Preparation method of polysubstituted spiro-cyclopropyl indolone compound

Abstract

The invention discloses a heating-promoted synthesis method of a polysubstituted spiro-cyclopropyl indolone compound, which is characterized by comprising the following steps: adding 3-alkenyl indolone and trifluoroacetyl imine sulfoxide ylide into an organic solvent, reacting at 20-40 DEG C for 10-16 hours, and after the reaction is completed, separating and purifying to obtain the polysubstituted spiro-cyclopropyl indolone compound. And carrying out post-treatment to obtain the polysubstituted spiro-cyclopropyl indolone compound. The preparation method has the advantages that the operation is simple, the starting raw materials are cheap and easy to obtain, the reaction does not need any catalyst and additive, the inert gas atmosphere is not needed, the reaction can be smoothly carried out only by stirring in the air at normal temperature, the operation is convenient, the applicability of the method is widened, and the method also conforms to the concept of green chemistry.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing a multi-substituted spiro-cyclopropyl indole one compound without the participation of a metal catalyst, an oxidant and an additive. Background Art

[0002] Cyclopropane molecules are widely used as versatile synthetic skeletons in organic synthesis. They are also present in many biologically active molecules and clinical drugs with important characteristics (Chem. Rev. 2003, 103, 977-1050, J. Med. Chem. 2016, 59, 8712-8756). Among them, spirocyclopropane indole one compounds have significant biological activity because they contain two unique pharmacophoric groups (cyclopropane and indole one), and are the key structures of various inhibitors and drug molecules. In recent years, they have attracted widespread attention (Bioorg. Med. Chem. Lett. 2006, 16, 2109-2112, J. Med. Chem. 2011, 46, 1181-1188). Multi-substituted spiro-cyclopropyl indole one compounds can significantly improve the physicochemical properties of the parent molecule because of their functional groups, and it is of great significance to develop a simple and efficient synthesis method thereof.

[0003]

[0004] Traditional methods for preparing spiro-cyclopropylindolones include: Lewis acid-catalyzed cyclopropanation of 3-alkenyloxindole with diazomethane; chiral metal complex-catalyzed asymmetric Michael-alkylation of 3-chlorooxindole with β,γ-unsaturated α-ketoesters; palladium-catalyzed intramolecular carbon-hydrogen activated arylation of cyclopropane; and palladium / copper co-catalyzed tandem cyclization of ortho-alkenylaryl isocyanates and sulfonyl ylides and alcohols. Based on the concepts of green chemistry and atom economy, developing simple, green and easy-to-operate synthetic methods to construct multifunctional spiro-cyclopropylindolones has important research significance and application value.

[0005] Based on this, we developed a simple and efficient method for the synthesis of polysubstituted spiro-cyclopropylindolone compounds using cheap and readily available 3-alkenyl indole and trifluoroacetimide sulfoxide ylides as starting materials, without the presence of any metal catalysts, oxidants or additives, and only requiring conventional room temperature stirring to promote the synthesis. Summary of the invention

[0006] The invention provides a method for preparing a polysubstituted spiro-cyclopropyl indole one compound. The preparation method has simple steps, cheap and readily available starting materials, extremely simple reaction conditions, only room temperature stirring is required, and no catalyst or additive is required, so the method is easy to operate and can be applied on a large scale in the later stage.

[0007] A method for preparing a polysubstituted spiro-cyclopropyl indole ketone compound comprises the following steps: adding 3-alkenyl indole ketone and trifluoroacetimide sulfoxide ylide to an organic solvent, reacting at 20-40° C. for 10-16 hours, and after the reaction is complete, post-treating to obtain the polysubstituted spiro-cyclopropyl indole ketone compound;

[0008] The structure of the 3-alkenyl indole ketone is shown in formula (II):

[0009]

[0010] The structure of the trifluoroacetimide sulfoxide ylide is shown in formula (III):

[0011]

[0012] The structure of the polysubstituted spiro-cyclopropyl indole one compound is shown in formula (I):

[0013]

[0014] In formulas (I) to (III),

[0015] R 1 and R 2 Independently H, C 1 ~C 4 Alkyl, halogen, C 1 ~C 4 Alkanoyl or C 1 ~C 4 Alkoxyacyl; R 3 C 1 ~C 4 Alkoxy acyl or cyano; R 4 is substituted or unsubstituted aryl or naphthyl;

[0016] In R 4 In the above, the substituents on the aryl group are selected from C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 alkylthio, halogen, nitro or trifluoromethyl.

[0017] R 4 The substituent position of the phenyl group may be ortho, para or meta.

[0018] The reaction formula is as follows:

[0019]

[0020] The reaction may first undergo a Macheal addition reaction between trifluoroacetimidohydrazine and 3-enyl indolone to generate a zwitterionic intermediate, and then undergo an intramolecular nucleophilic substitution reaction to obtain the final multi-substituted spiro-cyclopropyl indolone compound, while simultaneously releasing a molecule of dimethyl sulfoxide.

[0021] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding multi-substituted spiro-cyclopropyl indole one compound. Column chromatography purification is a commonly used technical means in the art.

[0022] Preferably, R 1 is H, methyl, ethyl, chlorine or bromine; R 2 is H, methyl, acetyl and tert-butyloxycarbonyl; R 3 is ethoxycarbonyl, methoxycarbonyl or cyano. In this case, the 3-alkenyl indole ketone is relatively easy to obtain;

[0023] R 4 It is a substituted or unsubstituted phenyl or naphthyl group, and the substituent on the phenyl group is selected from methyl, methoxy, methylthio, chlorine, bromine, nitro or trifluoromethyl. At this time, the aromatic amine and trifluoroacetimide sulfoxide ylide are easy to obtain, and the reaction yield is high.

[0024] The p-trifluoroacetimide sulfoxide ylide starting material is relatively cheap and easy to obtain, and is used in excess relative to the 3-vinyl indole ketone. Preferably, on a molar basis, the ratio of 3-vinyl indole ketone to trifluoroacetimide sulfoxide ylide is 1:1-2; and further preferably, on a molar basis, the ratio of 3-vinyl indole ketone to trifluoroacetimide sulfoxide ylide is 1:1.5.

[0025] In the present invention, any organic solvent that can fully dissolve the raw materials can cause the reaction to occur, but the reaction efficiency varies greatly. Preferred are aprotic solvents and halogenated solvents, which can effectively promote the reaction. Preferably, the organic solvent is tetrahydrofuran, 1,4-dioxane or dichloroethane. As a further preference, the organic solvent is dichloroethane, which is the most suitable. At this time, various raw materials can be converted into products at a higher conversion rate.

[0026] The amount of the organic solvent used is sufficient to dissolve the raw material well. The amount of the organic solvent used for 1 mmol of 3-vinyl indole ketone is about 5 to 10 mL.

[0027] Preferably, the reaction conditions are only ordinary heating, which is sufficient to achieve complete conversion of the reaction.

[0028] As a further preference, the polysubstituted spiro-cyclopropyl indolinone compound is one of the compounds represented by formula (I-1) to formula (I-5):

[0029]

[0030]

[0031] In the above preparation method, the 3-alkenyl indolone can be quickly synthesized from isatin and alkenyl phosphine ylide; the trifluoroacetimide sulfoxide ylide can be obtained from trifluoroethylimidoyl chloride and trimethyl iodide sulfonate with a higher yield, and trifluoroethylimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid. The aromatic amine and isatin are generally commercially available products and can be easily obtained from the market.

[0032] Compared with the prior art, the beneficial effects of the present invention are embodied in that: the preparation method is simple to operate and the post-treatment is simple; the starting raw materials for the reaction are cheap and easily available, and no catalyst or additive is required; the reaction substrate is highly designable and has a wide tolerance range for substrate functional groups; and spiro-cyclopropyl indole one compounds with different substitutions and trifluoromethyl groups and various electron-withdrawing groups can be designed and synthesized according to actual needs, which is highly practical and conforms to the concept of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The results of transcriptional expression levels of A.bdnf, B.lrrk, C.dj1 and D.pink1 in test example 1. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with specific embodiments.

[0035] According to the raw material ratio in Table 1, 3-vinyl indole ketone (II), trifluoroacetimide sulfoxide ylide (III) and 2 mL of organic solvent were added to a 35 mL Schlenk tube, mixed and stirred evenly, reacted for 10-16 hours according to the reaction conditions in Table 2, filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding multi-substituted spiro-cyclopropyl indole ketone compound (I). The reaction process is shown in the following formula:

[0036]

[0037] Table 1 Amount of raw materials added in Examples 1 to 15

[0038]

[0039] Table 2

[0040]

[0041] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, OMe is methoxy, SMe is methylthio, Boc is tert-butyloxy, Ac is acetyl, CO is 2 Et is ethoxy, CN is cyano, NO 2 For nitro, CF 3 DCE is dichloroethane.

[0042] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0043] The NMR ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0044]

[0045] 1 H NMR (400 MHz, CDCl 3 )δ7.70(d,J=8.2Hz,1H),7.29(t,J=5.8Hz,1H),7.25(d,J=6.3Hz,1H),7.11(t,J=7.3Hz,1H),6.66(d,J=8.8Hz,2H),6.42(d,J =8.6Hz,2H),4.22-4.06(m,2H),3.62(s,3H),3.26(d,J=8.5Hz,1H),3.05(d,J=8.1Hz,1H),1.61(s,9H),1.19(t,J=7.1Hz,3H).

[0046] 13 C NMR (101 MHz, CDCl 3 )δ169.2,166.8,158.1,148.6(CF,q, 2 J (C-F) =34.0Hz),148.5,140.7,138.6,128.6,124.4,123.1,122.6,121.7,119.8(CF,q, 1 J (C-F) =278.9Hz),114.9,113.7,84.6,62.2,55.3,38.7,38.3,31.9,28.2,14.1. 19 F NMR (377 MHz, CDCl 3 )δ-70.5.

[0047] Mp137.5-138.2℃

[0048] HRMS(ESI):[M+Na] + calcd.for C 27 H 27 F 3 N 2 NaO 6 + 555.1713, found 555.1721.

[0049] The NMR ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0050]

[0051] 1 H NMR (400 MHz, CDCl 3 )δ7.78(d,J=1.7Hz,1H),7.25(d,J=8.3Hz,1H),7.10(dd,J=8.3,1.9Hz,1H),6.63(d,J=8.7Hz,2H),6.45(d,J=8.7Hz, 2H), 4.21-4.09 (m, 2H), 3.65 (s, 3H), 3.23 (d, J = 8.5Hz, 1H), 3.07 (d, J = 8.2Hz, 1H), 1.62 (s, 9H), 1.20 (t, J = 7.1Hz, 3H).

[0052] 13 C NMR (101 MHz, CDCl 3 )δ168.8,166.7,158.2,148.6(CF,q, 2 J (C-F) =34.3Hz),148.2,141.6,138.5,134.5,124.4,122.8,122.5,121.6,119.8(CF,q, 1 J (C-F) =275.5Hz),115.6,113.7,85.2,62.4,55.4,53.6,38.4,32.1,28.2,14.2. 19 F NMR (377 MHz, CDCl 3 )δ-70.0.

[0053] Mp152.2-152.7℃

[0054] HRMS(ESI):[M+Na] + calcd.for C 27 H 26 CIF 3 N 2 NaO 6 + 589.1324, found 589.1332.

[0055] The NMR ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0056]

[0057] 1 H NMR (400 MHz, CDCl 3 )δ8.10(d,J=8.2Hz,1H),7.35(d,J=7.6Hz,1H),7.30(t,J=7.9Hz,1H),7.17(t,J=7.2Hz,1H),6.69(d,J=8.8Hz,2H),6.42(d,J =8.7Hz,2H),4.25-4.09(m,2H),3.63(s,3H),3.33(d,J=8.5Hz,1H),3.04(d,J=8.3Hz,1H),2.45(s,3H),1.21(t,J=7.1Hz,3H).

[0058] 13 C NMR (101 MHz, CDCl 3 )δ171.8,170.1,166.5,158.5,148.0(CF,q, 2 J (C-F) =34.1Hz),141.0,138.2,128.9,125.3,123.4,123.0,121.6,119.8(CF,q, 1 J (C-F) =279.0Hz),116.5,113.8,62.4,55.4,38.8,38.4,32.1,26.8,14.2.

[0059] 19 F NMR (377 MHz, CDCl 3 )δ-67.2,-67.0.

[0060] Mp122.1-122.6℃

[0061] HRMS(ESI):[M+Na] + calcd.for C 24 H 21 F 3 N 2 NaO 5 + 497.1295, found 497.1302.

[0062] The NMR ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0063]

[0064] 1 H NMR (400 MHz, CDCl 3 )δ7.81(d,J=8.2Hz,1H),7.42(t,J=7.4Hz,1H),7.28(t,J=7.1Hz,1H),7.21(d,J=7.1Hz,1H),6.69(d,J=8 .8Hz,2H),6.52(d,J=8.7Hz,2H),3.69(s,3H),2.99(d,J=8.1Hz,1H),2.86(d,J=8.0Hz,1H),1.64(s,9H).

[0065] 13 C NMR (101 MHz, CDCl 3 )δ167.8,158.6,148.1,145.7(CF,q, 2 J (C-F) =34.9Hz),140.8,137.9,129.8,125.0,122.8,121.3,120.0,119.6(CF,q, 1 J (C-F) =276.4Hz),115.4,114.6,114.0,85.1,55.4,37.0,32.5,28.1,20.9.

[0066] 19 F NMR (377 MHz, CDCl 3 )δ-69.1,-69.7,-75.7.

[0067] Mp140.4-140.8℃

[0068] HRMS(ESI):[M+Na] + calcd.for C 25 H 22 F 3 N 3 NaO 4 + 508.1455, found 508.1464.

[0069] The NMR of the polysubstituted spiro-cyclopropylindole one compound (I-5) prepared in Example 5 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0070]

[0071] 1 H NMR (400 MHz, CDCl 3 )δ7.61(d,J=8.1Hz,1H),7.55(d,J=8.7Hz,1H),7.37-7.33(m,2H),7.30(d,J=6.8Hz,1H),7.22-7.20(m,1H),7.16(d,J=2.6Hz ,1H),7.02-6.96(m,4H),4.08-3.95(m,2H),3.33(d,J=8.5Hz,1H),2.94(d,J=5.8Hz,1H),1.59(s,9H),1.05(t,J=7.0Hz,3H).

[0072] 13 C NMR (101 MHz, CDCl 3 )δ169.5,166.6,150.6(CF,q, 2 J (C-F) =34.4Hz),148.2,143.6,140.0,133.1,131.3,128.8,128.7,127.8,127.5,126.6,125.8,124.2,122.4,121.6,120.6,119.7(CF,q, 1 J (C-F) =279.2Hz),116.8,114.6,84.6,62.1,39.0,38.2,31.7,28.2,14.0.

[0073] 19F NMR (377 MHz, CDCl 3 )δ-70.4.

[0074] Mp148.6-148.9℃

[0075] HRMS(ESI):[M+Na] + calcd.for C 31 H 27 F 5 N 2 NaO 5 + 625.1732, found 625.1724.

[0076] The role of spirocyclopropane indole ketone compounds in the nervous system has also gradually attracted attention. Studies have shown that these compounds exhibit certain neuroprotective effects by reducing neuroinflammation, inhibiting neuronal apoptosis and promoting the secretion of nerve growth factor. This makes them promising to play a role in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Parkinson's disease (PD) is one of the most common neurodegenerative diseases caused by the loss of dopaminergic neurons in the substantia nigra midbrain. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that destroys the mitochondria of dopaminergic neurons, resulting in impaired oxidant-antioxidant balance. Both zebrafish and zebrafish embryos are sensitive to MPTP. In zebrafish embryos, MPTP reduces dopaminergic cells in the diencephalon by destroying dopaminergic neurons, for which the present invention conducted the following test examples.

[0077] Test Example 1

[0078] Methods: The zebrafish used in this experiment were wild WT / AB strains, aged 2 to 4 months, weighing 0.5 to 1.0 g, and were purchased from the China National Zebrafish Resource Center. Zebrafish embryos were cultured in E3 medium (mg·L -1 :NaCl 5,KCl 0.17,CaCl 2 0.33,MgSO 4 0.33). The primers were synthesized by Shanghai Bioengineering Co., Ltd. The primer sequences are shown in Table 1.

[0079] Table 1. Primer information

[0080]

[0081] Experimental procedures: A blank control group (E3 culture medium), a PD model group (800 μM MPTP), and polysubstituted spiro-cyclopropyl indole compounds I-1 (10 μM), I-2 (10 μM), I-3 (10 μM), I-4 (10 μM), and I-5 (10 μM) were set up. After obtaining healthy zebrafish eggs, they were exposed to different experimental groups for 120 hours, with 120 eggs in each group. The exposure solution was changed every day, and dead embryos were cleaned up in time. After each group of zebrafish embryos was exposed for 120 hours, 30 embryos were randomly selected from each concentration and homogenized to prepare RNA according to the instructions of the Trizol reagent. The purified total RNA (1 μg) was reverse transcribed using the cDNA FirstStrand Synthesis Kit from Takara (Dalian, China). According to the instructions of the SYBR Green Master Mix kit, the real-time quantitative polymerase chain reaction (qPCR) method was used for analysis. The cycling conditions were: 94°C for 3 min, 94°C for 20 s, 58°C for 30 s, and 72°C for 20 s. β-actin was used as an internal reference to detect the relative expression levels of Parkinson's disease marker genes bdnf, dj1, lrrk, and pink1. The experiment was repeated 3 times. (ΔΔCt) Methods Analysis of relative quantification of gene expression.

[0082] Figure 1 The transcriptional expression levels of A.bdnf, B.lrrk, C.dj1 and D.pink1 were quantified by RT-PCR. All RT-PCR results were normalized to β-actin (housekeeping gene) as the reference standard and expressed as changes relative to their respective control groups. Data are expressed as mean ± standard deviation (SD). One-way ANOVA was used to analyze the differences between different exposure groups and the control or model group. a represents significantly different from the control group, p<0.05; b represents significantly different from the MPTP group, p<0.05.

[0083] The relationship between genes such as bdnf, lrrk, dj1 and pink1 and Parkinson's disease is mainly reflected in their protective effects on neurons, mitochondrial function, anti-oxidative stress and regulation of cell autophagy. Their mutations or loss of function will lead to neuronal damage and the occurrence of Parkinson's disease. The experimental results show that I-3 has the most obvious potential therapeutic effect on Parkinson's disease, significantly changing the abnormal expression of Parkinson's disease marker genes bdnf, dj1, lrrk and pink1 caused by MPTP. Prove the application potential of this chemical synthesis method.

Claims

1. A method for preparing a polysubstituted spiro-cyclopropyl indole ketone compound, characterized in that: The method comprises the following steps: adding 3-alkenyl indole ketone and trifluoroacetimide sulfoxide ylide to an organic solvent, reacting at 20-40° C. for 10-16 hours, and after the reaction is complete, post-treating to obtain the polysubstituted spiro-cyclopropyl indole ketone compound; The structure of the 3-alkenyl indole ketone is shown in formula (II): The structure of the trifluoroacetimide sulfoxide ylide is shown in formula (III): The structure of the polysubstituted spiro-cyclopropyl indole one compound is shown in formula (I): In formulas (I) to (III), R 1 and R 2 R is independently H, C1-C4 alkyl, halogen, C1-C4 alkanoyl or C1-C4 alkoxyacyl; 3 is C1-C4 alkoxy acyl or cyano; R 4 is substituted or unsubstituted aryl or naphthyl; In R 4 In the above, the substituent on the aryl group is selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, halogen, nitro or trifluoromethyl.

2. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: R 1 is H, methyl, ethyl, chlorine or bromine.

3. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: R 2 It is H, methyl, acetyl and tert-butyloxycarbonyl.

4. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: R 3 It is ethoxycarbonyl, methoxycarbonyl or cyano.

5. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: R 4 is substituted or unsubstituted phenyl or naphthyl; The substituents on the phenyl group are selected from methyl, methoxy, methylthio, chlorine, bromine, nitro or trifluoromethyl.

6. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: The organic solvent is ethylene dichloride.

7. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: In terms of molar amount, 3-vinyl indole ketone: trifluoroacetimide sulfoxide ylide = 1:1-2.

8. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: No other catalysts or additives were added during the reaction.

9. The method for preparing a polysubstituted spiro-cyclopropylindole one compound according to claim 1, characterized in that: The polysubstituted spiro-cyclopropyl indole one compound is one of the compounds represented by formula (I-1) to formula (I-5):

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