A method for synthesizing 2-substituted cycloheptatrienone compounds

Abstract

The present invention belongs to the field of organic synthetic chemistry, and in particular to a method for synthesizing 2-substituted cycloheptatrienone compounds, comprising the steps of: in the presence of an alkaline agent, heating a compound of formula I and a compound of formula II in a solvent to react, to obtain a 2-substituted cycloheptatrienone compound of formula III structure. The synthesis method provided by the present invention uses tropine quaternary ammonium salt (Formula I) and an aldehyde compound (Formula II) as raw materials, and in the presence of an alkaline agent, the reaction is carried out only by heating to generate a 2-substituted cycloheptatrienone compound (Formula III). The synthesis method provided by the present invention has the advantages of cheap and readily available raw materials, simple operation, no need for inert gas protection, simple post-processing, good functional group compatibility, high yield, and high site selectivity, and the method can be scaled up to the gram level, and the yield can still be maintained, making it easy to industrialize. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the field of organic synthetic chemistry, and particularly relates to a method for synthesizing 2-substituted cycloheptatrienone compounds. Background Art

[0002] Cycloheptatrienone compounds belong to a family of seven-membered aromatic rings. Their skeletons are found in a variety of natural products, some of which possess antibacterial, antifungal, anticancer, and antiviral activities and are used as monotherapy for acute gout attacks and familial Mediterranean fever. Therefore, the efficient preparation of compounds containing cycloheptatrienone skeletons is of great scientific significance and application value.

[0003] Known methods for constructing the tropinone skeleton include elimination reactions of tropinone quaternary ammonium salt derivatives containing a leaving group, oxidation reactions of seven-membered carbon rings, cyclization reactions, ring expansion reactions, and cycloaddition reactions. However, these methods suffer from problems such as difficulty in preparing reactants and reagents, a narrow substrate range, poor site selectivity, and low yields. Among them, tropinone quaternary ammonium salt contains a β-aminoketone structural unit and a seven-membered carbon ring skeleton, and the bridge ring tension can promote the C(sp 3 The )–N bond breaks under relatively mild conditions. In the 1950s, Lornitzo, Chapman, and others prepared quaternary ammonium salt derivatives of tropinone containing leaving groups through a multi-step reaction. These starting materials were heated in an alkaline solution and subjected to a cascade elimination reaction to obtain cycloheptatrienone or 4-substituted cycloheptatrienone. These reactions are not suitable for the preparation of 2-substituted cycloheptatrienone compounds. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a method for synthesizing 2-substituted cycloheptatrienone compounds. The synthesis method provided by the present invention has cheap and readily available raw materials, is simple to operate, has a high yield, and can be scaled up, thus having good industrial application prospects.

[0005] The present invention provides a method for synthesizing 2-substituted cycloheptatrienone compounds, comprising the following steps:

[0006] In the presence of an alkaline reagent, the compound of formula I and the compound of formula II are heated in a solvent to react to obtain a 2-substituted cycloheptatrienone compound of formula III;

[0007]

[0008] Among them, R 1 and R 2 independently selected from methyl, n-butyl, allyl or benzyl; X - is a negative ion; R is an aromatic group or an alkyl group.

[0009] Preferably, the R 1 and R2 All are methyl.

[0010] Preferably, the aryl group is phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracenyl, substituted anthracenyl, aromatic heterocyclic group, substituted aromatic heterocyclic group, benzoaromatic heterocyclic group or substituted benzoaromatic heterocyclic group; the alkyl group is a chain alkyl group or a cyclic alkyl group.

[0011] Preferably, the aromatic heterocyclic group is pyridyl, furyl, thienyl or pyrrolyl; the benzoaromatic heterocyclic group is quinolyl, benzofuranyl, benzothienyl, carbazolyl or indolyl.

[0012] Preferably, the negative ion is a bromide negative ion, an iodide negative ion or a trifluoromethanesulfonate negative ion.

[0013] Preferably, the alkaline agent is an organic base and / or an inorganic base.

[0014] Preferably, the molar ratio of the compound of formula I, the compound of formula II and the alkaline agent is (1-1.2):1:(0.2-0.6).

[0015] Preferably, the temperature of the heating reaction is 80-120° C.; and the time of the heating reaction is 6-15 hours.

[0016] Preferably, the solvent is an alcohol solvent.

[0017] Preferably, the synthesis method further comprises: after the heating reaction is completed, removing the solvent and purifying the obtained reaction product.

[0018] Compared with the prior art, the present invention provides a method for synthesizing 2-substituted cycloheptatrienone compounds. The method provided by the present invention comprises the following steps: in the presence of an alkaline reagent, heating a compound of formula I and a compound of formula II in a solvent to react to obtain a 2-substituted cycloheptatrienone compound of formula III; wherein R 1 and R 2 independently selected from methyl, n-butyl, allyl or benzyl; X - is a negative ion; R is an aryl or alkyl group. The synthesis method provided by the present invention uses a quaternary ammonium salt of tropinone (Formula I) and an aldehyde compound (Formula II) as raw materials. In the presence of an alkaline reagent, the reaction is carried out by heating alone to produce a 2-substituted cycloheptatrienone compound (Formula III). The synthesis method provided by the present invention has the advantages of inexpensive and readily available raw materials, simple operation, no need for inert gas protection, simple post-processing, good functional group compatibility, high yield, and high site selectivity. Moreover, the method can be scaled up to the gram level with maintained yield, making it easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0020] Figure 1 is the hydrogen spectrum of the product obtained in Example 1;

[0021] Figure 2 This is the carbon spectrum of the product obtained in Example 1;

[0022] Figure 3 is the hydrogen spectrum of the product obtained in Example 2;

[0023] Figure 4 This is the carbon spectrum of the product obtained in Example 2;

[0024] Figure 5 is the hydrogen spectrum of the product obtained in Example 3;

[0025] Figure 6 This is the carbon spectrum of the product obtained in Example 3;

[0026] Figure 7 is the hydrogen spectrum of the product obtained in Example 4;

[0027] Figure 8 This is the carbon spectrum of the product obtained in Example 4;

[0028] Figure 9 is the hydrogen spectrum of the product obtained in Example 6;

[0029] Figure 10 This is the carbon spectrum of the product obtained in Example 6;

[0030] Figure 11 is the hydrogen spectrum of the product obtained in Example 8;

[0031] Figure 12 This is the carbon spectrum of the product obtained in Example 8;

[0032] Figure 13 is the hydrogen spectrum of the product obtained in Example 9;

[0033] Figure 14 This is the carbon spectrum of the product obtained in Example 9;

[0034] Figure 15 is the hydrogen spectrum of the product obtained in Example 10;

[0035] Figure 16 is the carbon spectrum of the product obtained in Example 10;

[0036] Figure 17 is the hydrogen spectrum of the product obtained in Example 11;

[0037] Figure 18 is the carbon spectrum of the product obtained in Example 11;

[0038] Figure 19 is the hydrogen spectrum of the product obtained in Example 13;

[0039] Figure 20 is the carbon spectrum of the product obtained in Example 13;

[0040] Figure 21 is the hydrogen spectrum of the product obtained in Example 14;

[0041] Figure 22 is the carbon spectrum of the product obtained in Example 14;

[0042] Figure 23 is the hydrogen spectrum of the product obtained in Example 17;

[0043] Figure 24 is the carbon spectrum of the product obtained in Example 17;

[0044] Figure 25 is the hydrogen spectrum of the product obtained in Example 18;

[0045] Figure 26 This is the carbon spectrum of the product obtained in Example 18. DETAILED DESCRIPTION

[0046] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0047] The present invention provides a method for synthesizing a 2-substituted cycloheptatrienone compound, comprising the following steps: in the presence of an alkaline reagent, heating a compound of formula I and a compound of formula II in a solvent to react to obtain a 2-substituted cycloheptatrienone compound of formula III. The specific reaction formula is as follows:

[0048]

[0049] In the synthesis method provided by the present invention, the compound of formula I is a quaternary ammonium salt of tropinone, wherein R 1 and R 2 Independently select methyl, n-butyl, allyl or benzyl; the R 1 and R 2 The best is when all are methyl; X -is a negative ion, including but not limited to a bromide negative ion, an iodide negative ion or a trifluoromethanesulfonate negative ion; - The best is when it is iodine negative ion.

[0050] In the synthesis method provided by the present invention, the compound of formula II is an aldehyde compound, wherein R is an aryl group or an alkyl group; the aryl group is preferably a phenyl group, a substituted phenyl group, a naphthyl group, a substituted naphthyl group, an anthracenyl group, a substituted anthracenyl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, a benzoaromatic heterocyclic group or a substituted benzoaromatic heterocyclic group; the aromatic heterocyclic group is preferably a pyridyl group, a furyl group, a thienyl group or a pyrrolyl group; the benzoaromatic heterocyclic group is preferably a quinolyl group, a benzofuranyl group, a benzothienyl group, a carbazolyl group or an indolyl group; and the alkyl group is preferably a chain alkyl group or a cyclic alkyl group.

[0051] In the synthesis method provided by the present invention, the compound of formula II can specifically be selected from p-bromobenzaldehyde, p-methoxybenzaldehyde, 2-methylbenzaldehyde, 3-nitrobenzaldehyde, 1,3-benzodioxy-4-carboxaldehyde, 2-naphthaldehyde, 9-anthracenecarboxaldehyde, 9-ethyl-9H-carbazole-2-carboxaldehyde, 3-formylbenzofuran, 3-acetylthiophene, 8-formyl-7-hydroxy-4-methylcoumarin, phenylpropionaldehyde, 2-phenylpropionaldehyde, n-octanal, cyclohexanecarboxaldehyde, tetrahydropyran-4-carboxaldehyde, 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde or citronellal.

[0052] In the synthesis method provided by the present invention, the alkaline reagent is preferably an organic base and / or an inorganic base, including but not limited to one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium acetate, potassium carbonate, triethylamine and triethylenediamine (DABCO); the alkaline reagent is optimal when it is triethylenediamine (DABCO).

[0053] In the synthesis method provided by the present invention, the solvent is preferably an alcohol solvent, including but not limited to one or more of methanol, ethanol and isopropanol; methanol is the most optimal solvent.

[0054] In the synthesis method provided by the present invention, the molar ratio of the compound of formula I, the compound of formula II and the alkaline reagent is preferably (1-1.2):1:(0.2-0.6), more preferably 1.1:1:0.4.

[0055] In the synthesis method provided by the present invention, the heating reaction is preferably carried out under closed conditions, and the reactor used is preferably a sealed tube; the temperature of the heating reaction is preferably 80-120°C, more preferably 100°C; the time of the heating reaction is preferably 6-15h, more preferably 10h.

[0056] In the synthesis method provided by the present invention, after the heating reaction is completed, the obtained reaction product is preferably subjected to solvent removal and purification. The solvent removal is preferably preceded by cooling; the solvent removal method is preferably vacuum distillation; and the purification method is preferably silica gel column chromatography.

[0057] The synthesis method provided by the present invention uses tropinone quaternary ammonium salt (Formula I) and aldehyde compound (Formula II) as raw materials. In the presence of an alkaline reagent, the reaction is carried out by heating only to produce a 2-substituted cycloheptatrienone compound (Formula III). The synthesis method provided by the present invention has the advantages of cheap and readily available raw materials, simple operation, no need for inert gas protection, simple post-processing, good functional group compatibility, high yield, and high site selectivity. Moreover, the method can be scaled up to the gram level with maintained yield, making it easy to industrialize.

[0058] For the purpose of greater clarity, the present invention is described in detail with reference to the following examples.

[0059] Example 1

[0060] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0061]

[0062] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), p-bromobenzaldehyde 2a (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 mL) are charged into a 10 mL sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3a in an 89% yield.

[0063] The NMR spectrum data of the obtained product 3a are: 1 H NMR (500MHz, CDCl3) δ7.42-7.39(m,2H),7.15-7.08(m,5H),6.96-6.91(m,2H),3.91(s,2H); 13 C NMR(125MHz, CDCl3)δ186.5,154.1,140.8,138.2,135.8,135.8,133.8,133.2,131.7,131.2,120.4,40.3; HRMS(ESI)calcd forC 14 H 12 BrO + (M+H) + 275.0066,found275.0070.

[0064] Amplified preparation of Example 1:

[0065] To a 100 ml sealed tube equipped with a magnetic stirrer at room temperature were charged tropinone quaternary ammonium salt 1a (6.6 mmol), p-bromobenzaldehyde 2a (6.0 mmol), triethylenediamine (2.4 mmol), and methanol (20 ml). The mixture was heated to 100°C in an oil bath and stirred for 10 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product 3a in an 84% yield.

[0066] Example 2

[0067] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0068]

[0069] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), p-anisaldehyde 2b (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3b in a yield of 69%.

[0070] The NMR spectrum data of the obtained product 3b are: 1 H NMR (500MHz, CDCl3) δ7.16(d,J=8.5Hz,2H),7.12-7.11(m,2H),7.09-7.07(m,1H),6.94-6.90(m,2H),6.86-6.84(m,2H),3.91(s,2H),3.79(s,3H); 13 C NMR(125MHz, CDCl3)δ186.9,158.4,155.3,140.7,135.7,135.6,133.9,132.8,131.1,130.7,114.1,55.3,39.8; HRMS(ESI)calcd for C 15 H 15 O2 + (M+H) + 227.1067,found 227.1072.

[0071] Example 3

[0072] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0073]

[0074] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 2-methylbenzaldehyde 2c (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 mL) were charged into a 10 mL sealed tube equipped with a magnetic stirrer at room temperature. The mixture was heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3c in an 86% yield.

[0075] The obtained product 3c NMR spectrum data is: 1 H NMR (400MHz, CDCl3) δ7.21-7.16(m,3H),7.15-7.09(m,3H),6.93-6.83(m,2H),6.79-6.75(m,1H),3.96(s,2H),2.18(s,3H); 13 C NMR (100MHz, CDCl3) δ187.0,154.2,140.2,137.2,137.2,135.7,134.6,133.8,132.7,130.7,130.5,127.0,126.3,37.9,19.5; HRMS(ESI)calcd for C 15 H 15 O + (M+H) + 211.1117,found211.1121.

[0076] Example 4

[0077] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0078]

[0079] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 3-nitrobenzaldehyde 2d (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain the target product 3d in a yield of 54%.

[0080] The 3D NMR spectrum data of the obtained product are: 1H NMR (500MHz, CDCl3) δ8.11-8.07(m,2H),7.66(d,J=7.5Hz,1H),7.46(t,J=8.0Hz,1H),7.2 7-7.25(m,1H),7.18-7.14(m,1H),7.10(d,J=12.0Hz,1H),7.02-6.97(m,2H),4.05(s,2H); 13 CNMR(125MHz, CDCl3)δ186.4,152.9,148.4,141.3,141.2,136.3,136.0,135.9,133.8,133.7,129.4,124.0,121.8,41.0; HRMS(ESI)calcd for C 14 H 12 NO3 + (M+H) + 242.0812,found 242.0816.

[0081] Example 5

[0082] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0083]

[0084] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 1,3-benzodioxy-4-carbaldehyde 2e (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 mL) are charged into a 10 mL sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3e in an 82% yield.

[0085] The obtained product 3e NMR spectrum data is: 1 H NMR (500MHz, CDCl3) δ7.15-7.07(m,3H),6.91-6.90(m,2H),6.78-6.70(m,3H),5.90(s,2H),3.92(s,2H); 13 C NMR (125MHz, CDCl3) δ186.6,152.9,147.2,146.0,140.5,135.5,135.2,133.7,132.9,123.6,121.6,120.3,107.1,100.6,34.1; HRMS(ESI)calcd for C 15 H 15O2 + (M+H) + 241.0859,found 241.0864.

[0086] Example 6

[0087] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0088]

[0089] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 2-naphthaldehyde 2f (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3f in an 84% yield.

[0090] The 3f NMR spectrum data of the obtained product are: 1 H NMR(400MHz, CDCl3)δ7.78(t,J=8.8Hz,3H),7.69(s,1H),7.47-7.40(m,2H),7 .34(dd,J=8.6,1.8Hz,1H),7.14-7.06(m,3H),6.90-6.82(m,2H),4.12(s,2H); 13 C NMR (100MHz, CDCl3) δ186.8,154.8,140.8,136.7,135.9,135.7,133.8,133.7,133 .0,132.3,128.3,128.1,128.1,127.7,127.7,126.1,125.6,40.7; HRMS(ESI)calcd for C 18 H 15 O + (M+H) + 247.1117, found 247.1121.

[0091] Example 7

[0092] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0093]

[0094] The specific synthesis process is as follows: tropinone quaternary ammonium salt 1a (0.22 mmol), 9-anthracenecarboxaldehyde 2 g (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain 3 g of the desired product in a yield of 56%.

[0095] The NMR spectrum data of the obtained product 3g are: 1 H NMR (500MHz, CDCl3) δ8.47(s,1H),8.07-8.05(m,2H),7.99(d,J=8.0Hz,2H),7.49-7.44(m,4H),7.35(d,J=12.0H z,1H),7.21(dd,J=12.0,8.0Hz,1H),6.87-6.83(m,1H),6.60(t,J=10Hz,1H),6.48(d,J=9.0Hz,1H),4.96(s,2H); 13 C NMR (125MHz, CDCl3) δ187.1,154.4,140.3,136.2,135.4,134.2,133.0,131.8,130.9,130.7,129.3,127.2,126.4,125.3,124.6,32.2; HRMS(ESI)calcd for C 22 H 17 O + (M+H) + 297.1274,found 297.1274.

[0096] Example 8

[0097] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0098]

[0099] The specific synthesis process is as follows: At room temperature, tropinone quaternary ammonium salt 1a (0.22 mmol), 9-ethyl-9H-carbazole-2-carboxaldehyde 2h (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain the target product 3h in a yield of 68%.

[0100] The 3h NMR spectrum data of the obtained product are:1 H NMR (500MHz, CDCl3) δ8.02(d,J=7.5Hz,1H),7.93(s,1H),7.39(t,J=7.5Hz,1H),7.31-7.25(m,3H),7.16(t,J =7.5Hz,1H),7.08-6.96(m,3H),6.74-6.73(m,2H),4.23(q,J=7.2Hz,2H),4.12(s,2H),1.33(t,J=7.0Hz,3H); 13 C NMR (125MHz, CDCl3) δ186.8,155.7,140.5,140.1,138.8,135.5,135.4,133.7,132.5,129.2,12 7.4,125.6,123.1,122.6,121.2,120.4,118.7,108.5,108.4,40.4,37.4,13.8; HRMS(ESI)calcd for C 22 H 20 NO + (M+H) + 314.1539, found 314.1543.

[0101] Example 9

[0102] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0103]

[0104] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 3-formylbenzofuran 2i (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain the target product 3i in a yield of 76%.

[0105] The 3i NMR spectrum data of the obtained product are: 1 H NMR (500MHz, CDCl3) δ7.54(s,1H),7.46(d,J=8.0Hz,1H),7.43(d,J=7.5Hz,1H),7.27( t,J=7.8Hz,1H),7.20-7.14(m,2H),7.12-7.08(m,2H),6.89-6.81(m,2H),4.02(s,2H); 13C NMR (125MHz, CDCl3) δ186.7,155.4,152.5,143.2,140.5,135.7,135.0,133.7,133.1,127.8,124.3,122.5,119.9,117.3,111.6,28.3; HRMS(ESI)calcd for C 16 H 13 O2 + (M+H) + 237.0910,found 237.0915.

[0106] Example 10

[0107] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0108]

[0109] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 3-acetylthiophene 2j (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3j in a 65% yield.

[0110] The NMR spectrum data of the obtained product 3j are: 1 H NMR (500MHz, CDCl3) δ7.28-7.27(m,1H),7.14-7.12(m,3H),7.07(d,J=2.0Hz,1H),6.97-6.92(m,3H),3.99(s,2H); 13 C NMR(125MHz, CDCl3)δ186.8,154.3,140.8,139.1,135.7,135.5,133.9,133.1,129.0,125.8,122.6,35.2; HRMS(EI)calcd for C 12 H 10 OS + (M + )202.0447,found 202.0444.

[0111] Example 11

[0112] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0113]

[0114] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 8-formyl-7-hydroxy-4-methylcoumarin 2k (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain the target product 3k in a yield of 52%.

[0115] The 3k NMR spectrum data of the obtained product are: 1 H NMR (500MHz, CDCl3) δ11.11 (s, 1H), 8.34 (d, J = 9.0Hz, 1H), 7.41-7.28 (m, 4H), 7.1 6(t,J=9.3Hz,1H),6.92(d,J=9.0Hz,1H),6.10(s,1H),4.13(s,2H),2.38(s,3H); 13 C NMR (125MHz, CDCl3) δ188.8,161.4,159.9,153.7,152.2,141.0,140.9,138.3, 136.1,135.3,124.3,115.1,113.1,112.8,110.80,29.9,19.0; HRMS(ESI)calcd for C 18 H 15 O4 + (M+H) + 295.0965,found 295.0962.

[0116] Example 12

[0117] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0118]

[0119] The specific synthesis process is as follows: tropinone quaternary ammonium salt 1a (0.22 mmol), phenylpropionaldehyde 2l (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3l in a yield of 77%.

[0120] The NMR spectrum data of the obtained product 3l are:1 H NMR (500MHz, CDCl3) δ7.29-7.26(m,2H),7.23-7.16(m,4H),7.12-7.06(m,2H),6.96-6.88(m,2H),2.71-2.68(m,4H),1.93-1.87(m,2H); 13 CNMR(125MHz, CDCl3)δ187.1,155.8,142.2,140.5,135.6,135.1,134.0,132.8,128.5,128.4,125.9,35.9,35.4,30.5; HRMS(EI)calcd for C 16 H 16 O + (M + )224.1196,found224.1193.

[0121] Example 13

[0122] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0123]

[0124] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 2-phenylpropanal 2m (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3m in a yield of 77%.

[0125] The 3m NMR spectrum data of the obtained product are: 1 H NMR (500MHz, CDCl3) δ7.27-7.24(m,2H),7.18-7.14(m,3H),7.06(d,J=4.0Hz,2H),6.93(d,J=9.0Hz,1H),6.86-6.82(m,1H),6 .80-6.76(m,1H),3.16(sext,J=7.1Hz,1H),2.95(dd,J=12.5,7.0Hz,1H),2.82(dd,J=12.5,7.5Hz,1H),1.30(d,J=7.0Hz,3H); 13CNMR(125MHz, CDCl3)δ187.2,153.9,146.7,140.5,136.3,135.5,133.7,132.8,128.4,127.2,126.1,45.1,38.6,21.6; HRMS(EI)calcd forC 16 H 16 O + (M + )224.1196,found 224.1193.

[0126] Example 14

[0127] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0128]

[0129] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), n-octanal 2n (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3n in a yield of 68%.

[0130] The 3n NMR spectrum data of the obtained product are: 1 H NMR(500MHz, CDCl3)δ7.25(d,J=8.5Hz,1H),7.12-7.05(m,2H),6.98-6.89(m,2H) ,2.64(t,J=7.8Hz,2H),1.59-1.53(m,2H),1.37-1.26(m,10H),0.89-0.86(m,3H); 13 C NMR(125MHz, CDCl3)δ187.2,156.4,140.4,135.4,134.8,134.0,132.5,35.7,32.0,29.8,29.6,29.4,29.0,22.8,14.2; HRMS(EI)calcd for C 15 H 22 O + (M + )218.1665,found 218.1662.

[0131] Example 15

[0132] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0133]

[0134] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), cyclohexanecarboxaldehyde 2o (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3o in a yield of 53%.

[0135] The 3o NMR spectrum data of the obtained product are: 1 H NMR(500MHz, CDCl3)δ7.21(d,J=8.5Hz,1H),7.13-7.07(m,2H),6.98-6.90(m,2H),2 .54(d,J=7.0Hz,2H),1.69-1.61(m,6H),1.26-1.10(m,3H),0.95(q,J=10.8Hz,2H); 13 C NMR(125MHz, CDCl3)δ187.3,154.8,140.4,136.1,135.5,133.9,132.7,43.8,37.0,33.6,26.6,26.4; HRMS(EI)calcd for C 14 H 18 O + (M + )202.1352,found 202.1349.

[0136] Example 16

[0137] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0138]

[0139] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), tetrahydropyran-4-carboxaldehyde 2p (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1) to obtain the target product 3p in a yield of 59%.

[0140] The 3p NMR spectrum data of the obtained product are: 1HNMR (500MHz, CDCl3) δ7.22-7.20(m,1H),7.13-7.09(m,1H),7.05(d,J=12.0Hz,1H),6.97-6.91(m,2H),3.93(dd,J=11.0,4.0Hz,2H) ,3.34(td,J=11.8,1.5Hz,2H),2.59(d,J=7.0Hz,2H),1.97-1.88(m,1H),1.57(dd,J=13.0,1.5Hz,2H),1.34(qd,J=12.3,4.5Hz,2H); 13 C NMR(125MHz, CDCl3)δ187.2,153.4,140.6,136.2,135.5,133.6,133.0,68.0,43.5,33.9,33.3; HRMS(ESI)calcd for C 13 H 17 O2 + (M+H) + 205.1223,found205.1227.

[0141] Example 17

[0142] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0143]

[0144] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde 2q (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain the target product 3q in a yield of 49%.

[0145] The 3q NMR spectrum data of the obtained product are: 1 H NMR (500MHz, CDCl3) δ7.20 (dd, J=7.5, 2.0Hz, 1H), 7.13-7.09 (m, 1H), 7.05 (d, J=12.0Hz, 1H), 6.97-6.91 (m, 2H), 4. 06(s,2H),2.64-2.58(m,4H),1.88-1.79(m,1H),1.62(d,J=13.5Hz,2H),1.45(s,9H),1.15(qd,J=12.4,4.3Hz,2H); 13C NMR(125MHz, CDCl3)δ187.1,154.9,153.5,140.6,136.2,135.5,133.6,132.9,79.2,43.1,34.9,32.3,28.5; HRMS(ESI)calcd for C 18 H 26 NO3 + (M+H) + 304.1907,found304.1910.

[0146] Example 18

[0147] According to the following reaction formula, 2-substituted cycloheptatrienone compounds were synthesized:

[0148]

[0149] The specific synthesis process is as follows: Tropinone quaternary ammonium salt 1a (0.22 mmol), citronellal 2r (0.2 mmol), triethylenediamine (0.08 mmol), and methanol (1.2 ml) are charged into a 10 ml sealed tube equipped with a magnetic stirrer at room temperature. The mixture is heated to 100°C in an oil bath, stirred for 10 hours, cooled to room temperature, and concentrated under reduced pressure. The residue is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain the target product 3r in a yield of 71%.

[0150] The 3r NMR spectrum data of the obtained product are: 1 H NMR (500MHz, CDCl3) δ7.24(d,J=8.5Hz,1H),7.11-7.03(m,2H),6.97-6.87(m,2H),5.10(t,J=7.3Hz,1H),2.72-2.58(m,2H), 2.05-1.92(m,2H),1.68(s,3H),1.60(s,3H),1.58-1.47(m,2H),1.43-1.34(m,2H),1.23-1.15(m,1H),0.95(d,J=6.5Hz,3H); 13 C NMR (125MHz, CDCl3) δ187.0,156.7,140.3,135.3,134.6,133.9,132.4,131.1,124.9,36.9,36.2,33.2,32.6,25.8,25.5,19.5,17.7; HRMS(EI)calcd forC 17 H 24 O + (M + )244.1822,found 244.1820.

[0151] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for synthesizing a 2-substituted cycloheptatrienone compound, comprising the following steps: In the presence of an alkaline reagent, the compound of formula I and the compound of formula II are heated in a solvent to react to obtain a 2-substituted cycloheptatrienone compound of formula III; In Formula I, R 1 and R 2 independently selected from methyl, n-butyl, allyl or benzyl, X - It is a negative ion; The compound of formula II is p-bromobenzaldehyde, p-methoxybenzaldehyde, 2-methylbenzaldehyde, 3-nitrobenzaldehyde, 1,3-benzodioxy-4-carbaldehyde, 2-naphthaldehyde, 9-anthracenecarboxaldehyde, 9-ethyl-9H-carbazole-2-carboxaldehyde, 3-formylbenzofuran, 3-acetylthiophene, 8-formyl-7-hydroxy-4-methylcoumarin, phenylpropionaldehyde, 2-phenylpropionaldehyde, n-octanal, cyclohexanecarboxaldehyde, tetrahydropyran-4-carbaldehyde, 1-tert-butyloxycarbonylpiperidine-4-carbaldehyde or citronellal; The temperature of the heating reaction is 80-120°C.

2. The synthesis method according to claim 1, wherein The R 1 and R 2 All are methyl.

3. The synthesis method according to claim 1, wherein The negative ion is a bromide negative ion, an iodide negative ion or a trifluoromethanesulfonate negative ion.

4. The synthesis method according to claim 1, characterized in that The alkaline agent is an organic base and / or an inorganic base.

5. The synthesis method according to claim 1, characterized in that The molar ratio of the compound of formula I, the compound of formula II and the alkaline agent is (1-1.2):1:(0.2-0.6).

6. The synthesis method according to claim 1, characterized in that The heating reaction time is 6 to 15 hours.

7. The synthesis method according to claim 1, characterized in that The solvent is an alcohol solvent.

8. The synthesis method according to claim 1, characterized in that Also includes: After the heating reaction is completed, the obtained reaction product is subjected to solvent removal and purification.

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