A method for synthesizing cyclopentyl-substituted fatty amides

Abstract

The application belongs to the technical field of medicine and chemical industry, and discloses a synthesis method of a cyclopentyl-substituted fatty amide compound. The cyclopentyl-substituted fatty amide compound is synthesized through a nickel-catalyzed cyclization reaction of an alkenyl amide and 1,3-dihalogenated alkane. The method has the advantages of easy raw material, simple synthesis steps, no need of using active organic metal reagent or expensive ligand, mild reaction condition, few side reactions, simple post-treatment and suitability for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and specifically relates to a method for synthesizing cyclopentyl-substituted fatty amides. Background Technology

[0002] Cyclopentyl-substituted fatty amides and their carboxylic acids, esters, amines, and alcohol derivatives are widely used in the production processes of pharmaceuticals and fine chemicals due to their general biological activity and unique cyclopentane structure.

[0003] Currently, the main methods for synthesizing cyclopentyl-substituted fatty amide compounds are as follows:

[0004] 1. Cyclopentyl-substituted fatty amides were synthesized by direct condensation reaction of cyclopentyl-substituted carboxylic acids and 8-aminoquinoline (Org. Lett. 2022, 24, 2738-2743), as shown in the following formula.

[0005]

[0006] The disadvantages of this route are: the range of cyclopentylcarboxylic acid feedstocks is narrow and the cost is too high. At the same time, the use of 1.3 equivalents of condensing agent EDCI and 0.1 equivalents of catalyst DMAP is not only expensive but also requires a large amount, making it unsuitable for large-scale synthesis.

[0007] 2. Cyclopentyl-substituted fatty amides were obtained by amidation reaction of cyclopentyl-substituted acyl chlorides and 8-aminoquinoline (Chem.Sci.2016,7,2804-2808), as shown in the following formula.

[0008]

[0009] The disadvantage of this route is that although using acyl chloride as a raw material avoids the use of expensive condensing agents, acyl chloride is reactive, difficult to store, and requires conversion through carboxylic acid. The limited source and high price of carboxylic acid still limit the scale of the reaction.

[0010] 3. When cyclopentyl-substituted carboxylic acid raw materials cannot be obtained directly, the preparation of cyclopentyl-substituted fatty amides usually requires complex chemical synthesis steps (Chem.Sci.2017,8,2431-2435), as shown in the following formula.

[0011]

[0012] The disadvantages of this route are: the synthesis involves a series of complex steps including α-alkyl substitution, ester hydrolysis, acyl chloride synthesis, and amidation, making the route cumbersome and unable to reduce production costs. The reaction also requires a highly reactive strong base and anhydrous reaction conditions, placing high demands on the production process, generating a large amount of synthetic waste, and posing safety concerns.

[0013] 4. Complex cyclopentyl-substituted amides can also be synthesized from simple cyclopentyl-substituted amides and iodoalkanes via palladium-catalyzed β-C–H alkylation reactions (J.Am.Chem.Soc.2013,135,12135-12141), as shown in the following formula.

[0014]

[0015] The disadvantages of this route are: the reaction is only applicable to the alkylation of iodomethane or ethyl iodopropionate, the range of synthesized cyclopentyl substituted amides is too narrow, and it requires a noble metal palladium catalyst and a large amount of silver salt, resulting in high reaction costs. The reaction needs to be carried out at 110°C in an inert gas atmosphere, which presents significant challenges for large-scale production.

[0016] In summary, the development of a novel synthetic method for cyclopentyl-substituted fatty amide compounds is of great significance in overcoming the difficulties in the synthesis of cyclopentyl-substituted fatty amides, such as high cost of raw materials and reagents, narrow range of applications, complex operation, and large amount of waste generated. Summary of the Invention

[0017] In view of this, the technical problem to be solved by the present invention is to provide a method for synthesizing cyclopentyl-substituted fatty amides. This method uses readily available raw materials, involves simple post-processing, employs mild reaction conditions, and yields high product yields.

[0018] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0019] This invention provides a method for synthesizing cyclopentyl-substituted fatty amides, the synthesis steps of which are as follows:

[0020] The raw materials alkenylamide 1, 1,3-dihaloalkane 2, nickel catalyst, reducing agent and auxiliary reagent were added to the reaction solvent to carry out a cyclization reaction to synthesize a fatty amide compound 3 containing cyclopentyl substitution.

[0021] The reaction equations for the above synthesis method are as follows:

[0022]

[0023] In this invention, alkenylamide 1 is synthesized via a known synthetic route (Adv. Synth. Catal. 2022, 364, 1109-1116). The reaction steps are as follows: alkenyl carboxylic acid, amine, HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), and DMAP (4-dimethylaminopyridine) are stirred in dichloromethane solvent at room temperature for 12 h. The reaction is quenched with water, and the mixed solution is extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure to obtain the crude product. Further column chromatography separation yields alkenylamide raw material 1. The yield of the alkenylamide is generally above 95%. The reaction equation is as follows:

[0024]

[0025] In the above-mentioned method for synthesizing alkenylamide raw materials, the alkenyl carboxylic acid is a β,γ-unsaturated carboxylic acid or a γ,δ-unsaturated carboxylic acid, and the synthesized alkenylamide is a β,γ-unsaturated amide or a γ,δ-unsaturated amide. The amine is preferably any one of 8-aminoquinoline, 2-methyl-8-aminoquinoline, 2-isopropyl-8-aminoquinoline, or 3-methyl-8-aminoquinoline; more preferably, it is 8-aminoquinoline.

[0026] Preferably, in the cyclopentyl-substituted fatty amide synthesis step, the 1,3-dihaloalkane is any one or more of 1,3-diiodoalkane, 1,3-dibromoalkane, 1,3-dichloroalkane, 1-iodo-3-bromoalkane, 1-bromo-3-iodoalkane, 1-iodo-3-chloroalkane, 1-chloro-3-iodoalkane, 1-bromo-3-chloroalkane, and 1-chloro-3-bromoalkane; more preferably, it is 1,3-dibromoalkane.

[0027] Preferably, the molar ratio of the 1,3-dibromoalkane to the alkenylamide is (1.0-3.0):1; more preferably (1.5-2.2):1; and even more preferably 2:1.

[0028] Preferably, in the cyclopentyl-substituted fatty amide synthesis step, the nickel catalyst is any one or more of nickel dichloride, nickel dibromide, nickel diiodide, and nickel diacetylacetonate; more preferably, it is nickel dibromide.

[0029] Preferably, the molar ratio of the nickel catalyst to the alkenylamide raw material is (0.02-0.2):1; more preferably (0.08-0.13):1; and even more preferably 0.1:1.

[0030] Preferably, in the cyclopentyl-substituted fatty amide synthesis step, the reducing agent is any one or more of zinc powder, magnesium powder, manganese powder, and iron powder; more preferably, it is manganese powder.

[0031] Preferably, the molar ratio of the reducing agent manganese powder to the alkenylamide raw material is (2.0-4.0):1; more preferably (2.5-3.2):1; and even more preferably 3:1.

[0032] Preferably, in the cyclopentyl-substituted fatty amide synthesis step, the auxiliary reagent is any one or more of sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, and potassium iodide; more preferably, it is sodium iodide.

[0033] Preferably, the molar ratio of the auxiliary reagent sodium iodide to the alkenylamide raw material is (1.0-3.0):1; more preferably (1.0-2.2):1; and even more preferably 2:1.

[0034] Preferably, in the cyclopentyl-substituted fatty amide synthesis step, the reaction solvent is any one or more of dichloromethane, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, and ethanol. More preferably, it is N,N-dimethylformamide or N,N-dimethylacetamide.

[0035] In this invention, the reaction temperature in the cyclopentyl-substituted fatty amide synthesis step is preferably 30–80°C; more preferably 60–80°C. In some specific embodiments of this invention, the reaction temperature is preferably 80°C.

[0036] The reaction time for the cyclopentyl-substituted fatty amide synthesis is preferably 16–36 h; more preferably 20–24 h. In some specific embodiments of the present invention, the reaction time is preferably 24 h.

[0037] The post-processing operation of this invention is simple. After the synthesis reaction of the cyclopentyl-substituted fatty amide is completed, the purification operation of the cyclopentyl-substituted fatty amide product is also included.

[0038] In some specific embodiments of the present invention, the purification steps are as follows: the reaction solution is transferred from the reaction tube to a round-bottom flask, the solvent is removed under reduced pressure, and the crude product is purified by column chromatography to obtain high-purity cyclopentyl-substituted fatty amide. The stationary phase used in the column chromatography is 300-400 mesh silica gel, and the eluent is a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:10.

[0039] Compared with existing technologies, the cyclopentyl-substituted fatty amide synthesis method provided by this invention uses alkenyl carboxylic acids and 1,3-dibromoalkane as raw materials, which are inexpensive and readily available. The synthesis route is simple, including the synthesis of alkenyl amide raw materials and nickel-catalyzed cyclization reaction to prepare the final product cyclopentyl-substituted fatty amide. The reaction cost is low, avoiding the use of expensive precious metal catalysts and ligands, and avoiding the use of strong acids, strong bases, unstable or difficult-to-obtain additives. The reaction conditions are mild and the operation is simple, requiring no anhydrous or oxygen-free reaction conditions, and the reaction temperature is moderate, below the boiling point of the solvent. The reaction has high selectivity, few side reactions, and high yield. It can synthesize a wide range of cyclopentyl-substituted fatty amides, not limited to a few raw materials or reaction reagents, and is suitable for large-scale production. Attached Figure Description

[0040] Figure 1 The hydrogen nuclear magnetic resonance spectrum of N-(quinolin-8-yl)-2-cyclopentylacetamide (3a) prepared in Example 1;

[0041] Figure 2 The carbon NMR spectrum of N-(quinolin-8-yl)-2-cyclopentylacetamide (3a) prepared in Example 1;

[0042] Figure 3 The 1H NMR spectrum of N-(quinolin-8-yl)-2-methyl-2-cyclopentylacetamide (3b) prepared in Example 2;

[0043] Figure 4 The carbon NMR spectrum of N-(quinolin-8-yl)-2-methyl-2-cyclopentylacetamide (3b) prepared in Example 2;

[0044] Figure 5 The 1H NMR spectrum of N-(quinolin-8-yl)-2,2-dimethyl-2-cyclopentylacetamide (3c) prepared in Example 3;

[0045] Figure 6 The carbon NMR spectrum of N-(quinolin-8-yl)-2,2-dimethyl-2-cyclopentylacetamide (3c) prepared in Example 3;

[0046] Figure 7 The 1H NMR spectrum of N-(quinolin-8-yl)-3-cyclopentylpropionamide (3d) prepared in Example 4;

[0047] Figure 8 The carbon NMR spectrum of N-(quinolin-8-yl)-3-cyclopentylpropionamide (3d) prepared in Example 4;

[0048] Figure 9 The 1H NMR spectrum of N-(quinolin-8-yl)-2,2-dimethyl-3-cyclopentylpropionamide (3e) prepared in Example 5;

[0049] Figure 10 The carbon NMR spectrum of N-(quinolin-8-yl)-2,2-dimethyl-3-cyclopentylpropionamide (3e) prepared in Example 5;

[0050] Figure 11 The 1H NMR spectrum of N-(quinolin-8-yl)-2-(3-methylcyclopentyl)acetamide (3f) prepared in Example 6;

[0051] Figure 12 The carbon NMR spectrum of N-(quinoline-8-yl)-2-(3-methylcyclopentyl)acetamide (3f) prepared in Example 6. Detailed Implementation

[0052] To further illustrate the present invention, the synthesis method of cyclopentyl-substituted fatty amides provided by the present invention will be described in detail below with reference to embodiments.

[0053] Example 1

[0054] Preparation of N-(quinolin-8-yl)-2-cyclopentylacetamide (3a)

[0055] 10.9 mg (0.05 mmol) of nickel dibromide, 106 mg (0.5 mmol) of N-(quinolin-8-yl)-3-butenamide, 202 mg (1.0 mmol) of 1,3-dibromopropane, 82.5 mg (1.5 mmol) of manganese powder, and 150 mg (1.0 mmol) of sodium iodide were added to a 25 mL dry Schlenk tube. 5 mL of N,N-dimethylacetamide was added, the Schlenk stopcock was tightened, and the mixture was placed on a stirrer at 80 °C for 24 h. After the reaction was complete, the reaction solution was transferred to a round-bottom flask, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a 1:10 mixture of ethyl acetate and petroleum ether) to obtain a colorless oily liquid product 3a (122 mg, yield 96%).

[0056] The structure and NMR spectral data of compound 3a are as follows:

[0057]

[0058] 1H NMR(400MHz, CDCl3)δ9.81(brs,1H),8.85–8.72(m,2H),8.16(dd,J=8.3,1.6Hz,1H),7.59–7.41(m,3H) ,2.57(d,J=7.4Hz,2H),2.43(p,J=7.7Hz,1H),2.01–1.88(m,2H),1.78–1.53(m,4H),1.36–1.20(m,2H). 13 C NMR (101MHz, CDCl3) δ171.6,148.1,138.3,136.4,134.5,127.9,127.4,121.5,121.3,116.4,44.5,37.2,32.6,25.0.

[0059] Example 2

[0060] Preparation of N-(quinolin-8-yl)-2-methyl-2-cyclopentylacetamide (3b)

[0061] 10.9 mg (0.05 mmol) of nickel dibromide, 113 mg (0.5 mmol) of N-(quinolin-8-yl)-2-methyl-3-butenamide, 202 mg (1.0 mmol) of 1,3-dibromopropane, 82.5 mg (1.5 mmol) of manganese powder, and 150 mg (1.0 mmol) of sodium iodide were added to a 25 mL dry Schlenk tube. 5 mL of N,N-dimethylacetamide was added, the Schlenk stopcock was tightened, and the tube was placed on a stirrer at 80 °C for 24 h. After the reaction was complete, the reaction solution was transferred to a round-bottom flask, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a 1:10 mixture of ethyl acetate and petroleum ether) to give a colorless oily liquid product 3b (122 mg, 91% yield).

[0062] The structure and NMR spectral data of compound 3b are as follows:

[0063]

[0064] 1 H NMR(400MHz, CDCl3)δ9.83(brs,1H),8.85–8.76(m,2H),8.16(dd,J=8.2,1.7Hz,1H),7.59–7.41(m,3H),2.44–2 .31(m,1H),2.22–2.08(m,1H),1.98–1.78(m,2H),1.72–1.49(m,4H),1.34(d,J=6.8Hz,3H),1.32–1.16(m,2H).13 C NMR (101MHz, CDCl3) δ175.4,148.1,138.4,136.3,134.5,127.9,127.4,121.5,121.3,116.4,48.9,44.1,31.3,30.6,25.2,25.0,17.1.

[0065] Example 3

[0066] Preparation of N-(quinolin-8-yl)-2,2-dimethyl-2-cyclopentylacetamide (3c)

[0067] Add 10.9 mg (0.05 mmol) of nickel dibromide, 120 mg (0.5 mmol) of N-(quinolin-8-yl)-2,2-dimethyl-3-butenamide, 202 mg (1.0 mmol) of 1,3-dibromopropane, 82.5 mg (1.5 mmol) of manganese powder, and 150 mg (1.0 mmol) of sodium iodide to a 25 mL dry Schlenk tube. Add 5 mL of N,N-dimethylacetamide, tighten the Schlenk stopcock, and react on a stirrer at 80 °C for 24 h. After the reaction is complete, transfer the reaction solution to a round-bottom flask, remove the solvent under reduced pressure, and separate the crude product by column chromatography (using a 300-400 mesh silica gel column, with an eluent of ethyl acetate and petroleum ether at a volume ratio of 1:10) to obtain a colorless oily liquid product 3c (118 mg, yield 84%).

[0068] The 3c structure and NMR spectral data of the compound are as follows:

[0069]

[0070] 1 H NMR(400MHz, CDCl3) δ10.26(brs,1H),8.85–8.76(m,2H),8.15(dd,J=8.3,1.5Hz,1H),7.58 –7.40(m,3H),2.39–2.26(m,1H),1.79–1.67(m,2H),1.66–1.50(m,4H),1.46–1.32(m,8H). 13 C NMR (101MHz, CDCl3) δ176.9,148.2,138.8,136.3,134.7,127.9,127.4,121.5,121.1,116.2,48.5,45.6,27.5,25.5,22.8.

[0071] Example 4

[0072] Preparation of N-(quinolin-8-yl)-3-cyclopentylpropionamide (3d)

[0073] 10.9 mg (0.05 mmol) of nickel dibromide, 113 mg (0.5 mmol) of N-(quinolin-8-yl)-4-pentenamide, 202 mg (1.0 mmol) of 1,3-dibromopropane, 82.5 mg (1.5 mmol) of manganese powder, and 150 mg (1.0 mmol) of sodium iodide were added to a 25 mL dry Schlenk tube. 5 mL of N,N-dimethylacetamide was added, the Schlenk stopcock was tightened, and the tube was placed on a stirrer at 80 °C for 24 h. After the reaction was complete, the reaction solution was transferred to a round-bottom flask, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a 1:10 mixture of ethyl acetate and petroleum ether) to give a colorless oily liquid product 3d (119 mg, yield 88%).

[0074] The 3d structure and NMR spectral data of the compound are as follows:

[0075]

[0076] 1 H NMR(400MHz, CDCl3)δ9.81(brs,1H),8.85–8.75(m,2H),8.16(dd,J=8.3,1.6Hz,1H),7.58– 7.41(m,3H),2.58(t,J=7.3,2H),1.95–1.76(m,5H),1.69–1.45(m,4H),1.23–1.10(m,2H). 13 C NMR (101MHz, CDCl3) δ172.0,148.1,138.3,136.4,134.5,127.9,127.4,121.5,121.3,116.3,39.7,37.6,32.5,31.8,25.2.

[0077] Example 5

[0078] Preparation of N-(quinolin-8-yl)-2,2-dimethyl-3-cyclopentylpropionamide (3e)

[0079] 10.9 mg (0.05 mmol) of nickel dibromide, 127 mg (0.5 mmol) of N-(quinolin-8-yl)-2,2-dimethyl-4-pentenamide, 202 mg (1.0 mmol) of 1,3-dibromopropane, 82.5 mg (1.5 mmol) of manganese powder, and 150 mg (1.0 mmol) of sodium iodide were added to a 25 mL dry Schlenk tube. 5 mL of N,N-dimethylacetamide was added, the Schlenk stopcock was tightened, and the mixture was placed on a stirrer at 80 °C for 24 h. After the reaction was complete, the reaction solution was transferred to a round-bottom flask, and the solvent was removed by vacuum distillation. The crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a 1:10 mixture of ethyl acetate and petroleum ether) to give a colorless oily liquid product 3e (120 mg, yield 81%).

[0080] The structure and NMR spectral data of compound 3e are as follows:

[0081]

[0082] 1 H NMR(400MHz, CDCl3)δ10.27(brs,1H),8.16(dd,J=8.2,1.0Hz,2H),8.20–8.09(m,1H),7.58–7.41(m, 3H),1.94–1.73(m,4H),1.60–1.48(m,2H),1.46–1.33(m,8H),1.19–1.03(m,2H),0.97–0.67(m,1H). 13 C NMR (101MHz, CDCl3) δ177.0,148.2,138.7,136.3,134.7,127.9,127.5,121.5,121.1,116.1,47.8,43.9,37.3,34.0,26.3,24.9.

[0083] Example 6

[0084] Preparation of N-(quinolin-8-yl)-2-(3-methylcyclopentyl)acetamide (3f)

[0085] Add 10.9 mg (0.05 mmol) of nickel dibromide, 106 mg (0.5 mmol) of N-(quinolin-8-yl)-3-butenamide, 216 mg (1.0 mmol) of 2-methyl-1,3-dibromopropane, 82.5 mg (1.5 mmol) of manganese powder and 150 mg (1.0 mmol) of sodium iodide to a 25 mL dry Schlenk tube, add 5 mL of N,N-dimethylacetamide, tighten the Schlenk stopcock, and react on a stirrer at 80 °C for 24 h. After the reaction was completed, the reaction solution was transferred to a round-bottom flask, the solvent was removed by vacuum distillation, and the crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:10) to obtain a colorless oily liquid product 3f (127 mg, yield 95%, a mixture of cis and trans diastereomers).

[0086] The structure and NMR spectral data of compound 3f are as follows:

[0087]

[0088] 1 H NMR(400MHz, CDCl3)δ9.81(brs,1H),8.84–8.73(m,2H),8.15(dd,J=8.2,1.3Hz,1H),7.61–7.38(m,3H),2.67–2 .39(m,3H),2.16–1.75(m,3H),1.62–1.48(m,1H),1.46–1.11(m,2H),0.99(t,J=7.2Hz,3H),0.92–0.80(m,1H). 13 C NMR (101MHz, CDCl3) δ171.6,148.1,138.3,136.3,134.5,127.9,127.4,121.5,121.3,116 .3,44.99,44.95,42.3,40.4,37.4,35.9,34.6,34.5,33.5,33.1,33.0,31.7,21.2,20.9.

[0089] Example 7

[0090] Preparation of N-(quinolin-8-yl)-2-(2,4-dimethylcyclopentyl)acetamide (3g)

[0091] Add 10.9 mg (0.05 mmol) of nickel dibromide, 106 mg (0.5 mmol) of N-(quinolin-8-yl)-3-butenamide, 230 mg (1.0 mmol) of 2,4-dibromopentane, 82.5 mg (1.5 mmol) of manganese powder, and 150 mg (1.0 mmol) of sodium iodide to a 25 mL dry Schlenk tube. Add 5 mL of N,N-dimethylacetamide, tighten the Schlenk stopcock, and react on a stirrer at 80 °C for 24 h. After the reaction is complete, transfer the reaction solution to a round-bottom flask, remove the solvent under reduced pressure, and separate the crude product by column chromatography (using a 300-400 mesh silica gel column, with an eluent of ethyl acetate and petroleum ether at a volume ratio of 1:10) to obtain 3 g (127 mg, 90% yield, a mixture of various diastereomers) of a colorless oily liquid product.

[0092] The structure and NMR spectral data of compound 3g are as follows:

[0093]

[0094] 1 H NMR (400MHz, CDCl3) δ9.82(brs,1H),8.84–8.75(m,2H),8.15(d,J=8.2Hz,1H),7.59–7.39(m,3H),2.81–2. 47(m,2H),2.48–2.13(m,2H),2.13–1.90(m,2H),1.67–1.55(m,1H),1.57–1.35(m,1H),1.11–0.79(m,7H). 13 C NMR (101MHz, CDCl3) δ171.93,171.91,171.7,148.08,148.05,138.3,136.3,134.53,134.50 ,127.9,127.4,121.5,121.3,116.3,45.5,44.5,43.62,43.57,43.4,43.0,42.6,42.34,42.3 2,41.6,40.4,40.3,40.1,39.7,39.6,39.3,39.2,38.53,38.46,36.58,36.56,35.6,33.3,32.4,32.0,31.8,30.3,23.2,22.4,21.7,21.6,21.4,20.1,19.7,19.5,19.0,17.1,15.3,14.4.

[0095] Example 8

[0096] Preparation of N-(quinolin-8-yl)-2-(3-benzylcyclopentyl)acetamide (3h)

[0097] Add 10.9 mg (0.05 mmol) of nickel dibromide, 106 mg (0.5 mmol) of N-(quinolin-8-yl)-3-butenamide, 292 mg (1.0 mmol) of 2-benzyl-1,3-dibromopentane, 82.5 mg (1.5 mmol) of manganese powder and 150 mg (1.0 mmol) of sodium iodide to a 25 mL dry Schlenk tube, add 5 mL of N,N-dimethylacetamide, tighten the Schlenk stopcock, and react on a stirrer at 80 °C for 24 h. After the reaction was completed, the reaction solution was transferred to a round-bottom flask, the solvent was removed by vacuum distillation, and the crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:10) to obtain a colorless oily liquid product 3h (149mg, yield 87%, a mixture of cis and trans diastereomers).

[0098] The structure and NMR spectral data of compound 3h are as follows:

[0099]

[0100] 1 H NMR(400MHz, CDCl3)δ9.79(brs,1H),8.87–8.71(m,2H),8.15(dd,J=8.3,1.4Hz,1H ),7.58–7.40(m,3H),7.25(t,J=7.4Hz,2H),7.21–7.11(m,3H),2.70–2.52(m,4H),2 .52–2.41(m,0.62H),2.37–2.15(m,1H),2.15–2.00(m,1H),2.01–1.90(m,0.47H), 1.89–1.65(m,2H),1.58–1.49(m,0.48H),1.48–1.22(m,2H),1.06–0.94(m,0.52H). 13 C NMR (101MHz, CDCl3) δ171.38,171.36,148.1,141.89,141.86,138.3,136.3,134.5,128.8,128.7,128.1,127.9,127. 4,125.6,121.5,121.3,116.3,44.85,44.82,42.4,42.3,41.8,40.6,40.2,38.1,36.9,35.7,32.6,32.5,31.3,31.2.

[0101] Example 9

[0102] Preparation of N-(quinolin-8-yl)-2-(3-methoxypropylcyclopentyl)acetamide (3i)

[0103] Add 10.9 mg (0.05 mmol) of nickel dibromide, 106 mg (0.5 mmol) of N-(quinoline-8-yl)-3-butenamide, 274 mg (1.0 mmol) of 2-methoxypropyl-1,3-dibromopentane, 82.5 mg (1.5 mmol) of manganese powder and 150 mg (1.0 mmol) of sodium iodide to a 25 mL dry Schlenk tube, add 5 mL of N,N-dimethylacetamide, tighten the Schlenk stopcock, and react on a stirrer at 80 °C for 24 h. After the reaction was completed, the reaction solution was transferred to a round-bottom flask, the solvent was removed by vacuum distillation, and the crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:10) to obtain a colorless oily liquid product 3i (138 mg, yield 85%, a mixture of cis and trans diastereomers).

[0104] The structure and NMR spectral data of compound 3i are as follows:

[0105]

[0106] 1 H NMR(400MHz, CDCl3)δ9.80(brs,1H),8.87–8.73(m,2H),8.16(dd,J=8.3,1.5Hz,1H),7.59–7.39(m,3H),3.46 –3.20(m,5H),2.65–2.50(m,2H),2.21–1.75(m,3H),1.65–1.49(m,3H),1.47–1.11(m,5H),0.96–0.80(m,1H). 13 C NMR (101MHz, CDCl3) δ171.5,148.1,138.3,136.3,134.5,127.9,127.4,121.5,121.3,116.3,73.0 ,58.5,44.85,44.83,40.3,39.8,38.6,38.4,37.1,35.9,32.9,32.8,32.7,31.5,31.4,28.7,28.6.

[0107] Example 10

[0108] Preparation of N-(quinolin-8-yl)-2-(3-p-methylphenylcyclopentyl)acetamide (3j)

[0109] Add 10.9 mg (0.05 mmol) of nickel dibromide, 106 mg (0.5 mmol) of N-(quinolin-8-yl)-3-butenamide, 292 mg (1.0 mmol) of 2-p-methylphenyl-1,3-dibromopentane, 82.5 mg (1.5 mmol) of manganese powder and 150 mg (1.0 mmol) of sodium iodide to a 25 mL dry Schlenk tube, add 5 mL of N,N-dimethylacetamide, tighten the Schlenk stopcock, and react on a stirrer at 80 °C for 24 h. After the reaction was completed, the reaction solution was transferred to a round-bottom flask, the solvent was removed by vacuum distillation, and the crude product was separated by column chromatography (the column was packed with 300-400 mesh silica gel, and the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:10) to obtain a colorless oily liquid product 3j (139 mg, yield 81%, a mixture of cis and trans diastereomers).

[0110] The structure and NMR spectral data of compound 3j are as follows:

[0111]

[0112] 1 H NMR(400MHz, CDCl3)δ9.85(brs,1H),8.85–8.76(m,2H),8.17(d,J=8.2Hz,1H),7.59–7.41(m,3H),7.20–7.04(m,4H),3.26–3.04(m,1H) ,2.84–2.73(m,0.59H),2.71–2.61(m,2H),2.43–2.34(m,0.41H),2.31(s,3H),2.25–1.84(m,3H),1.81–1.54(m,2H),1.54–1.34(m,1H). 13 C NMR (101MHz, CDCl3) δ171.29,171.26,148.1,143.2,142.7,138.3,136.4,135.3,135.2,134.5,128.9,127.9,127. 4,126.9,126.8,121.6,121.4,116.4,45.2,45.0,44.7,44.0,42.0,40.2,37.1,36.3,35.1,33.3,33.2,31.8,20.9.

[0113] In summary, the preparation method described in this invention is characterized by mild conditions, simple operation, and high safety for industrial production. The synthesis reaction of cyclopentyl-substituted fatty amides described in this invention involves few side reactions, high yield, simple post-processing, and low production cost, significantly improving the synthesis efficiency of cyclopentyl-substituted fatty amides and facilitating large-scale industrial production.

[0114] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing a cyclopentyl-substituted fatty amide, characterized in that, Compound 1, compound 2, nickel catalyst and reducing agent were added to the auxiliary reagents, and a cyclization reaction was carried out in the reaction solvent to synthesize fatty amide compound 3; The reaction equation for the synthesis method is as follows: ； Compound 1 is one of N-(quinolin-8-yl)-2-methyl-3-butenamide, N-(quinolin-8-yl)-2,2-dimethyl-3-butenamide, N-(quinolin-8-yl)-4-pentenamide, N-(quinolin-8-yl)-2,2-dimethyl-4-pentenamide and N-(quinolin-8-yl)-3-butenamide; Compound 2 is one of the compounds shown in formulas 2a-2f; ; The nickel catalyst is nickel dibromide; The reducing agent is manganese powder; The auxiliary reagent is sodium iodide. The reaction solvent is N,N-dimethylformamide; The molar ratio of the auxiliary reagent to compound 1 is (1.0~3.0):1; The fatty amide compound 3 is any one of the compounds shown in formulas 3a-3j: 。 2. The synthesis method according to claim 1, characterized in that, The molar ratio of the nickel catalyst to compound 1 is (0.02~0.2):

1.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of the reducing agent to compound 1 is (2.0~4.0):

1.

4. The synthesis method according to claim 1, characterized in that, The reaction conditions for the cyclization reaction are: continuous stirring at 60 ~ 80℃ for 20 ~ 24 h.

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