Synthesis method of 7,8-dihydroindazol-5(6H)-one

Abstract

The present invention belongs to the field of organic chemical industry, and particularly relates to a method for synthesizing 7,8-dihydroindazin-5(6H)-one. Using O-acetyl ketoxime and 2-alkyl-substituted cyclohexanedione as raw materials, under the catalysis of a copper salt, heating to 80-120 °C in a nitrogen atmosphere, various substituted 7,8-dihydroindazin-5(6H)-one derivatives are obtained in one step through consecutive C-C radical coupling, intramolecular cyclization, and rearrangement reactions. The raw materials and catalysts used in the present invention are cheap and easily available, the substrate range is wide, and the functional group compatibility is good. This method has many advantages such as a short synthesis route and convenient separation and purification, and has important practical application value for the synthesis of 7,8-dihydroindazin-5(6H)-one derivatives.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical industry, and particularly relates to a method for synthesizing 7,8-dihydroindazin-5(6H)-one. Background Art

[0002] The bicyclic skeleton of 7,8-dihydroindazin-5(6H)-one widely exists in natural products and shows significant biological activities. For example, Rhazinicine belongs to the natural products of the Rhazinilam family. In vitro cell experiments have proved that it is a good cancer cell inhibitor, with an anti-tumor mechanism similar to that of paclitaxel, and can induce and promote the polymerization of tubulin and stabilize cell microtubules. Eburnamonine is an orally active drug with cerebral and vasodilatory activities and can relieve memory impairment. Fusing an aromatic ring on the pyrrole ring of the 7,8-dihydroindazin-5(6H)-one skeleton can obtain a new class of HSP90 inhibitors and 5-HT3 receptor antagonists. However, there are very few methods for constructing this bicyclic 7,8-dihydroindazin-5(6H)-one skeleton.

[0003]

[0004] Method 1: Appropriate functional groups are first introduced at the N- or 2-position of pyrrole through reactions, and then 7,8-dihydroindazin-5(6H)-one is constructed through intramolecular N-acylation [Tetrahedron 2015, 71, 1276; Green Chem. 2016, 18, 2453; Tetrahedron Lett. 2004, 45, 6587.], Friedel-Crafts acylation [Synthesis 2016, 48, 1910; J. Org. Chem. 2019, 84, 10785.], or radical cyclization reaction [Org. Lett. 2006, 8, 4561; Org. Lett. 2010, 12, 368.]. However, for these methods, a pyrrole ring must be introduced into the substrate, some require the use of stoichiometric oxidants or expensive transition metal catalysts, and some substrates are not easily obtained.

[0005]

[0006] Method 2: Starting from N-(3-iodoallyl)-succinimide, vinyl carbanions are generated under the action of Bu 3 SnSiMe 3 and then undergo intramolecular addition, followed by dehydration under acidic conditions to construct 7,8-dihydroindazin-5(6H)-one [J. Org. Chem. 1993, 58, 6503.]. This method uses expensive reagents, the double bond in the raw material must be in a cis configuration, and the principle is not easily obtained.

[0007]

[0008] Method 3: Motherwell used electron-deficient allenes to react with dimethylaminoacetaldehyde acetal to form enamine, and then acryloyl chloride underwent a double nucleophilic reaction to form a six-membered lactam ring, and finally further cyclized under acidic conditions to form the second pyrrole ring [Synlett 2007, 431.]; Tokuyama used N-acetal-substituted ynamides to first undergo intramolecular addition under the action of a gold catalyst, and then further cyclized to form 7,8-dihydroindazin-5(6H)-one [Angew.Chem.Int.Ed. 2013, 52, 7168.]. Both of these methods obtained the final product through the same type of key intermediate, but the disadvantages are that expensive catalysts are used and the starting material structures are complex and difficult to obtain.

[0009]

[0010] Method 4: [J.Chem.Soc.Chem.Commun. 1984, 354; J.Chem.Soc.Perkin Tans.I 1988, 161.] 7,8-Dihydroindazin-5(6H)-one was formed by the reaction of 2-alkyl-2-acylmethyl-substituted cyclohexanedione with ammonium acetate. The disadvantage of this method is that the starting material is not easy to obtain, and a large amount of O-alkylation by-products will be produced when 2-monosubstituted 1,3-cyclohexanedione reacts with halides to form 2,2-disubstituted-1,3-cyclohexanedione because the carbanion has an enolate resonance form.

[0011] Summary of the Invention

[0012] O-acyl oxime compounds are very easy to prepare from aldehydes and ketones, and their N-O bonds are easily broken, thus showing extremely high reactivity. Nowadays, O-acyl oximes have been widely used in a series of addition, coupling, and cyclization reactions, and various types of heterocyclic skeletons can be constructed based on O-acyl oximes. At the same time, O-acyl oxime itself can also be used as an internal oxidant. If the reaction involves an oxidation process, the use of additional oxidants can be avoided, making the reaction more green and efficient.

[0013] The present invention provides a convenient method for synthesizing a series of 7,8-dihydroindazin-5(6H)-one compounds 3 by using O-acyl oxime 1 and 2-monosubstituted-1,3-cyclohexanedione 2 as starting materials under the catalysis of cheap copper salts through a one-step reaction. The synthesis route is as follows:

[0014]

[0015] R 1Including H, 5,5-dimethyl, 4,4-dimethyl, 5-oxo;

[0016] R 2 Including methyl, benzyl, various substituted benzyl, 2-furyl, 2-thienyl, 3-pyridyl, allyl, 2-cyanoethyl, 2-methoxycarbonylethyl;

[0017] R 3 Is various substituted phenyl, 2-furyl, 2-thienyl, 2-(N-methylpyrrole)yl, 3-pyridyl;

[0018] The copper salt catalyst used is CuCl, CuBr, CuI, Cu(OAc) 2 , CuSCN, CuCN, CuCl 2 , CuBr, CuTc, and one of them, preferably CuBr;

[0019] The solvent used is benzene, toluene, xylene, n-butyl acetate, ethyl acetate, dichloroethane, preferably n-butyl acetate;

[0020] The reaction conditions are as follows: Mix O-acyl ketoxime 1, 2-substituted 1,3-cyclohexanedione 2, and copper salt, and then add an appropriate amount of solvent. React under N 2 atmosphere for 1 - 5 h, and obtain 7,8-dihydroindazin-5(6H)-one compounds 3 through subsequent separation and purification.

[0021] The feed ratio of compound 1: compound 2: [Cu] catalyst = 1 - 1.8:1:0.01 - 0.2, preferably 1.3:1:0.1;

[0022] The reaction temperature is 80 - 120 °C, preferably 90 °C.

[0023] The beneficial effects of the present invention: (1) The raw materials are cheap and easily available; (2) The reaction does not require the use of precious metal catalysts, and only cheap copper salts can catalyze the reaction; (3) This method has a wide application range, and various substituted substrates can participate in the reaction, ensuring the diversity of product structures; (4) The reaction steps are short, only one-step reaction, simple operation, and convenient separation. In short, our method is more simple, efficient and low-cost compared with the existing methods, so it has a wider application prospect. Brief Description of the Drawings

[0024] Figure 1 , Figure 2 Is for compound 3aa 1 H NMR and 13 C NMR spectra;

[0025] Figure 3 , Figure 4 Is for compound 3ba1 1H NMR and 13 13C NMR spectra;

[0026] Figure 5 、 Figure 6 are the 1 1H NMR and 13 13C NMR spectra of compound 3ca;

[0027] Figure 7 、 Figure 8 are the 1 1H NMR and 13 13C NMR spectra of compound 3da;

[0028] Figure 9 、 Figure 10 are the 1 1H NMR and 13 13C NMR spectra of compound 3ea;

[0029] Figure 11 、 Figure 12 are the 1 1H NMR and 13 13C NMR spectra of compound 3fa;

[0030] Figure 13 、 Figure 14 are the 1 1H NMR and 13 13C NMR spectra of compound 3ga;

[0031] Figure 15 、 Figure 16 are the 1 1H NMR and 13 13C NMR spectra of compound 3ha;

[0032] Figure 17 、 Figure 18 are the 1 1H NMR and 13 13C NMR spectra of compound 3ia;

[0033] Figure 19 、 Figure 20 are the 1 1H NMR and 13 13C NMR spectra of compound 3ja;

[0034] Figure 21 、 Figure 22 are the 1 1H NMR and 13 13C NMR spectra of compound 3ka;

[0035] Figure 23 、 Figure 24For the 1 H NMR and 13 C NMR spectra of compound 3la;

[0036] Figure 25 、 Figure 26 For the 1 H NMR and 13 C NMR spectra of compound 3ma;

[0037] Figure 27 、 Figure 28 For the 1 H NMR and 13 C NMR spectra of compound 3na;

[0038] Figure 29 、 Figure 30 For the 1 H NMR and 13 C NMR spectra of compound 3ab;

[0039] Figure 31 、 Figure 32 For the 1 H NMR and 13 C NMR spectra of compound 3ac;

[0040] Figure 33 、 Figure 34 For the 1 H NMR and 13 C NMR spectra of compound 3ad;

[0041] Figure 35 、 Figure 36 For the 1 H NMR and 13 C NMR spectra of compound 3ae;

[0042] Figure 37 、 Figure 38 For the 1 H NMR and 13 C NMR spectra of compound 3af;

[0043] Figure 39 、 Figure 40 For the 1 H NMR and 13 C NMR spectra of compound 3ag;

[0044] Figure 41 、 Figure 42 For the 1 H NMR and 13 C NMR spectra of compound 3ah;

[0045] Figure 43 、Figure 44 1H NMR and 1 1H NMR and 13 13C NMR spectra of compound 3ai;

[0046] Figure 45 and Figure 46 1H NMR and 1 1H NMR and 13 13C NMR spectra of compound 3aj;

[0047] Figure 47 and Figure 48 1H NMR and 1 1H NMR and 13 13C NMR spectra of compound 3al;

[0048] Figure 49 and Figure 50 1H NMR and 1 1H NMR and 13 13C NMR spectra of compound 3am;

[0049] Figure 51 and Figure 52 1H NMR and 1 1H NMR and 13 13C NMR spectra of compound 3an. Detailed implementation manners

[0050] The present invention will be further described in detail below with reference to the drawings and tables.

[0051] Examples 1-24

[0052] First, using O-acetylacetophenone oxime 1aa and 2-(4-methoxycarbonylbenzyl)-5,5-dimethyl-1,3-cyclohexanedione 2a as raw materials, the reaction results under different raw material molar ratios, copper salts, solvents, and reaction temperatures were compared (Table 1). The specific operation steps were as follows: 0.3 mmol of raw material 2a was mixed with a specified amount of 1a and copper salt, 1.5 mL of solvent was added, a rubber stopper and a balloon were plugged, evacuated and then backfilled with N 2 , and this cycle was repeated 3 times, then heated and reacted for a specified time. After the reaction was completed, purification was carried out to obtain 3aa.

[0053]

[0054] Table 1

[0055]

[0056]

[0057] Examples 25-50

[0058] Using various O-acetyl ketoximes 1 and 2-substituted-1,3-cyclodiones 2 as raw materials, a series of 7,8-dihydroindazin-5(6H)-one compounds 3 with different substitution types were synthesized (Table 2). The specific operation steps were as follows: 0.3 mmol of raw material 2 was mixed with 0.39 mmol of 1 and 0.03 mmol of CuBr, 1.5 mL of n-butyl acetate was added, the rubber stopper and balloon were plugged, evacuated and then backfilled with N 2 , and this cycle was repeated 3 times, then the reaction was carried out at 90 °C. After the reaction was completed, it was cooled to room temperature, then water was added and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the crude product obtained by rotary evaporation was separated by silica gel column chromatography to obtain product 3.

[0059] Table 2

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] The NMR data of the product 3aa of Example 25 are as follows:

[0066] 1 H NMR(300MHz,CDCl 3 )δ7.96(d,J=8.0Hz,2H),7.19-7.41(m,7H),6.03(s,1H),3.89(s,3H),3.79(s,2H),2.65(s,2H),2.52(s,2H),1.09(s,6H); 13 C NMR(75MHz,CDCl 3 )δ168.7,167.1,146.2,133.9,133.9,130.1,129.9,128.9,128.5,128.2,127.6,127.2,120.7,116.9,52.1,48.5,35.9,33.7,32.0,27.9;

[0067] The NMR data of the product 3ba of Example 26 are as follows:

[0068] 1 H NMR(300MHz,CDCl 3)δ8.14(d, J = 8.9 Hz, 2H), 7.97(d, J = 8.3 Hz, 2H), 7.49(d, J = 8.9 Hz, 2H), 7.25(d, J = 8.2 Hz, 2H), 6.18(s, 1H), 3.90(s, 3H), 3.81(s, 2H), 2.69(s, 2H), 2.58(s, 2H), 1.11(s, 6H); 13 C NMR(75MHz, CDCl 3 )δ168.9, 167.0, 146.4, 145.7, 140.2, 132.3, 131.6, 130.0, 129.2, 128.5, 122.9, 121.5, 119.2, 52.2, 48.3, 35.9, 34.0, 31.9, 27.8;

[0069] The NMR data of the product 3ca of Example 27 are as follows:

[0070] 1 H NMR(300MHz, CDCl 3 )δ7.97(d, J = 8.2 Hz, 2H), 7.54(d, J = 8.2 Hz, 2H), 7.44(d, J = 8.2 Hz, 2H), 7.25(d, J = 8.2 Hz, 2H), 6.10(s, 1H), 3.90(s, 3H), 3.80(s, 2H), 2.67(s, 2H), 2.55(s, 2H), 1.10(s, 6H); 13 C NMR(75MHz, CDCl 3 )δ168.8, 167.1, 145.9, 137.3, 132.4, 131.1, 130.0, 129.0, 128.9(q, J 2 C-F = 32.2 Hz), 128.5, 128.4, 124.6(q, J 3 C-F = 3.8 Hz), 121.1, 118.1, 52.2, 48.4, 35.9, 33.8, 32.0, 27.9;

[0071] The NMR data of the product 3da of Example 28 are as follows:

[0072] 1 H NMR(300MHz, CDCl 3)δ 7.96 (d, J = 8.4 Hz, 2H), 7.28 - 7.34 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.98 (t, J = 8.8 Hz, 2H), 6.00 (s, 1H), 3.90 (s, 3H), 3.78 (s, 2H), 2.65 (s, 2H), 2.53 (s, 2H), 1.09 (s, 6H); 13 C NMR(75MHz, CDCl 3 )δ 168.9, 167.2, 162.2 (d, J 1 C-F = 246.3 Hz), 146.1, 132.8, 130.6 (d, J 3 C-F = 8.0 Hz), 130.04, 130.00, 129.9, 128.5, 128.3, 120.8, 116.9, 114.5 (d, J 2 C-F = 21.6 Hz), 52.2, 48.5, 35.9, 33.6, 32.0, 27.9;

[0073] The NMR data of the product 3ea of Example 29 are as follows:

[0074] 1 H NMR(300MHz, CDCl 3 )δ 7.96 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 6.03 (s, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 2.66 (s, 2H), 2.54 (s, 2H), 1.10 (s, 6H); 13 C NMR(75MHz, CDCl 3 )δ 168.9, 167.1, 148.3 (q, J 3 C-F = 2.0 Hz), 146.0, 132.6, 132.5, 130.5, 130.3, 130.0, 128.5, 128.3, 120.9, 120.1, 117.4, 52.2, 48.5, 35.9, 33.7, 32.0, 27.9;

[0075] The NMR data of the product 3fa of Example 30 are as follows:

[0076] 1 H NMR(300MHz, CDCl 3)δ 7.96 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.97 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.78 (s, 2H), 2.64 (s, 2H), 2.52 (s, 2H), 1.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 )δ 168.8, 167.2, 158.8, 146.3, 133.7, 130.2, 130.0, 129.6, 128.5, 128.2, 126.5, 120.6, 116.2, 113.1, 55.4, 52.2, 48.6, 35.9, 33.6, 32.0, 27.9;

[0077] The NMR data of the product 3ga of Example 31 are as follows:

[0078] 1 H NMR (300 MHz, CDCl 3 )δ 7.95 (d, J = 8.2 Hz, 2H), 7.84 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.22 - 7.27 (m, 4H), 6.00 (s, 1H), 3.89 (s, 3H), 3.77 (s, 2H), 2.64 (s, 2H), 2.53 (s, 2H), 2.06 (s, 3H), 1.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 )δ 169.1, 168.7, 167.2, 146.1, 137.2, 133.5, 130.0, 129.9, 129.5, 129.3, 128.5, 128.2, 120.9, 119.1, 116.9, 52.2, 48.6, 35.9, 33.7, 32.0, 27.8, 24.5;

[0079] The NMR data of the product 3ha of Example 32 are as follows:

[0080] 1 H NMR (300 MHz, CDCl 3)δ 7.96 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 5.89 (s, 1H), 3.89 (s, 3H), 3.80 (s, 2H), 2.62 (s, 2H), 2.46 (s, 2H), 2.32 (s, 3H), 2.08 (s, 3H), 1.07 (s, 6H); 13 C NMR (75 MHz, CDCl 3 )δ 168.1, 167.1, 146.3, 137.4, 137.3, 132.1, 131.5, 130.3, 129.9, 129.7, 128.5, 128.4, 128.0, 125.9, 120.2, 115.7, 52.1, 48.0, 35.6, 33.1, 32.0, 21.3, 20.0;

[0081] The NMR data of the product 3ia of Example 33 are as follows:

[0082] 1 H NMR (300 MHz, CDCl 3 )δ 7.96 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.73 - 6.84 (m, 3H), 5.99 (s, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 3.75 (s, 3H), 3.67 (s, 3H), 2.62 (s, 2H), 2.48 (s, 2H), 1.09 (s, 6H); 13 C NMR (75 MHz, CDCl 3 )δ 168.0, 167.2, 153.2, 151.9, 146.4, 129.9, 129.4, 129.3, 128.6, 128.1, 124.8, 120.2, 116.1, 116.0, 113.3, 111.2, 56.1, 55.8, 52.1, 48.1, 35.8, 33.4, 32.1, 27.8;

[0083] The NMR data of the product 3ja of Example 34 are as follows:

[0084] 1 H NMR (300 MHz, CDCl 3)δ 7.97 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.23 - 7.31 (m, 4H), 7.12 - 7.22 (m, 1H), 5.98 (s, 1H), 3.90 (s, 3H), 3.83 (s, 2H), 2.63 (d, J = 7.5 Hz, 2H), 2.49 (d, J = 16.9 Hz, 2H), 1.11 (s, 6H); 13 C NMR (75 MHz, CDCl 3 )δ 168.1, 167.2, 146.3, 136.1, 132.1, 131.2, 130.9, 130.0, 129.2, 129.1, 128.5, 128.2, 127.0, 125.3, 120.3, 116.4, 52.2, 47.8, 35.6, 33.3, 32.0, 28.4 (br), 27.5 (br);

[0085] The NMR data of the product 3ka of Example 35 are as follows:

[0086] 1 H NMR (300 MHz, CDCl 3 )δ 7.96 (d, J = 8.2 Hz, 2H), 7.39 (dd, J = 1.8, 0.8 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 3.2 Hz, 1H), 6.40 (dd, J = 3.2, 1.8 Hz, 1H), 6.35 (s, 1H), 3.90 (s, 3H), 3.79 (s, 2H), 2.63 (s, 2H), 2.55 (s, 2H), 1.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 )δ 168.2, 167.2, 146.9, 146.0, 141.8, 130.4, 130.0, 128.5, 128.3, 123.7, 120.9, 116.9, 111.1, 109.4, 52.2, 48.3, 35.9, 33.2, 32.0, 27.9;

[0087] The NMR data of the product 3la of Example 36 are as follows:

[0088] 1 H NMR (300 MHz, CDCl 3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.22 - 7.27 (m, 3H), 7.13 (dd, J = 3.6, 1.2 Hz, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 6.17 (s, 1H), 3.90 (s, 3H), 3.78 (s, 2H), 2.63 (s, 2H), 2.54 (s, 2H), 1.08 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.6, 167.1, 146.0, 134.9, 130.6, 130.0, 128.5, 128.3, 127.5, 126.6, 126.2, 125.5, 120.8, 118.2, 52.2, 48.5, 35.9, 33.3, 31.9, 27.9;

[0089] The NMR data of the product 3ma of Example 37 are as follows:

[0090] 1 H NMR (300 MHz, CDCl 3 ) δ 7.99 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.71 (dd, J = 2.5, 1.9 Hz, 1H), 6.08 - 6.16 (m, 3H), 3.92 (s, 3H), 3.81 (s, 2H), 3.40 (s, 3H), 2.65 (s, 2H), 2.51 (s, 2H), 1.09 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.0, 167.1, 146.1, 130.0, 129.8, 128.5, 128.2, 125.8, 123.5, 122.7, 120.4, 118.7, 110.1, 107.1, 52.2, 48.1, 35.8, 34.3, 33.2, 32.0, 27.9;

[0091] The NMR data of the product 3na of Example 38 are as follows:

[0092] 1 H NMR (300 MHz, CDCl 3 ) δ 8.51 (s, 1H), 8.41 (d, J = 4.2 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.61 (dt, J = 7.8, 1.6 Hz, 1H), 7.13 - 7.21 (m, 3H), 6.03 (s, 1H), 3.82 (s, 3H), 3.73 (s, 2H), 2.60 (s, 2H), 2.47 (s, 2H), 1.03 (s, 6H);13 C NMR (75 MHz, CDCl 3 ) δ 168.9, 167.1, 149.0, 147.9, 145.9, 136.6, 131.0, 130.05, 130.01, 130.00, 128.5, 128.3, 122.4, 121.1, 117.9, 52.2, 48.3, 35.8, 33.7, 31.9, 27.9; The NMR data of the product 3ab in Example 39 are as follows:

[0093] 1 H NMR (300 MHz, CDCl 3 ) δ 7.20 - 7.40 (m, 5H), 6.79 (d, J = 8.8 Hz, 1H), 6.69 - 6.74 (m, 2H), 6.05 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.68 (s, 2H), 2.67 (s, 2H), 2.52 (s, 2H), 1.10 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.8, 149.0, 147.5, 134.0, 133.7, 133.2, 129.7, 128.8, 127.5, 127.0, 121.8, 120.3, 117.1, 111.8, 111.3, 56.0, 55.9, 48.5, 35.9, 33.6, 31.4, 27.9;

[0094] The NMR data of the product 3ac in Example 40 are as follows:

[0095] 1 H NMR (300 MHz, CDCl 3 ) δ 7.08 - 7.30 (m, 10H), 5.97 (s, 1H), 3.65 (s, 2H), 2.59 (s, 2H), 2.44 (s, 2H), 1.01 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.8, 140.7, 134.0, 133.7, 129.8, 128.9, 128.6, 128.5, 127.5, 127.0, 126.2, 121.6, 117.2, 48.6, 35.9, 33.7, 31.9, 27.9;

[0096] The NMR data of the product 3ad in Example 41 are as follows:

[0097] 1 H NMR (300 MHz, CDCl 3) δ 7.13 - 7.31 (m, 6H), 6.19 (dd, J = 3.0, 1.7 Hz, 1H), 6.04 (s, 1H), 5.90 (dq, J = 3.1, 0.9 Hz, 1H), 3.64 (s, 2H), 2.58 (s, 2H), 2.43 (s, 2H), 1.01 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.7, 154.2, 141.4, 133.9, 133.6, 130.2, 128.9, 127.5, 127.1, 118.8, 116.9, 110.4, 105.7, 48.5, 35.7, 33.6, 27.8, 24.9;

[0098] The NMR data of the product 3ae of Example 42 are as follows:

[0099] 1 H NMR (300 MHz, CDCl 3 ) δ 7.14 - 7.31 (m, 5H), 7.05 (dd, J = 5.1, 1.2 Hz, 1H), 6.84 (dd, J = 5.1, 3.5 Hz, 1H), 6.73 (dq, J = 3.5, 1.1 Hz, 1H), 6.06 (s, 1H), 3.84 (s, 2H), 2.61 (s, 2H), 2.45 (s, 2H), 1.03 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.8, 144.1, 133.9, 133.8, 129.9, 128.9, 127.6, 127.1, 126.9, 124.6, 123.8, 121.3, 116.8, 48.6, 35.8, 33.7, 27.9, 26.3;

[0100] The NMR data of the product 3af of Example 43 are as follows:

[0101] 1 H NMR (300 MHz, CDCl 3 ) δ 8.42 (br, 2H), 7.41 (d, J = 7.1 Hz, 1H), 7.10 - 7.30 (m, 6H), 5.94 (s, 1H), 3.66 (s, 2H), 2.58 (s, 2H), 2.45 (s, 2H), 1.01 (s, 6H); 13 C NMR (75 MHz, CDCl 3)δ168.6,149.8,147.6,136.0,134.0,133.8,130.0,129.0(br),128.8,127.6,127.2,123.6(br),120.4,116.6,48.4,35.8,33.6,29.2,27.8;

[0102] The 3ag NMR data of the product of Example 44 are as follows:

[0103] 1 H NMR(300MHz,CDCl 3 )δ7.21 - 7.41(m,5H),6.07(s,1H),2.63(s,2H),2.50(s,2H),1.99(s,3H),1.09(s,6H); 13 C NMR(75MHz,CDCl 3 )δ168.7,134.2,133.3,129.3,128.9,127.6,127.0,117.92,117.89,48.5,35.8,33.5,27.9,10.8;

[0104] The 3ah NMR data of the product of Example 45 are as follows:

[0105] 1 H NMR(300MHz,CDCl 3 )δ7.15 - 7.34(m,5H),6.02(s,1H),5.83(ddt,J=16.8,10.2,6.2Hz,1H),4.93 - 5.01(m,2H),3.06(d,J=6.4Hz,2H),2.57(s,2H),2.44(s,2H),1.02(s,6H); 13 C NMR(75MHz,CDCl 3 )δ168.8,136.7,134.1,133.5,129.7,128.9,127.6,127.1,120.4,117.0,115.4,48.6,35.8,33.6,30.2,27.9;

[0106] The 3ai NMR data of the product of Example 46 are as follows:

[0107] 1 H NMR(300MHz,CDCl 3) δ 7.22 - 7.39 (m, 5H), 6.08 (s, 1H), 3.67 (s, 3H), 2.70 (t, J = 7.2 Hz, 2H), 2.68 (s, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.51 (s, 2H), 1.09 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.5, 168.8, 134.0, 133.7, 129.7, 128.9, 127.6, 127.1, 121.1, 116.0, 51.8, 48.6, 35.7, 34.7, 33.6, 27.9, 21.0;

[0108] The NMR data of the product 3aj of Example 47 are as follows:

[0109] 1 H NMR (300 MHz, CDCl 3 ) δ 7.27 - 7.40 (m, 5H), 6.11 (s, 1H), 2.75 (t, J = 7.2 Hz, 2H), 2.72 (s, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.54 (s, 2H), 1.12 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.6, 134.3, 133.7, 130.5, 128.9, 127.6, 127.3, 119.5, 119.1, 115.3, 48.5, 35.7, 33.6, 27.9, 22.1, 18.8;

[0110] The NMR data of the product 3al of Example 48 are as follows:

[0111] 1 H NMR (300 MHz, CDCl 3 ) δ 7.18 - 7.37 (m, 10H), 6.04 (s, 1H), 3.75 (s, 2H), 2.83 (t, J = 6.1 Hz, 2H), 2.68 (t, J = 6.2 Hz, 2H), 2.07 (quint, J = 6.2 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 169.1, 140.6, 134.2, 133.7, 130.7, 128.9, 128.6, 128.6, 127.6, 127.1, 126.2, 120.8, 117.0, 35.1, 32.0, 22.1, 21.8;

[0112] The NMR data of the product 3am of Example 49 are as follows:

[0113] 1 H NMR(300MHz,CDCl 3 ) δ 7.98 (d, J = 8.3 Hz, 2H), 7.38 - 7.42 (m, 2H), 7.31 - 7.36 (m, 3H), 7.27 (d, J = 8.3 Hz, 2H), 6.09 (s, 1H), 4.72 (s, 2H), 4.36 (s, 2H), 3.91 (s, 3H), 3.80 (s, 2H); 13 C NMR(75MHz,CDCl 3 ) δ 167.1, 165.6, 145.2, 134.4, 132.5, 130.1, 129.0, 128.7, 128.6, 127.9, 127.8, 127.2, 119.8, 116.8, 69.1, 62.5, 52.2, 32.0;

[0114] The NMR data of the product 3an of Example 50 are as follows:

[0115] 1 H NMR(300MHz,CDCl 3 ) δ 7.89 (d, J = 8.3 Hz, 2H), 7.14 - 7.27 (m, 7H), 5.94 (s, 1H), 3.82 (s, 3H), 3.71 (s, 2H), 2.76 (t, J = 6.5 Hz, 2H), 1.88 (t, J = 6.5 Hz, 2H), 1.24 (s, 6H); 13 C NMR(75MHz,CDCl 3 ) δ 175.0, 167.2, 146.1, 134.3, 134.1, 130.5, 130.0, 128.7, 128.6, 127.6, 127.1, 126.3, 119.4, 116.9, 52.2, 40.4, 35.4, 32.0, 25.4, 18.7.

Claims

1. A method for synthesizing 7,8-dihydroindazol-5(6H)-one, characterized in that: The synthesis method uses O-acetyl ketoxime 1 and 2-alkyl-substituted cyclohexanedione 2 as raw materials, a copper salt as a catalyst, and reacts in the presence of an organic solvent under an N 2 atmosphere. After the reaction, the 7,8-dihydroindazin-5(6H)-one compound 3 is obtained through subsequent separation and purification; the raw materials and products are shown as follows: The copper salt catalyst is CuBr, CuCl, CuI, Cu(OAc) 2 , CuCN, CuSCN, CuTc; the reaction conditions are: reacting at 80-120 °C, reaction time: 1-5 hours; the organic solvent is: dichloroethane, toluene, benzene, xylene, n-butyl acetate.

2. The method for synthesizing 7,8-dihydroindazol-5(6H)-one according to claim 1, characterized in that: the molar ratio of the O-acetyl ketoxime, 2-alkyl-substituted cyclohexanedione and the copper salt catalyst is: 1-1.8:1:0.01-0.2.

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