added. The mixture was stirred at room temperature for 7 h. After the reaction, it was separated and purified by silica gel to obtain dimethyl 2-(8-oxo-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dec-9-en-6-yl)malonate (yield 67%).
2-(8-氧-4-甲苯磺基-1-氧-4-氮杂螺[4.5]癸-9-烯-6-基)丙二酸二甲酯的核磁数据具体如下:The NMR data of dimethyl 2-(8-oxo-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dec-9-en-6-yl)malonate are as follows:
1H NMR (400MHz, CDCl3)δ(ppm):7.74 (d,J= 8.3 Hz, 2H), 7.33 (d,J= 8.3Hz, 2H), 6.62 (d,J= 10.2 Hz, 1H), 6.03 (d,J= 10.2 Hz, 1H), 4.06 – 3.91 (m,2H), 3.80 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.63 (m, 1H), 3.51 (d,J= 3.6Hz, 1H), 3.02 (m, 1H), 2.82 (m, 1H), 2.45 (s, 3H); 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.74 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 6.62 (d, J = 10.2 Hz, 1H), 6.03 (d, J = 10.2 Hz, 1H), 4.06 – 3.91 (m,2H), 3.80 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.63 (m, 1H), 3.51 (d, J = 3.6 Hz, 1H), 3.02 (m, 1H), 2.82 (m, 1H), 2.45 (s, 3H);
13C NMR (400MHz, CDCl3)δ(ppm):197.2, 168.4, 167.9, 145.3, 144.5,136.6, 130.5, 130.0, 127.4, 94.1, 64.9, 52.8, 52.3, 49.9, 47.3, 42.3, 37.9,21.6; 13 C NMR (400 MHz, CDCl 3 ) δ (ppm): 197.2, 168.4, 167.9, 145.3, 144.5,136.6, 130.5, 130.0, 127.4, 94.1, 64.9, 52.8, 52.3, 49.9, 47.3, 42.3, 37.9,21.6;
HRMS (ESI)m/z(%) forC20H24NO8S (M+H):Calcd. 438.1223Found. 438.1214。HRMS ( ESI ) m/z ( %) for C20H24NO8S (M+H): Calcd. 438.1223Found. 438.1214.
实施例3Example 3
4-甲苯磺基-10-(2H-1,2,3-三唑-2-基)-1-氧-4-氮杂螺[4.5]癸-6-烯-8-酮(I-5),具有如下式所示结构:4-Toluenesulfonyl-10-( 2H -1,2,3-triazol-2-yl)-1-oxo-4-azaspiro[4.5]dec-6-en-8-one (I-5) has the following structure:
。 .
本实施例中4-甲苯磺基-10-(2H-1,2,3-三唑-2-基)-1-氧-4-氮杂螺[4.5]癸-6-烯-8-酮的制备过程如下:The preparation process of 4-toluenesulfonyl-10-( 2H -1,2,3-triazol-2-yl)-1-oxo-4-azaspiro[4.5]dec-6-en-8-one in this embodiment is as follows:
S1、将2-苯氧基乙胺溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺、对甲苯磺酰氯于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用聚酰胺进行分离纯化,得中间化合物1;S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution in an ice bath, stirring and reacting at room temperature for 8 h, washing the reaction solution with saturated brine, and then separating and purifying with polyamide to obtain an intermediate compound 1;
S3、将中间化合物1、碘苯三氟乙酸酯、二聚醋酸铑及氧化钙混合加入到二氯甲烷中,于50℃搅拌反应8 h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物2;S3, adding the intermediate compound 1, iodobenzene trifluoroacetate, dimerized rhodium acetate and calcium oxide into dichloromethane, stirring and reacting at 50° C. for 8 h, and separating and purifying the reaction solution after the reaction with polyamide to obtain the intermediate compound 2;
S4、将中间化合物2溶于乙腈中,加入DBU,再加入2H-1,2,3-三唑,室温下搅拌反应8 h,反应后用聚酰胺进行分离纯化,即得4-甲苯磺基-10-(2H-1,2,3-三唑-2-基)-1-氧-4-氮杂螺[4.5]癸-6-烯-8-酮(产率47%)。S4. The intermediate compound 2 was dissolved in acetonitrile, DBU was added, and then 2H -1,2,3-triazole was added. The reaction was stirred at room temperature for 8 h. After the reaction, polyamide was used for separation and purification to obtain 4-toluenesulfonyl-10-( 2H -1,2,3-triazole-2-yl)-1-oxo-4-azaspiro[4.5]dec-6-en-8-one (yield 47%).
4-甲苯磺基-10-(2H-1,2,3-三唑-2-基)-1-氧-4-氮杂螺[4.5]癸-6-烯-8-酮的核磁数据具体如下:The NMR data of 4-toluenesulfonyl-10-( 2H -1,2,3-triazol-2-yl)-1-oxo-4-azaspiro[4.5]dec-6-en-8-one are as follows:
1H NMR (400MHz, CDCl3)δ(ppm):7.98 (d,J= 8.4 Hz, 2H), 7.67 (s, 2H),7.36 (d,J= 8.4 Hz, 2H), 6.82 (d,J= 10.2 Hz, 1H), 6.27 (dd,J= 10.2, 1.1 Hz,1H), 6.03 (m, 1H), 3.93 – 3.86 (m, 1H), 3.71 (dd,J= 16.7, 12.6 Hz, 1H), 3.47– 3.39 (m, 1H), 3.06 (m, 1H), 2.96 – 2.87 (m, 2H), 2.46 (s, 3H); 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 7.98 (d, J = 8.4 Hz, 2H), 7.67 (s, 2H),7.36 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 10.2 Hz, 1H), 6.27 (dd, J = 10.2, 1.1 Hz,1H), 6.03 (m, 1H), 3.93 – 3.86 (m, 1H), 3.71 (dd, J = 16.7, 12.6 Hz, 1H), 3.47– 3.39 (m, 1H), 3.06 (m, 1H), 2.96 – 2.87 (m, 2H), 2.46 (s, 3H);
13C NMR (400MHz, CDCl3)δ(ppm):195.2, 144.7, 144.1, 135.9, 134.6,131.3, 129.7, 128.4, 92.7, 65.7, 63.7, 46.6, 40.5, 21.7; 13 C NMR (400 MHz, CDCl 3 ) δ (ppm): 195.2, 144.7, 144.1, 135.9, 134.6,131.3, 129.7, 128.4, 92.7, 65.7, 63.7, 46.6, 40.5, 21.7;
HRMS (ESI)m/z(%) forC17H19N4O4S(M+H):Calcd. 375.1127Found. 375.1119。HRMS (ESI) m/z (%) for C 17 H 19 N 4 O 4 S (M+H): Calcd. 375.1127 Found. 375.1119.
实施例4Example 4
10-(1H-咪唑-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(I-3),具有如下式所示结构:10-( 1H -imidazol-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one (I-3) has the following structure:
。 .
本实施例中10-(1H-咪唑-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的制备过程如下:The preparation process of 10-( 1H -imidazol-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one in this embodiment is as follows:
S1、将2-苯氧基乙胺溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺、对甲苯磺酰氯于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用硅胶进行分离纯化,得中间化合物1;S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution in an ice bath, stirring and reacting at room temperature for 8 h, washing the reaction solution with saturated brine, and then separating and purifying with silica gel to obtain intermediate compound 1;
S3、将中间化合物1、碘苯三氟乙酸酯、二聚醋酸铑及氧化钙混合加入到二氯甲烷中,于50℃搅拌反应8 h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物2;S3, adding the intermediate compound 1, iodobenzene trifluoroacetate, dimerized rhodium acetate and calcium oxide into dichloromethane, stirring and reacting at 50° C. for 8 h, and separating and purifying the reaction solution after the reaction with silica gel to obtain the intermediate compound 2;
S4、将中间化合物2溶于乙腈中,加入DBU,再加入咪唑,室温下搅拌反应8 h,反应后用硅胶进行分离纯化,即得10-(1H-咪唑-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(产率61%)。S4. The intermediate compound 2 was dissolved in acetonitrile, DBU was added, and then imidazole was added. The mixture was stirred at room temperature for 8 h. After the reaction, silica gel was used for separation and purification to obtain 10-( 1H -imidazole-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one (yield 61%).
10-(1H-咪唑-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的核磁数据具体如下:The NMR data of 10-( 1H -imidazol-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.73 (d,J= 8.1 Hz, 2H), 7.69 (s, 1H),7.38 (d,J= 8.0 Hz, 2H), 7.13 (d,J= 25.3 Hz, 2H), 6.54 (d,J= 10.2 Hz, 1H),6.18 (d,J= 10.2 Hz, 1H), 5.50 (dd,J= 13.6, 4.4 Hz, 1H), 3.88 (td,J= 7.2, 4.2Hz, 1H), 3.42 – 3.32 (m, 1H), 3.32 – 3.19 (m, 2H), 3.13 (ddd,J= 8.5, 5.9, 4.2Hz, 1H), 2.98 – 2.89 (m, 1H), 2.47 (s, 3H); 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J = 8.1 Hz, 2H), 7.69 (s, 1H),7.38 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 25.3 Hz, 2H), 6.54 (d, J = 10.2 Hz, 1H),6.18 (d, J = 10.2 Hz, 1H), 5.50 (dd, J = 13.6, 4.4 Hz, 1H), 3.88 (td, J = 7.2, 4.2Hz, 1H), 3.42 – 3.32 (m, 1H), 3.32 – 3.19 (m, 2H), 3.13 (ddd, J = 8.5, 5.9, 4.2 Hz, 1H), 2.98 – 2.89 (m, 1H), 2.47 (s, 3H);
13C NMR (101 MHz, Chloroform-d)δ194.69, 145.07, 144.07, 137.40,135.91, 131.21, 130.17, 129.10, 127.58, 119.27, 92.51, 65.82, 57.47, 47.00,41.46, 21.65 13 C NMR (101 MHz, Chloroform-d) δ 194.69, 145.07, 144.07, 137.40,135.91, 131.21, 130.17, 129.10, 127.58, 119.27, 92.51, 65.82, 57.47, 47.00,41.46, 21.65
HRMS(ESI)m/z: calculated for C18H19N3O4S [M+H]+374.1173, found374.1173。HRMS(ESI) m/z : calculated for C 18 H 19 N 3 O 4 S [M+H] + 374.1173, found374.1173.
实施例5Example 5
10-(4-甲基哌嗪-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(I-4),具有如下式所示结构:10-(4-methylpiperazine-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one (I-4) has the following structure:
。 .
本实施例中10-(4-甲基哌嗪-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的制备过程如下:The preparation process of 10-(4-methylpiperazine-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one in this embodiment is as follows:
S1、将2-苯氧基乙胺溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺、对甲苯磺酰氯于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用聚酰胺进行分离纯化,得中间化合物1;S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution in an ice bath, stirring and reacting at room temperature for 8 h, washing the reaction solution with saturated brine, and then separating and purifying with polyamide to obtain intermediate compound 1;
S3、将中间化合物1、碘苯三氟乙酸酯、二聚醋酸铑及氧化钙混合加入到二氯甲烷中,于50℃搅拌反应8 h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物2;S3, adding the intermediate compound 1, iodobenzene trifluoroacetate, dimerized rhodium acetate and calcium oxide into dichloromethane, stirring and reacting at 50° C. for 8 h, and separating and purifying the reaction solution after the reaction with polyamide to obtain the intermediate compound 2;
S4、将中间化合物2溶于乙腈中,加入DBU,再加入1-甲基哌嗪,室温下反应8 h,反应后用聚酰胺进行分离纯化,即得10-(4-甲基哌嗪-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(产率36%)。S4. The intermediate compound 2 was dissolved in acetonitrile, DBU was added, and then 1-methylpiperazine was added, and the reaction was carried out at room temperature for 8 h. After the reaction, polyamide was used for separation and purification to obtain 10-(4-methylpiperazine-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one (yield 36%).
10-(4-甲基哌嗪-1-基)-4-甲苯磺基-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的核磁数据具体如下:The NMR data of 10-(4-methylpiperazine-1-yl)-4-toluenesulfonyl-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.90 – 7.70 (m, 2H), 7.34 (d,J= 8.1Hz, 2H), 6.64 (d,J= 10.2 Hz, 1H), 6.04 (dd,J= 10.2, 1.3 Hz, 1H), 4.20 – 4.11(m, 1H), 4.02 (q,J= 7.1 Hz, 1H), 3.90 – 3.81 (m, 1H), 3.75 (dd,J= 13.0, 4.2Hz, 1H), 3.66 (ddd,J= 8.1, 6.6, 4.6 Hz, 1H), 3.00 – 2.63 (m, 4H), 2.59 – 1.76(m, 12H); 1 H NMR (400 MHz, Chloroform- d ) δ 7.90 – 7.70 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 10.2 Hz, 1H), 6.04 (dd, J = 10.2, 1.3 Hz, 1H), 4.20 – 4.11 (m, 1H), 4.02 (q, J = 7.1 Hz, 1H), 3.90 – 3.81 (m, 1H), 3.75 (dd, J = 13.0, 4.2 Hz, 1H), 3.66 (ddd, J = 8.1, 6.6, 4.6 Hz, 1H), 3.00 – 2.63 (m, 4H), 2.59 – 1.76(m, 12H);
13C NMR (101 MHz, Chloroform-d)δ198.67, 146.88, 144.03, 137.43,130.35, 129.83, 127.32, 95.68, 65.80, 63.58, 55.87, 48.06, 45.83, 36.89,21.56; 13 C NMR (101 MHz, Chloroform- d ) δ 198.67, 146.88, 144.03, 137.43,130.35, 129.83, 127.32, 95.68, 65.80, 63.58, 55.87, 48.06, 45.83, 36.89,21.56;
HRMS(ESI)m/z: calculated for C20H27N3O4S [M+H]+406.1788, found406.1788。HRMS(ESI) m/z : calculated for C 20 H 27 N 3 O 4 S [M+H] + 406.1788, found 406.1788.
实施例6Example 6
4-((4-氟苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(I-2),具有如下式所示结构:4-((4-fluorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one (I-2) has the following structure:
。 .
本实施例中4-((4-氟苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的制备过程如下:The preparation process of 4-((4-fluorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one in this embodiment is as follows:
S1、将2-苯氧基乙胺溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺、对氟苯磺酰氯于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用硅胶进行分离纯化,得中间化合物1;S2, sequentially dissolving triethylamine and p-fluorobenzenesulfonyl chloride in a 2-phenoxyethylamine solution in an ice bath, stirring and reacting at room temperature for 8 h, washing the reaction solution with saturated brine, and then separating and purifying with silica gel to obtain intermediate compound 1;
S3、将中间化合物1、碘苯三氟乙酸酯、二聚醋酸铑及氧化钙混合加入到二氯甲烷中,于50℃搅拌反应8 h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物2;中间化合物2的核磁数据具体如下:S3. The intermediate compound 1, iodobenzene trifluoroacetate, dimerized rhodium acetate and calcium oxide were mixed and added into dichloromethane, and the mixture was stirred at 50°C for 8 h. The reaction solution after the reaction was separated and purified by silica gel to obtain the intermediate compound 2. The specific NMR data of the intermediate compound 2 are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.83 (dd,J= 8.6, 5.0 Hz, 2H), 7.22 (t,J= 8.4 Hz, 2H), 6.50 (d,J= 9.8 Hz, 2H), 6.22 (d,J= 9.8 Hz, 2H), 4.19 (t,J=6.1 Hz, 2H), 3.73 (t,J= 6.1 Hz, 2H); 1 H NMR (400 MHz, Chloroform-d) δ 7.83 (dd, J = 8.6, 5.0 Hz, 2H), 7.22 (t, J = 8.4 Hz, 2H), 6.50 (d, J = 9.8 Hz, 2H), 6.22 (d, J = 9.8 Hz, 2H), 4.19 (t, J =6.1 Hz, 2H), 3.73 (t, J = 6.1 Hz, 2H);
13C NMR (101 MHz, Chloroform-d)δ184.63, 165.46, 143.03, 135.04,130.50, 129.68, 116.48, 86.29, 65.56, 47.05; 13 C NMR (101 MHz, Chloroform-d) δ 184.63, 165.46, 143.03, 135.04,130.50, 129.68, 116.48, 86.29, 65.56, 47.05;
HRMS(ESI)m/z: calculated for C14H12FNO4S [M+H]+310.0545, found310.0545;HRMS(ESI) m/z : calculated for C 14 H 12 FNO 4 S [M+H] + 310.0545, found310.0545;
S4、将中间化合物2溶于乙腈中,加入DBU,再加入咪唑,室温下搅拌反应8 h,反应后用硅胶进行分离纯化,即得4-((4-氟苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(产率55%)。S4. Dissolve the intermediate compound 2 in acetonitrile, add DBU, then add imidazole, and stir the mixture at room temperature for 8 h. After the reaction, separate and purify the mixture using silica gel to obtain 4-((4-fluorophenyl)sulfonyl)-10-(1H-imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one (yield 55%).
4-((4-氟苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的核磁数据具体如下:The NMR data of 4-((4-fluorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.95 – 7.80 (m, 2H), 7.73 (s, 1H),7.34 – 7.22 (m, 2H), 7.15 (d,J= 19.7 Hz, 2H), 6.52 (d,J= 10.2 Hz, 1H), 6.20(dd,J= 10.2, 1.1 Hz, 1H), 5.51 (dd,J= 13.6, 4.4 Hz, 1H), 3.91 (ddd,J= 8.0,6.5, 4.4 Hz, 1H), 3.43 – 3.21 (m, 3H), 3.19 – 3.08 (m, 1H), 2.95 (ddd,J=15.8, 4.4, 1.2 Hz, 1H); 1 H NMR (400 MHz, Chloroform- d ) δ 7.95 – 7.80 (m, 2H), 7.73 (s, 1H),7.34 – 7.22 (m, 2H), 7.15 (d, J = 19.7 Hz, 2H), 6.52 (d, J = 10.2 Hz, 1H), 6.20(dd, J = 10.2, 1.1 Hz, 1H), 5.51 (dd, J = 13.6, 4.4 Hz, 1H), 3.91 (ddd, J = 8.0,6.5, 4.4 Hz, 1H), 3.43 – 3.21 (m, 3H), 3.19 – 3.08 (m, 1H), 2.95 (ddd, J = 15.8, 4.4, 1.2 Hz, 1H);
13C NMR (101 MHz, Chloroform-d)δ194.43, 165.73, 143.63, 137.31,134.92, 131.52, 130.39, 129.07, 119.26, 116.96, 92.75, 65.81, 57.50, 47.03,41.50; 13 C NMR (101 MHz, Chloroform- d ) δ 194.43, 165.73, 143.63, 137.31,134.92, 131.52, 130.39, 129.07, 119.26, 116.96, 92.75, 65.81, 57.50, 47.03,41.50;
HRMS(ESI)m/z: calculated for C17H16FN3O4S [M+H]+378.0916, found378.0916。HRMS(ESI) m/z : calculated for C 17 H 16 FN 3 O 4 S [M+H] + 378.0916, found378.0916.
实施例7Example 7
4-((4-氯苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(I-1),具有如下式所示结构:4-((4-chlorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one (I-1) has the following structure:
。 .
本实施例中4-((4-氯苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的制备过程如下:The preparation process of 4-((4-chlorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one in this embodiment is as follows:
S1、将2-苯氧基乙胺溶于二氯甲烷中,得2-苯氧基乙胺溶液;S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2、依次将三乙胺、对氯苯磺酰氯于冰浴下共溶于2-苯氧基乙胺溶液中,室温下搅拌反应8 h,反应后的反应溶液用饱和食盐水洗涤,再用聚酰胺进行分离纯化,得中间化合物1;S2, sequentially dissolving triethylamine and p-chlorobenzenesulfonyl chloride in a 2-phenoxyethylamine solution in an ice bath, stirring and reacting at room temperature for 8 h, washing the reaction solution with saturated brine, and then separating and purifying with polyamide to obtain an intermediate compound 1;
S3、将中间化合物1、碘苯三氟乙酸酯、二聚醋酸铑及氧化钙混合加入到二氯甲烷中,于50℃搅拌反应8 h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物2;中间化合物2的核磁数据具体如下:S3. The intermediate compound 1, iodobenzene trifluoroacetate, dimerized rhodium acetate and calcium oxide were mixed and added into dichloromethane, and the mixture was stirred at 50°C for 8 h. The reaction solution after the reaction was separated and purified by polyamide to obtain the intermediate compound 2. The specific NMR data of the intermediate compound 2 are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.80 – 7.66 (m, 2H), 7.57 – 7.43 (m,2H), 6.57 – 6.40 (m, 2H), 6.29 – 6.14 (m, 2H), 4.19 (t,J= 6.1 Hz, 2H), 3.73(t,J= 6.1 Hz, 2H); 1 H NMR (400 MHz, Chloroform-d) δ 7.80 – 7.66 (m, 2H), 7.57 – 7.43 (m,2H), 6.57 – 6.40 (m, 2H), 6.29 – 6.14 (m, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.73(t, J = 6.1 Hz, 2H);
13C NMR (101 MHz, Chloroform-d)δ184.60, 142.91, 140.06, 137.44,129.75, 129.51, 129.11, 86.36, 65.56, 47.08; 13 C NMR (101 MHz, Chloroform-d) δ 184.60, 142.91, 140.06, 137.44,129.75, 129.51, 129.11, 86.36, 65.56, 47.08;
HRMS(ESI)m/z: calculated for C14H12ClNO4S [M+H]+326.0246, found326.0246;HRMS(ESI) m/z : calculated for C 14 H 12 ClNO 4 S [M+H] + 326.0246, found326.0246;
S4、将中间化合物2溶于乙腈中,加入DBU,再加入咪唑,室温下搅拌反应8 h,反应后用聚酰胺进行分离纯化,即得4-((4-氯苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮(产率47%)。S4. The intermediate compound 2 was dissolved in acetonitrile, DBU was added, and then imidazole was added. The mixture was stirred at room temperature for 8 h. After the reaction, polyamide was used for separation and purification to obtain 4-((4-chlorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-8-one (yield 47%).
4-((4-氯苯基)磺酰基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-8-酮的核磁数据具体如下:The NMR data of 4-((4-chlorophenyl)sulfonyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-en-8-one are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.79 (d,J= 8.2 Hz, 2H), 7.73 (s, 1H),7.57 (d,J= 8.2 Hz, 2H), 7.15 (d,J= 19.7 Hz, 2H), 6.50 (d,J= 10.2 Hz, 1H),6.20 (d,J= 10.2 Hz, 1H), 5.50 (dd,J= 13.6, 4.4 Hz, 1H), 3.91 (dt,J= 11.9, 5.4Hz, 1H), 3.45 – 3.04 (m, 4H), 2.95 (dd,J= 15.8, 4.4 Hz, 1H); 1 H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H),7.57 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 19.7 Hz, 2H), 6.50 (d, J = 10.2 Hz, 1H),6.20 (d, J = 10.2 Hz, 1H), 5.50 (dd, J = 13.6, 4.4 Hz, 1H), 3.91 (dt, J = 11.9, 5.4Hz, 1H), 3.45 – 3.04 (m, 4H), 2.95 (dd, J = 15.8, 4.4 Hz, 1H);
13C NMR (151 MHz, Chloroform-d)δ194.38, 143.50, 140.65, 137.28,137.24, 131.54, 129.90, 129.07, 128.91, 119.23, 92.73, 65.78, 57.50, 47.01,41.44; 13 C NMR (151 MHz, Chloroform-d) δ 194.38, 143.50, 140.65, 137.28,137.24, 131.54, 129.90, 129.07, 128.91, 119.23, 92.73, 65.78, 57.50, 47.01,41.44;
HRMS(ESI)m/z: calculated for C17H16ClN3O4S [M+H]+394.0626, found394.0626。HRMS(ESI) m/z : calculated for C 17 H 16 ClN 3 O 4 S [M+H] + 394.0626, found394.0626.
实施例8Example 8
二甲基-2-(4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-3,8-二氧-1-氧-4-氮杂螺[4.5]十二-9-烯-6-基)丙二酸二甲酯(II-3),具有如下式所示结构:Dimethyl-2-(4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-3,8-dioxo-1-oxo-4-azaspiro[4.5]dodec-9-en-6-yl)malonate (II-3) has the structure shown in the following formula:
。 .
本实施例中二甲基-2-(4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-3,8-二氧-1-氧-4-氮杂螺[4.5]十二-9-烯-6-基)丙二酸二甲酯的制备过程如下:The preparation process of dimethyl-2-(4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-3,8-dioxo-1-oxo-4-azaspiro[4.5]dodec-9-ene-6-yl)malonate in this embodiment is as follows:
S1、将3-氯苯甲醛、氨基氰、甲醇、叔丁醇钾及N-溴代琥珀酰亚胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物7;S1. Add 3-chlorobenzaldehyde, cyanamide, methanol, potassium tert-butoxide and N-bromosuccinimide into a reaction bottle, stir evenly and react at room temperature for 8 hours. After the reaction, the reaction solution is separated and purified by polyamide to obtain intermediate compound 7.
S2、将中间化合物7、苯肼及三乙胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物8;S2, adding intermediate compound 7, phenylhydrazine and triethylamine into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with polyamide to obtain intermediate compound 8;
S3、将中间化合物8、2-(4-甲氧基苯氧基)乙酸、碳化二亚胺及1-羟基苯并三唑加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物9;S3, adding intermediate compound 8, 2-(4-methoxyphenoxy)acetic acid, carbodiimide and 1-hydroxybenzotriazole into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with polyamide to obtain intermediate compound 9;
S4、将中间化合物9、碘苯三氟乙酸酯及高氯酸四乙腈铜加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用聚酰胺进行分离纯化,得中间化合物10;S4, adding intermediate compound 9, iodobenzene trifluoroacetate and copper perchlorate tetraacetonitrile into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with polyamide to obtain intermediate compound 10;
S5、将中间化合物10溶于乙腈中,加入DBU,再加入丙二酸二甲酯,30℃下搅拌反应8 h,反应后用聚酰胺进行分离纯化,即得二甲基-2-(4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-3,8-二氧-1-氧-4-氮杂螺[4.5]十二-9-烯-6-基)丙二酸二甲酯(产率:59.6%)。S5. The intermediate compound 10 was dissolved in acetonitrile, DBU was added, and then dimethyl malonate was added. The reaction was stirred at 30°C for 8 h. After the reaction, polyamide was used for separation and purification to obtain dimethyl 2-(4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-3,8-dioxo-1-oxo-4-azaspiro[4.5]dodec-9-ene-6-yl)malonate (yield: 59.6%).
二甲基-2-(4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-3,8-二氧-1-氧-4-氮杂螺[4.5]十二-9-烯-6-基)丙二酸二甲酯的核磁数据具体如下:The NMR data of dimethyl-2-(4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-3,8-dioxo-1-oxo-4-azaspiro[4.5]dodec-9-en-6-yl)malonate are as follows:
1H NMR (400 MHz, Chloroform-d)δ8.05 (d,J= 1.7 Hz, 1H), 7.95 (dt,J=7.0, 1.6 Hz, 1H), 7.63–7.51 (m, 5H), 7.44–7.33 (m, 2H), 6.52 (d,J= 10.2 Hz,1H), 6.00 (d,J= 9.5 Hz, 1H), 4.49–4.36 (m, 2H), 3.78 (d,J= 2.7 Hz, 1H), 3.74(s, 3H), 3.74 (s, 3H), 3.24–3.13 (m, 1H), 3.03 (dd,J= 16.7, 12.8 Hz, 1H),2.77 (dd,J= 16.4, 4.4 Hz, 1H); 1 H NMR (400 MHz, Chloroform- d ) δ 8.05 (d, J = 1.7 Hz, 1H), 7.95 (dt, J =7.0, 1.6 Hz, 1H), 7.63–7.51 (m, 5H), 7.44–7.33 (m, 2H), 6.52 (d, J = 10.2 Hz,1H), 6.00 (d, J = 9.5 Hz, 1H), 4.49–4.36 (m, 2H), 3.78 (d, J = 2.7 Hz, 1H), 3.74(s, 3H), 3.74 (s, 3H), 3.24–3.13 (m, 1H), 3.03 (dd, J = 16.7, 12.8 Hz, 1H),2.77 (dd, J = 16.4, 4.4 Hz, 1H);
13C NMR (100 MHz, Chloroform-d)δ196.1, 171.1, 168.1, 167.5, 160.8,143.7, 142.8, 135.9, 134.7, 132.1, 131.6, 130.4, 123.0, 129.7, 126.6, 125.0,124.4, 95.0, 66.3, 53.1, 52.5, 49.1, 41.3,36.3; 13 C NMR (100 MHz, Chloroform- d ) δ 196.1, 171.1, 168.1, 167.5, 160.8,143.7, 142.8, 135.9, 134.7, 132.1, 131.6, 130.4, 123.0, 129.7, 126.6, 125.0,124.4, 95.0, 66.3, 53.1, 52.5, 49.1, 41.3,36.3;
HRMS(ESI-TOF) m/z: [M+H]+calcd for C27H24ClN4O7, 551.1328; found,551.1324。HRMS (ESI-TOF) m/z: [M+H] + calcd for C 27 H 24 ClN 4 O 7 , 551.1328; found,551.1324.
实施例9Example 9
4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(II-2),具有如下式所示结构:4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodecan-6-ene-3,8-dione (II-2) has the following structure:
。 .
本实施例中4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的制备过程如下:The preparation process of 4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione in this embodiment is as follows:
S1、将3-氯苯甲醛、氨基氰、甲醇、叔丁醇钾及N-溴代琥珀酰亚胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物7;S1. Add 3-chlorobenzaldehyde, cyanamide, methanol, potassium tert-butoxide and N-bromosuccinimide into a reaction bottle, stir evenly and react at room temperature for 8 hours. After the reaction, the reaction solution is separated and purified by silica gel to obtain intermediate compound 7.
S2、将中间化合物7、苯肼及三乙胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物8;S2, adding intermediate compound 7, phenylhydrazine and triethylamine into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 8;
S3、将中间化合物8、2-(4-甲氧基苯氧基)乙酸、碳化二亚胺及1-羟基苯并三唑加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物9;S3, adding intermediate compound 8, 2-(4-methoxyphenoxy)acetic acid, carbodiimide and 1-hydroxybenzotriazole into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 9;
S4、将中间化合物9、碘苯三氟乙酸酯及高氯酸四乙腈铜加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物10;S4, adding intermediate compound 9, iodobenzene trifluoroacetate and copper perchlorate tetraacetonitrile into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 10;
S5、将中间化合物10溶于乙腈中,加入DBU,再加入咪唑,30℃下搅拌反应8 h,反应后用硅胶进行分离纯化,即得4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(产率:46.6%)。S5. The intermediate compound 10 was dissolved in acetonitrile, DBU was added, and then imidazole was added. The mixture was stirred at 30°C for 8 h. After the reaction, the mixture was separated and purified using silica gel to obtain 4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-( 1H -imidazole-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione (yield: 46.6%).
4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的核磁数据具体如下:The NMR data of 4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione are as follows:
1H NMR (400 MHz, Chloroform-d)δ8.13 (s, 1H), 8.03 (d,J= 8.9 Hz, 2H),7.58–7.51 (m, 3H), 7.50–7.42 (m, 4H), 7.20 (s, 1H), 6.38 (d,J= 10.2 Hz, 1H),6.25 (d,J= 10.2 Hz, 1H), 5.72 (dd,J= 13.8, 4.3 Hz, 1H), 4.25–4.06 (m, 2H),3.50–3.38 (m, 2H), 3.06 (dd,J= 15.8, 3.8 Hz, 1H); 1 H NMR (400 MHz, Chloroform- d ) δ 8.13 (s, 1H), 8.03 (d, J = 8.9 Hz, 2H),7.58–7.51 (m, 3H), 7.50–7.42 (m, 4H), 7.20 (s, 1H), 6.38 (d, J = 10.2 Hz, 1H),6.25 (d, J = 10.2 Hz, 1H), 5.72 (dd, J = 13.8, 4.3 Hz, 1H), 4.25–4.06 (m, 2H),3.50–3.38 (m, 2H), 3.06 (dd, J = 15.8, 3.8 Hz, 1H);
HRMS (ESI-TOF) m/z: [M+H]+calcd for C25H20ClN6O3, 487.1280; found,487.1281。HRMS (ESI-TOF) m/z: [M+H] + calcd for C 2 5 H 2 0 ClN 6 O 3 , 487.1280; found,487.1281.
实施例10Example 10
4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(II-5),具有如下式所示结构:4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodecan-6-ene-3,8-dione (II-5) has the following structure:
。 .
本实施例中4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的制备过程如下:The preparation process of 4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione in this embodiment is as follows:
S1、将3-氯苯甲醛、氨基氰、甲醇、叔丁醇钾及N-溴代琥珀酰亚胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物7;S1. Add 3-chlorobenzaldehyde, cyanamide, methanol, potassium tert-butoxide and N-bromosuccinimide into a reaction bottle, stir evenly and react at room temperature for 8 hours. After the reaction, the reaction solution is separated and purified by silica gel to obtain intermediate compound 7.
S2、将中间化合物7、苯肼及三乙胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物8;S2, adding intermediate compound 7, phenylhydrazine and triethylamine into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 8;
S3、将中间化合物8、2-(4-甲氧基苯氧基)乙酸、碳化二亚胺及1-羟基苯并三唑加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物9;S3, adding intermediate compound 8, 2-(4-methoxyphenoxy)acetic acid, carbodiimide and 1-hydroxybenzotriazole into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 9;
S4、将中间化合物9、碘苯三氟乙酸酯及高氯酸四乙腈铜加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物10;S4, adding intermediate compound 9, iodobenzene trifluoroacetate and copper perchlorate tetraacetonitrile into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 10;
S5、将中间化合物10溶于乙腈中,加入DBU,再加入乙硫醇,30℃下搅拌反应8 h,反应后用硅胶进行分离纯化,即得4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(产率:42.3%)。S5. The intermediate compound 10 was dissolved in acetonitrile, DBU was added, and then ethyl mercaptan was added. The mixture was stirred at 30°C for 8 h. After the reaction, the mixture was separated and purified using silica gel to obtain 4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione (yield: 42.3%).
4-(3-(3-氯苯基)-1-苯基-1H-1,2,4-三唑-5-基)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的核磁数据具体如下:The NMR data of 4-(3-(3-chlorophenyl)-1-phenyl- 1H -1,2,4-triazol-5-yl)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodecan-6-ene-3,8-dione are as follows:
1H NMR (400 MHz, Chloroform-d)δ8.06 (d,J= 1.8 Hz, 1H), 7.95 (td,J=6.8, 1.7 Hz, 1H), 7.65 (dd,J= 8.2, 1.5 Hz, 2H), 7.59–7.55 (m, 1H), 7.55–7.49(m, 2H), 7.42–7.35 (m, 2H), 6.56 (d,J= 10.1 Hz, 1H), 6.12 (dd,J= 10.1, 1.0Hz, 1H), 4.75 (d,J= 14.4 Hz, 1H), 4.37 (d,J= 14.4 Hz, 1H), 4.23 (dd,J= 13.0,5.0 Hz, 1H), 3.12–2.87 (m, 3H), 2.69 (dd,J= 12.5, 7.5 Hz, 1H), 1.33–1.28 (m,3H); 1 H NMR (400 MHz, Chloroform- d ) δ 8.06 (d, J = 1.8 Hz, 1H), 7.95 (td, J =6.8, 1.7 Hz, 1H), 7.65 (dd, J = 8.2, 1.5 Hz, 2H), 7.59–7.55 (m, 1H), 7.55–7.49(m, 2H), 7.42–7.35 (m, 2H), 6.56 (d, J = 10.1 Hz, 1H), 6.12 (dd, J = 10.1, 1.0Hz, 1H), 4.75 (d, J = 14.4 Hz, 1H), 4.37 (d, J = 14.4 Hz, 1H), 4.23 (dd, J = 13.0,5.0 Hz, 1H), 3.12–2.87 (m, 3H), 2.69 (dd, J = 12.5, 7.5 Hz, 1H), 1.33–1.28 (m,3H);
13C NMR (100 MHz, Chloroform-d)δ196.1, 169.7, 160.1, 144.4, 143.3,137.0, 134.8, 133.4, 131.7, 130.0, 130.0, 129.7, 129.7, 126.4, 124.3, 124.3,94.9, 68.0, 49.1, 43.1, 26.2, 15.1。 13 C NMR (100 MHz, Chloroform- d ) δ 196.1, 169.7, 160.1, 144.4, 143.3,137.0, 134.8, 133.4, 131.7, 130.0, 130.0, 129.7, 129.7, 126.4, 124.3, 124.3,94.9, 68.0, 49.1, 43.1, 26.2, 15.1.
实施例11Embodiment 11
4-(2,6-二氯苯)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮4-(2,6-Dichlorophenyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione
(II-7),具有如下式所示结构:(II-7) has the following structure:
。 .
本实施例中4-(2,6-二氯苯)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的制备过程如下:The preparation process of 4-(2,6-dichlorobenzene)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione in this embodiment is as follows:
S1、将对氨基苯酚、乙醇酸及二甲基二氰胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物3;S1, adding p-aminophenol, glycolic acid and dimethyl dicyanamide into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 3;
S2、将中间化合物3、二乙酰氧基碘苯、高氯酸四乙腈铜及二氯甲烷加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物4;S2, adding intermediate compound 3, diacetoxyiodobenzene, copper perchlorate tetraacetonitrile and dichloromethane into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 4;
S3、将中间化合物4、DBU、四氢呋喃及2,6-二氯苄基氯加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物5;S3, adding intermediate compound 4, DBU, tetrahydrofuran and 2,6-dichlorobenzyl chloride into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 5;
S4、将中间化合物5溶于乙腈中,加入DBU,再加入咪唑,30℃下搅拌反应8 h,反应后用硅胶进行分离纯化,即得4-(2,6-二氯苯)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(产率:53.3%)。S4. The intermediate compound 5 was dissolved in acetonitrile, DBU was added, and then imidazole was added. The mixture was stirred at 30°C for 8 h. After the reaction, silica gel was used for separation and purification to obtain 4-(2,6-dichlorobenzene)-10-( 1H -imidazole-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione (yield: 53.3%).
4-(2,6-二氯苯)-10-(1H-咪唑-1-基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的核磁数据具体如下:The NMR data of 4-(2,6-dichlorophenyl)-10-( 1H -imidazol-1-yl)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.53 (s, 1H), 7.41–7.36 (m, 2H), 7.31(dd,J= 9.1, 6.8 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 6.06 (d,J= 10.2 Hz, 1H),5.79 (d,J= 10.2 Hz, 1H), 5.36 (d,J= 15.2 Hz, 1H), 5.22 (dd,J= 13.4, 4.3 Hz,1H), 4.59 (d,J= 15.2 Hz, 1H), 4.26 (d,J= 13.8 Hz, 1H), 3.70 (d,J= 13.8 Hz,1H), 3.34 (dd,J= 15.6, 13.5 Hz, 1H), 2.91 (dd,J= 15.6, 4.3 Hz, 1H); 1 H NMR (400 MHz, Chloroform- d ) δ 7.53 (s, 1H), 7.41–7.36 (m, 2H), 7.31 (dd, J = 9.1, 6.8 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 6.06 (d, J = 10.2 Hz, 1H),5.79 (d, J = 10.2 Hz, 1H), 5.36 (d, J = 15.2 Hz, 1H), 5.22 (dd, J = 13.4, 4.3 Hz,1H), 4.59 (d, J = 15.2 Hz, 1H), 4.26 (d, J = 13.8 Hz, 1H), 3.71 (d, J = 1 13.8 Hz,1H), 3.34 (dd, J = 15.6, 13.5 Hz, 1H), 2.91 (dd, J = 15.6, 4.3 Hz, 1H);
13C NMR (100 MHz, Chloroform-d)δ193.9, 168.3, 144.4, 136.8, 136.5,131.2, 131.1, 130.3, 130.1, 129.1, 118.3, 92.2, 66.4, 54.8, 40.5, 39.2; 13 C NMR (100 MHz, Chloroform- d ) δ 193.9, 168.3, 144.4, 136.8, 136.5,131.2, 131.1, 130.3, 130.1, 129.1, 118.3, 92.2, 66.4, 54.8, 40.5, 39.2;
HRMS(ESI-TOF) m/z: [M+H]+calcd for C18H16N3O3Cl2, 392.0563, found,392.0577。HRMS (ESI-TOF) m/z: [M+H] + calcd for C 18 H 16 N 3 O 3 Cl 2 , 392.0563, found,392.0577.
实施例12Example 12
4-(4-氯苯)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(II-8),具有如下式所示结构:4-(4-chlorophenyl)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodecan-6-ene-3,8-dione (II-8) has the following structure:
。 .
本实施例中4-(4-氯苯)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的制备过程如下:The preparation process of 4-(4-chlorobenzene)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione in this embodiment is as follows:
S1、将对氨基苯酚、乙醇酸及二甲基二氰胺加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物3;S1, adding p-aminophenol, glycolic acid and dimethyl dicyanamide into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 3;
S2、将中间化合物3、二乙酰氧基碘苯、高氯酸四乙腈铜及二氯甲烷加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物4;S2, adding intermediate compound 3, diacetoxyiodobenzene, copper perchlorate tetraacetonitrile and dichloromethane into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 4;
S3、将中间化合物4、DBU、四氢呋喃及2,6-二氯苄基氯加入到反应瓶中,搅拌均匀后室温下反应8h,反应后的反应溶液用硅胶进行分离纯化,得中间化合物5;S3, adding intermediate compound 4, DBU, tetrahydrofuran and 2,6-dichlorobenzyl chloride into a reaction bottle, stirring evenly and reacting at room temperature for 8 hours, and separating and purifying the reaction solution after the reaction with silica gel to obtain intermediate compound 5;
S4、将中间化合物5溶于乙腈中,加入DBU,再加入乙硫醇,30℃下搅拌反应8 h,反应后用硅胶进行分离纯化,即得4-(4-氯苯)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮(产率:41.1%)。S4. The intermediate compound 5 was dissolved in acetonitrile, DBU was added, and then ethyl mercaptan was added. The mixture was stirred at 30°C for 8 h. After the reaction, silica gel was used for separation and purification to obtain 4-(4-chlorobenzene)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione (yield: 41.1%).
4-(4-氯苯)-10-(乙硫基)-1-氧-4-氮杂螺[4.5]十二-6-烯-3,8-二酮的核磁数据具体如下:The NMR data of 4-(4-chlorophenyl)-10-(ethylthio)-1-oxo-4-azaspiro[4.5]dodec-6-ene-3,8-dione are as follows:
1H NMR (400 MHz, Chloroform-d)δ7.33–7.27 (m, 4H), 6.38 (d,J= 10.1 Hz,1H), 6.06 (dd,J= 10.1, 1.1 Hz, 1H), 4.57 (d,J= 13.5 Hz, 1H), 4.48–4.37 (m,3H), 3.19 (dd,J= 13.0, 4.4 Hz, 1H), 3.01 (dd,J= 16.2, 13.0 Hz, 1H), 2.81 (td,J= 16.2, 4.4, 1.1 Hz, 1H), 2.34 (td,J= 11.8, 7.4 Hz, 1H), 2.11 (dd,J= 11.8,7.4 Hz, 1H), 1.13 (t,J= 7.4 Hz, 3H); 1 H NMR (400 MHz, Chloroform- d ) δ 7.33–7.27 (m, 4H), 6.38 (d, J = 10.1 Hz,1H), 6.06 (dd, J = 10.1, 1.1 Hz, 1H), 4.57 (d, J = 13.5 Hz, 1H), 4.48–4.37 (m,3H), 3.19 (dd, J = 13.0, 4.4 Hz, 1H), 3.01 (dd, J = 16.2, 13.0 Hz, 1H), 2.81 (td, J = 16.2, 4.4, 1.1 Hz, 1H), 2.34 (td, J = 11.8, 7.4 Hz, 1H), 2.13 (dd, J = 13.5, 7.4 Hz, 1H). = 11.8,7.4 Hz, 1H), 1.13 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, Chloroform-d)δ196.3, 170.7, 146.1, 134.4, 134.3,132.5, 130.2, 129.0, 93.8, 68.0, 48.8, 43.3, 42.4, 25.2, 14.6; 13 C NMR (100 MHz, Chloroform- d ) δ 196.3, 170.7, 146.1, 134.4, 134.3,132.5, 130.2, 129.0, 93.8, 68.0, 48.8, 43.3, 42.4, 25.2, 14.6;
HRMS(ESI-TOF) m/z: [M+H]+calcd for C17H19NO3SCl, 352.0769, found,352.0785。HRMS (ESI-TOF) m/z: [M+H] + calcd for C 17 H 19 NO 3 SCl, 352.0769, found,352.0785.
实施例13 抗肿瘤活性测定Example 13 Antitumor Activity Assay
采用磺酰罗丹明B(SRB)法检测贴壁细胞的增殖。阳性对照药为苯达莫斯汀和伏立诺他。将处于对数生长期的人乳腺癌细胞MDA-MB-231接种于96孔板(200 µL/孔),于37℃及5%二氧化碳浓度的条件下培养24 h使其贴壁。然后用不同浓度的待测化合物处理,每个浓度设置3个复孔,并设置相应的空白对照和调零孔。孵育72 h后,用10%三氯乙酸(TCA)在4℃下固定1 h,倾倒固定液,用蒸馏水冲洗5次,自然风干。固定完成后的细胞用0.4%(w/v)SRB室温染色20 min,倾倒液体,用1%冰乙酸洗涤5次,去除多余的未结合的SRB染液,自然风干。结合SRB的蛋白用10 mM的三(羟甲基氨基)甲烷(Tris)溶解,水平摇床震荡20 min,以等量DMSO作为载体对照,苯达莫司汀(Bendamustiune,双功能烷化剂)和伏立诺他(SAHA,HDAC抑制剂)作为阳性对照。用细胞活力分析仪(Beckman-Coulter)计数细胞数。存活率为化合物处理细胞数与载体处理细胞数之比,从各化合物的剂量-响应曲线中获得IC50值。实验分三次进行,数据用平均值表示。The proliferation of adherent cells was detected by sulforhodamine B (SRB) method. Bendamustine and vorinostat were used as positive control drugs. Human breast cancer MDA-MB-231 cells in logarithmic growth phase were seeded in 96-well plates (200 µL/well) and cultured at 37°C and 5% carbon dioxide for 24 h to adhere to the plate. Then, the cells were treated with different concentrations of the test compound, with 3 replicates for each concentration, and corresponding blank controls and zero wells were set. After incubation for 72 h, the cells were fixed with 10% trichloroacetic acid (TCA) at 4°C for 1 h, the fixative was poured out, the cells were rinsed with distilled water 5 times, and the cells were naturally air-dried. After fixation, the cells were stained with 0.4% (w/v) SRB at room temperature for 20 min, the liquid was poured out, and the cells were washed with 1% glacial acetic acid 5 times to remove the excess unbound SRB dye, and the cells were naturally air-dried. The protein bound to SRB was dissolved with 10 mM tris (hydroxymethylamino) methane (Tris) and shaken on a horizontal shaker for 20 min. An equal amount of DMSO was used as a vehicle control, and bendamustine (Bendamustiune, a bifunctional alkylating agent) and vorinostat (SAHA, an HDAC inhibitor) were used as positive controls. The number of cells was counted using a cell viability analyzer (Beckman-Coulter). The viability was the ratio of the number of cells treated with the compound to the number of cells treated with the vehicle, and the IC 50 value was obtained from the dose-response curve of each compound. The experiment was performed three times, and the data are expressed as the average value.
对实施例1~12的化合物进行了体外抗肿瘤活性实验,以苯达莫司汀(Bendamustiune,双功能烷化剂)和伏立诺他(SAHA,HDAC抑制剂)作为阳性药物对照,测试了目标化合物对人乳腺癌细胞MDA-MB-231的体外细胞生长抑制能力,结果如表1所示。由表1可知,将中间化合物2中的亲核位点加成以后,制备的N-取代氮杂螺癸单烯酮类化合物的活性除实施例4和实施例5以外,其余N-取代氮杂螺癸单烯酮类化合物的活性均相对于亲核位点加成以前有显著的提高;同时,实施例1~12制备的N-取代氮杂螺癸单烯酮类化合物对肺癌细胞系A549、和宫颈癌细胞系Hela细胞也表现出一定的抑制增殖活性(IC500.13~4.66μM)。The compounds of Examples 1 to 12 were subjected to in vitro antitumor activity experiments, and bendamustine (Bendamustiune, a bifunctional alkylating agent) and vorinostat (SAHA, an HDAC inhibitor) were used as positive drug controls to test the in vitro cell growth inhibition ability of the target compounds on human breast cancer cells MDA-MB-231, and the results are shown in Table 1. As can be seen from Table 1, after the nucleophilic site in the intermediate compound 2 is added, the activities of the prepared N-substituted azaspirodecanone compounds are significantly improved compared with those before the addition of the nucleophilic site, except for Examples 4 and 5; at the same time, the N-substituted azaspirodecanone compounds prepared in Examples 1 to 12 also exhibited certain proliferation inhibition activity (IC 50 0.13~4.66μM) on lung cancer cell line A549 and cervical cancer cell line Hela cells.
表1Table 1
实施例14 急性毒性测定及化合物溶解行为分析Example 14 Acute toxicity assay and compound dissolution behavior analysis
对实施例1~7中制备的中间化合物2及N-取代氮杂螺癸单烯酮类化合物进行急性毒性测试,将SPF级Km小鼠分为两组,两组小鼠分别给药不同剂量的中间化合物2及N-取代氮杂螺癸单烯酮类化合物,给药剂量均为120~1000mg/kg,对给药后的小鼠进行14天观察。结果表明,中间化合物2组有小鼠死亡,而N-取代氮杂螺癸单烯酮类化合物组小鼠均未出现死亡现象,且小鼠行为无明显变化,饮食正常,无异常分泌物,体重持续增长;表明中间化合物2毒性高于N-取代氮杂螺癸单烯酮类化合物,即将中间化合物2中的亲核位点加成以后可降低毒性。同时,经体内外活性研究结果表明,中间化合物2在单侧α,β-不饱和酮结构被消除或进行其他类型的改造后合成的N-取代氮杂螺癸单烯酮类化合物中的某些化合物(I-2)的活性可提升至纳摩尔级水平且毒性大幅降低;动物毒性实验表明,中间化合物2的LD50为66.1~80 mg/kg,属于中等毒性范围,而N-取代氮杂螺癸单烯酮类化合物对Km小鼠半数致死量大于120~1000 mg/kg。The intermediate compound 2 and N-substituted azaspirodecanone compounds prepared in Examples 1 to 7 were subjected to acute toxicity tests, and SPF-grade Km mice were divided into two groups. The two groups of mice were administered with different doses of intermediate compound 2 and N-substituted azaspirodecanone compounds, and the doses were 120 to 1000 mg/kg, and the mice after administration were observed for 14 days. The results showed that there were mice deaths in the intermediate compound 2 group, while there were no deaths in the N-substituted azaspirodecanone compound group, and there was no obvious change in the behavior of the mice, the diet was normal, there was no abnormal secretion, and the weight continued to grow; indicating that the toxicity of intermediate compound 2 is higher than that of N-substituted azaspirodecanone compounds, that is, the toxicity can be reduced after the addition of the nucleophilic site in intermediate compound 2. At the same time, the results of in vivo and in vitro activity studies showed that the activity of some compounds (I-2) in the N-substituted azaspirodecanone compounds synthesized after the unilateral α, β-unsaturated ketone structure of intermediate compound 2 was eliminated or other types of modifications were performed, and the toxicity was greatly reduced; animal toxicity experiments showed that the LD50 of intermediate compound 2 was 66.1~80 mg/kg, which was in the moderate toxicity range, while the median lethal dose of N-substituted azaspirodecanone compounds for Km mice was greater than 120~1000 mg/kg.
进行动物水平抗肿瘤活性实验,将24只BALB/c荷瘤小鼠随机分为4组,每组6只,分别为空白对照组、阳性药物对照-苯达莫斯汀对照组10 mg/kg、低剂量N-取代氮杂螺癸单烯酮类化合物组10 mg/kg、高剂量N-取代氮杂螺癸单烯酮类化合物组20 mg/kg;四组小鼠每两天给药一次,连续给药7次,观察14天内小鼠体征。结果表明,N-取代氮杂螺癸单烯酮类化合物对BALB/c乳腺癌模型小鼠抑瘤率达61%;经过组织病理切片及染色结果显示,这些化合物并未引发正常组织明显的病变。即本发明的N-取代氮杂螺癸单烯酮类化合物在保留螺癸烯酮基本结构的前提下,减少了母核上的蛋白毒性位点,从而降低了化合物在体内的毒性。Animal level anti-tumor activity experiment was conducted, 24 BALB/c tumor-bearing mice were randomly divided into 4 groups, 6 mice in each group, namely blank control group, positive drug control-bendamustine control group 10 mg/kg, low-dose N-substituted azaspirodecanone compound group 10 mg/kg, high-dose N-substituted azaspirodecanone compound group 20 mg/kg; four groups of mice were given medication once every two days, for 7 consecutive times, and the physical signs of the mice were observed within 14 days. The results showed that the tumor inhibition rate of N-substituted azaspirodecanone compounds on BALB/c breast cancer model mice reached 61%; the results of tissue pathological sections and staining showed that these compounds did not cause obvious lesions in normal tissues. That is, the N-substituted azaspirodecanone compounds of the present invention reduce the protein toxicity sites on the mother nucleus while retaining the basic structure of spirodecanone, thereby reducing the toxicity of the compounds in vivo.
同时,由于亲核位点加成反应是在乙醇/水或乙腈/有机碱的条件下进行,残留的过渡金属盐溶于该体系,最终产物经该过程后得到进一步的纯化,使制得的N-取代氮杂螺癸单烯酮类化合物纯度提高。At the same time, since the nucleophilic site addition reaction is carried out under the conditions of ethanol/water or acetonitrile/organic base, the residual transition metal salt is dissolved in the system, and the final product is further purified after the process, so that the purity of the prepared N-substituted azaspirodecanone compound is improved.
此外,脂水分配系数是一个很重要的指标,决定着化合物在体内的的分布情况。合适的水溶性有助于药物溶解在体液中,在作用部位达到有效浓度,从而产生治疗效果。对抗肿瘤药物来说,较好的水溶性除了便于吸收分布外,还可以使药物能够快速的排出,减少蓄积及对肾脏的毒副作用。N-取代氮杂螺癸单烯酮类化合物中引入了一个或多个杂原子使得其与水形成氢键的可能性增加,相较于中间化合物2而言其溶解行为有一定改善,如在进行动物水平抗肿瘤活性探究实验时明显观察到2 mg的N-取代氮杂螺癸单烯酮类化合物在200μL的DMSO及1.8 mL的橄榄油溶液中完全溶解,而1 mg的中间化合物2在200 μL的DMSO及1.8mL的橄榄油溶液中仍然是混悬液。如此更有助于提高化合物与靶点结合力,改善脂水分配系数从而改善其药理活性。In addition, the lipid-water partition coefficient is a very important indicator that determines the distribution of the compound in the body. Appropriate water solubility helps the drug dissolve in body fluids and reach an effective concentration at the site of action, thereby producing a therapeutic effect. For anti-tumor drugs, good water solubility not only facilitates absorption and distribution, but also allows the drug to be quickly excreted, reducing accumulation and toxic side effects on the kidneys. The introduction of one or more heteroatoms into N-substituted azaspirodecanone compounds increases the possibility of forming hydrogen bonds with water, and its dissolution behavior is improved compared to intermediate compound 2. For example, in the animal level anti-tumor activity exploration experiment, it was clearly observed that 2 mg of N-substituted azaspirodecanone compounds were completely dissolved in 200 μL of DMSO and 1.8 mL of olive oil solution, while 1 mg of intermediate compound 2 was still a suspension in 200 μL of DMSO and 1.8 mL of olive oil solution. This is more helpful to improve the binding force between the compound and the target, improve the lipid-water partition coefficient, and thus improve its pharmacological activity.
本发明按照上述实施例进行了说明,应当理解,上述实施例不以任何形式限定本发明,凡采用等同替换或等效变换方式所获得的技术方案,均落在本发明的包含范围之内。The present invention has been described according to the above embodiments. It should be understood that the above embodiments do not limit the present invention in any form. Any technical solutions obtained by equivalent replacement or equivalent transformation shall fall within the scope of the present invention.
Claims (8)
- An n-substituted azaspiro-decarenone compound characterized by the specific structural formula:。
- 2. The process for the preparation of an N-substituted azaspiro-decarenone compound of claim 1, selected from the following synthetic routes:Synthesis path 1: dissolving a compound A and a compound B in an organic solvent, reacting under the action of a catalyst to obtain an intermediate compound 1, adding an oxidant to react to obtain an intermediate compound 2, and adding a nucleophile to react to obtain an N-substituted azaspiro-decamonoalkone compound shown in a formula I; the synthetic route is as follows:;synthesis path 2: dissolving a compound C and a compound D in an organic solvent, reacting under the action of a dehydrating agent to obtain an intermediate compound 3, adding an oxidant to react to obtain an intermediate compound 4, adding a compound B, reacting under the action of a catalyst to obtain an intermediate compound 5, and adding a nucleophile to react to obtain the N-substituted azaspiro-decone compound shown in the formula II; the synthetic route is as follows:;Synthesis path 3: adding a dehydrating agent into the compound E and the compound F to react to obtain an intermediate compound 6, adding an oxidant and a copper salt catalyst to react to obtain an intermediate compound 5, and adding a nucleophile to react to obtain the N-substituted azaspiro-decamonoalkenone compound shown in the formula II; the synthetic route is as follows:;R, R 2、R3, X and N in the synthetic routes 1-3 are corresponding and consistent with the structures of the N-substituted azaspiro-decarenone compounds I-1-II-12 in claim 1.
- 3. The process for the preparation of N-substituted azaspiro-decone compounds as claimed in claim 2, wherein the catalysts are selected from triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene or potassium tert-butoxide.
- 4. The method of preparing an N-substituted azaspiro-decarenone compound of claim 2, wherein the oxidizing agents are each selected from iodobenzene trifluoroacetate or diacetoxyiodobenzene; the copper salt catalyst is tetraacetonitrile copper perchlorate.
- 5. The method for preparing an N-substituted azaspiro-decarenone compound according to claim 2, wherein the dehydrating agent in the synthetic pathway 2 is 1, 3-dicyclohexylcarbodiimide; the dehydrating agent in the synthetic route 3 is a mixture of carbodiimide and 1-hydroxybenzotriazole.
- 6. The method for preparing an N-substituted azaspiro-decarenone compound according to claim 2, wherein the nucleophiles are each selected from the group consisting of ethanethiol, dimethyl malonate, 2H-1,2, 3-triazole, imidazole, and 1-methylpiperazine.
- 7. The method for preparing an N-substituted azaspiro-decarenone compound according to claim 2, wherein the organic solvents are selected from dichloromethane, acetonitrile, methanol, ethanol, diethyl ether, 1, 2-dichloroethane, chloroform, toluene, and xylene.
- 8. The use of an N-substituted azaspiro-decarenone compound of claim 1 for the preparation of an antitumor drug.
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