Synthesis method of beta-aryl ethyl amine medicine

Abstract

The invention discloses a synthesis method of a beta-aryl ethyl amine medicine, and belongs to the technical field of medicinal chemistry. The synthesis method comprises the following steps: S1, carrying out a reaction I on a mixed raw material containing a secondary amine compound and a nitrosation reaction solvent to obtain a nitrosamine compound; s2, a mixture containing a nitrosamine compound, aryl iodide, an oxidizing agent, a catalyst and a solvent is subjected to a reaction II, and an aryl ethyl amine prodrug is obtained; and S3, removing a nitroso group from the aryl ethyl amine drug precursor, so as to obtain the beta-aryl ethyl amine drug. The synthesis method takes simple and easily available initial raw materials as the starting end of a synthesis route, avoids the use of excessive metal compounds as oxidizing agents, reduces the synthesis cost and post-treatment difficulty, can be used for large-scale test, has high product purity, and is suitable for industrial production. The novel method for synthesizing the beta-aryl ethyl amine medicine, which is easy to operate, good in atom economy, high in selectivity, environment-friendly and novel, is realized.

Description

Technical Field

[0001] The present application relates to a method for synthesizing β-arylethylamine drugs, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] β-Arylethylamine compounds play an important role in the field of drug research and development. Many of these compounds have shown excellent pharmacological activities, such as potential application value in the treatment of cardiovascular diseases, nervous system diseases and anti-inflammatory. However, existing synthesis methods often have many problems such as cumbersome steps, low yields, and environmental unfriendliness, which limit the large-scale and efficient preparation of such drugs and further clinical application development. Therefore, it is of great significance to develop a simple, efficient and environmentally friendly method for the synthesis of various β-arylethylamine drugs. Summary of the invention

[0003] In order to solve the problems of excessive use of metal compounds as oxidants in the prior art of synthesizing β-arylethylamine compounds, resulting in high cost, difficulty in post-treatment and environmental pollution, the present application proposes a simple, efficient and environmentally friendly technical solution for the synthesis of β-arylethylamine drugs.

[0004] This application adopts the following technical solutions:

[0005] According to the first aspect of the present application, a method for synthesizing a β-arylethylamine drug is provided, comprising the following steps:

[0006] S1, reacting a mixed raw material containing a secondary amine compound and a nitrosation reaction solvent to obtain a nitrosamine compound;

[0007] S2, reacting a mixture containing a nitrosamine compound, an aryl iodide, an oxidant, a catalyst, and a solvent with II to obtain an arylethylamine drug precursor;

[0008] S3, removing the nitroso group from the arylethylamine drug precursor to obtain the β-arylethylamine drug;

[0009] The β-arylethylamine drug has a structure shown in Formula I-a6:

[0010]

[0011] Among them, R 1 is selected from the group consisting of methyl (Me), ethyl (Et), isopropyl (i-Pr), and isobutyl (i-Bu), R 3 Selected from hydrogen atom (-H), chlorine (-Cl), trifluoromethyl (-CF 3 )

[0012] Optionally, the secondary amine compound is selected from one of the structures shown in Formula I-a1:

[0013] Among them, R 1 , R 2 Independently selected from one of methyl (Me), ethyl (Et), isopropyl (i-Pr), and isobutyl (i-Bu).

[0014] Optionally, the nitrosation reaction solvent is selected from at least one of isoamyl nitrite and tert-butyl nitrite.

[0015] Optionally, the nitrosamine compound has a structure shown in Formula I-a3:

[0016] Among them, R 1 , R 2 Independently selected from one of methyl (Me), ethyl (Et), isopropyl (i-Pr), and isobutyl (i-Bu).

[0017] Optionally, the aryl iodide is selected from one of the structures shown in formula I-a4:

[0018] Among them, R 3 Selected from hydrogen atom (-H), chlorine (-Cl), trifluoromethyl (-CF 3 )

[0019] Optionally, the molar ratio of the secondary amine compound to the nitrosation reaction solvent is 1:1-2.

[0020] Optionally, the molar ratio of the nitrosamine compound to the aryl iodide is 1:1-5.

[0021] Optionally, the molar ratio of the nitrosamine compound to the oxidant is 1:1-5.

[0022] Optionally, the arylethylamine drug prodrug has the structure shown in Formula I-a5:

[0023] Formula I-a5, R 1 is selected from the group consisting of methyl (Me), ethyl (Et), isopropyl (i-Pr), and isobutyl (i-Bu), R 3 Selected from hydrogen atom (-H), chlorine (-Cl), trifluoromethyl (-CF 3 )

[0024] The oxidant is selected from at least one of silver tetrafluoroborate, silver trifluoroacetate, silver hexafluoroantimonate and silver acetate.

[0025] Optionally, the catalyst includes a metal catalyst and an organic hydroxypyridine-amide-ester catalyst.

[0026] Optionally, the metal catalyst is selected from palladium catalysts.

[0027] Optionally, the metal catalyst is selected from palladium acetate.

[0028] Optionally, the organic hydroxypyridine-amide-ester catalyst is selected from (5-nitro-6-oxo-1,6-dihydropyridine-2-carbonyl)glycine methyl ester.

[0029] (5-nitro-6-oxo-1,6-dihydropyridine-2-carbonyl)glycine methyl ester, the structural formula is shown in Formula I-b1:

[0030]

[0031] Optionally, the solvent is selected from hexafluoroisopropanol.

[0032] Optionally, the molar ratio of the nitrosamine compound to the metal catalyst is 1:0.01 to 0.1.

[0033] Optionally, the molar ratio of the nitrosamine compound to the organic hydroxypyridine-amide-ester catalyst is 1:0.01-0.1.

[0034] Optionally, the conditions of reaction I and reaction II independently include: reaction temperature of 60°C to 120°C, and reaction time of 8h to 48h.

[0035] Optionally, the step of removing the nitroso group from the arylethylamine drug precursor is selected from at least one of condition A and condition B;

[0036] Condition A comprises: stirring a mixture containing an arylethylamine drug precursor and a nitroso reduction catalyst A under acidic conditions;

[0037] Condition B comprises: vigorously stirring a mixture containing an arylethylamine drug precursor, a nitroso reduction catalyst B, and methanol in a reducing atmosphere.

[0038] Optionally, condition A specifically comprises: stirring a mixture containing an arylethylamine drug precursor, copper chloride, and concentrated hydrochloric acid under acidic conditions;

[0039] Optionally, condition B specifically includes: vigorously stirring a mixture containing an arylethylamine drug precursor, Raney nickel and methanol in a reducing atmosphere.

[0040] Optionally, in condition A, the molar ratio of the arylethylamine drug precursor to the nitroso reduction catalyst A is 1:10-20.

[0041] Optionally, in condition B, the molar ratio of the aromatic ethylamine drug precursor to the nitroso reduction catalyst B is 1:10-20.

[0042] Alternatively, after the reaction II, also include cooling to room temperature, using 10 milliliters of ethyl acetate diluted reaction mixture, and washing with saturated sodium bicarbonate solution to alkalize. Then, extract the mixture three times with ethyl acetate, merge organic phase, and use anhydrous sodium sulfate drying. Concentrated solvent under reduced pressure, and obtain corresponding product by column chromatography purification.

[0043] Optionally, in the condition A, the stirring process also includes monitoring by TLC thin layer chromatography.

[0044] Optionally, in the condition A, the stirring process further includes treating the reaction solution with an excess of saturated sodium carbonate and extracting with dichloromethane at least three times. The organic phases are combined, washed with a saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered and the solvent is removed under reduced pressure.

[0045] Optionally, in the condition B, after vigorous stirring, the solution is filtered through a diatomaceous earth plug, washed with a saturated saline solution and dried over sodium sulfate. The solvent is then removed by distillation under reduced pressure.

[0046] The beneficial effects of this application include:

[0047] The synthesis method of β-arylethylamine drugs provided by the present application uses simple and readily available initial raw materials as the beginning of the synthesis route, avoids the use of excessive metal compounds as oxidants, reduces the synthesis cost and post-processing difficulty, and meets the needs of green chemistry; large-scale experiments can be carried out, and the obtained products are of high purity. The present invention realizes a method for synthesizing β-arylethylamine drugs that is easy to operate, has good atom economy, is highly selective, is environmentally friendly, novel, and practical. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The compound of the structure shown in Formula 4b-1 in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0049] Figure 2 The compound of the structure shown in Formula 4b-1 in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0050] Figure 3 The compound of the structure shown in Formula 4b-1 in Example 1 of the present application 19 F NMR spectrum ( 19 F-NMR);

[0051] Figure 4 The compound of the structure shown in Formula 4b in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0052] Figure 5 The compound of the structure shown in Formula 4b in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0053] Figure 6 The compound of the structure shown in Formula 4b in Example 1 of the present application 19 F NMR spectrum ( 19 F-NMR);

[0054] Figure 7 The compound of the structure shown in Formula 4c-1 in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0055] Figure 8 The compound of the structure shown in Formula 4c-1 in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0056] Fig. 9 The compound of the structure shown in Formula 4c in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0057] Fig.10 The compound of the structure shown in Formula 4c in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0058] Fig.11 The compound of the structure shown in Formula 4d-1 in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0059] Fig.12 The compound of the structure shown in Formula 4d-1 in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0060] Fig.13 The compound of the structure shown in Formula 4d in Example 1 of the present application 1 H NMR spectrum ( 1H-NMR);

[0061] Fig.14 The compound of the structure shown in Formula 4d in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0062] Fig.15 The compound of the structure shown in Formula 4e-1 in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0063] Fig.16 The compound of the structure shown in Formula 4e-1 in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR);

[0064] Fig.17 The compound of the structure shown in Formula 4e in Example 1 of the present application 1 H NMR spectrum ( 1 H-NMR);

[0065] Fig.18 The compound of the structure shown in Formula 4e in Example 1 of the present application 13 C NMR spectrum ( 13 C-NMR).

[0066] Fig.19 This is a schematic diagram of the synthesis process of β-arylethylamine drugs in the synthesis example of this application. DETAILED DESCRIPTION

[0067] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0068] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0069] Unless otherwise specified, conventional methods were used for testing and instrument settings were those recommended by the manufacturer.

[0070] Synthesis Example Synthesis of β-arylethylamine drugs

[0071] The schematic diagram of the synthesis process of β-arylethylamine drugs is as follows Fig.19 shown.

[0072] (1) Synthesis of β-arylation products

[0073] A magnetic stirrer was added to a 25 ml Schlenk tube, and a secondary amine compound (0.2 mmol) and isoamyl nitrite (0.3 mmol, 1.5 equivalents) were added under a nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 12 hours to obtain an N-nitrosamine intermediate, i.e., a nitrosamine compound (the secondary amine compound was almost completely converted into a pure N-nitrosamine intermediate). The obtained N-nitrosamine intermediate, a palladium acetate catalyst (0.005 mmol, 2.5 mol%), a hydroxypyridine-amide-ester catalyst (0.0035 mmol, 1.75 mol%), an oxidant (0.4 mmol, 2.0 equivalents), an aryl iodide (0.36 mmol, 1.8 equivalents) and hexafluoroisopropanol (1 ml) were added to the Schlenk tube under a nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with 10 ml of ethyl acetate and washed with saturated sodium bicarbonate solution for alkalization. Then, the mixture was extracted three times with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain the corresponding β-arylated product, i.e., arylethylamine drug precursor;

[0074] Wherein, the secondary amine compound is selected from one of the structures shown in formula I-a1:

[0075] Among them, R 1 , R 2 One independently selected from methyl (Me), ethyl (Et), isopropyl (i-Pr), isobutyl (i-Bu);

[0076] The structural formula of isoamyl nitrite is shown in Formula I-a2:

[0077]

[0078] The aryl iodide is selected from one of the structures shown in formula I-a4:

[0079] Among them, R 3 Selected from hydrogen atom (-H), chlorine (-Cl), trifluoromethyl (-CF 3 )

[0080] The oxidant is selected from at least one of silver tetrafluoroborate, silver trifluoroacetate, silver hexafluoroantimonate, and silver acetate;

[0081] The hydroxypyridine-amide-ester catalyst is (5-nitro-6-oxo-1,6-dihydropyridine-2-carbonyl)glycine methyl ester, and the structural formula is shown in Formula I-b1:

[0082]

[0083] (2) Removal of nitroso groups

[0084] The β-arylation product obtained in step (1) is denitrosated by the method of condition A or condition B:

[0085] Condition A: In a 25 ml Schlenk flask equipped with a magnetic stirrer, the β-arylated product (0.2 mmol) was added. To the flask was further added a cold concentrated hydrochloric acid solution (2 ml) containing cupric chloride (3.5 mmol). The resulting mixture was stirred at room temperature for 6 hours and monitored by TLC thin layer chromatography. The reaction solution was treated with excess saturated sodium carbonate and extracted at least three times with dichloromethane. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The pure denitroso product was obtained without further purification.

[0086] Condition B: In a 25 ml Schlenk flask equipped with a magnetic stir bar, the β-arylated product (0.2 mmol), Raney nickel (4 mmol) and dry methanol (5 ml) were added. The flask was sealed with a rubber septum and filled with hydrogen through five evacuation / backfill cycles, during which the reaction mixture was vigorously stirred. A hydrogen balloon was then connected to the flask as a hydrogen source. The reaction was allowed to proceed at room temperature for 5 hours. The solution was then filtered through a plug of celite, washed with saturated brine solution and dried over sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain the pure denitroso product without further purification.

[0087] Example 1 Synthesis of Fenfluramine

[0088]

[0089] Using N-ethyl-2-propylamine and 1-iodo-3-(trifluoromethyl)benzene as starting materials (using silver tetrafluoroborate), palladium-catalyzed β-C(sp 3 )-H arylation step. After purification by flash column chromatography (n-pentane / ethyl acetate = 95 / 5), N-ethyl-N-(1-(3-(trifluoromethyl)phenyl)propan-2-yl)nitrosamide (4b-1) (cis:trans = 5.6:1) was obtained as a light brown oil (79%).

[0090] 1 H NMR (400 MHz, CDCl 3)δ7.51-7.31(m,4H),4.99(q,J=7.0Hz,0.15H),4.67(dt,J=8.2,6.8Hz,0.85H),4.07-3.88(m,0 .30H),3.58-3.46(m,0.85H),3.42-3.31(m,0.85H),3.24(dd,J=13.9,8.3Hz,0.85H),3.07(dd, J=13.9,6.8Hz,0.85H),2.98(dd,J=13.6,6.4Hz,0.15H),2.73(dd,J=13.6,8.3Hz,0.15H),1.49 (d,J=6.8Hz,2.5H),1.38(t,J=7.3Hz,0.5H),1.20(d,J=7.0Hz,0.5H),0.96(t,J=7.2Hz,2.5H). 13 C NMR (101 MHz, CDCl 3 )δ138.52,138.49,132.53,132.52,132.31,132.30,131.37,131.05,130 .73,130.41,129.08,129.02,128.01,125.74,125.70,125.66,125.62,12 5.59,125.31,123.74,123.70,123.66,123.62,123.60,122.60,119.89,6 0.62,50.72,44.50,41.67,39.12,38.66,19.92,16.07,15.45,11.62.19F 19 F NMR (376 MHz, CDCl 3 )δ-62.63.HRMS(DART)Calcd for C 12 H 16 ON 2 F 3 [M+H] + 261.1209, found 216.1207.

[0091]

[0092] The denitroso step was carried out according to the conditions B in the general procedure for synthesizing the denitroso product in the steps of the synthesis example to obtain fenfluramine (4b) as a colorless liquid.

[0093] 1 H NMR (400 MHz, CDCl 3)δ7.50-7.32(m,4H),2.98-2.58(m,5H),1.11-0.99(m,6H). 13 C NMR (101 MHz, CDCl 3 )δ140.46,132.73,δ130.67(q,J=32.0Hz)128.75,127.19(q,J=331.46Hz),δ125.86(q ,J=3.98Hz),123.08(q,J=3.62Hz),54.44,43.31,41.47,29.71,22.86,20.09,15.37. 19 FNMR (376MHz, CDCl 3 )δ-62.57.HRMS(DART)Calcd for C 12 H 17 NF 3 [M+H] + 232.1308, found 232.1306.

[0094] Example 2 Synthesis of Clobenzorex

[0095]

[0096] Using N-(2-chlorobenzyl)-2-propylamine and iodobenzene as starting materials (using silver tetrafluoroborate), the palladium-catalyzed β-C(sp3)-H arylation step was carried out according to the steps of the synthesis example. After purification by automatic rapid column chromatography (n-pentane / ethyl acetate = 92 / 8), N-(2-chlorobenzyl)-N-(1-phenylpropan-2-yl)nitrosamide (4c-1) (cis:trans = 7.4:1, mainly cis isomer, cis isomer is presented here) was obtained as a light brown oil (87%).

[0097] 1 H NMR (400 MHz, CDCl 3 )δ7.37-7.31(m,1H),7.30-7.23(m,4H),7.21-7.15(m,1H),7.14-7.04(m,3H),6.76-6.67(m,1H),4.83(d,J=15.4Hz,1H),4 .63(d,J=15.4Hz,1H),4.61-4.53(m,1H),3.23(dd,J=13.7,8.0Hz,1H),3.03(dd,J=13.7,7.0Hz,1H),1.49(d,J=6.7Hz,3H). 13 C NMR (101 MHz, CDCl 3)δ137.44,132.93,131.78,129.54,129.47,129.11,128.88,128.60,127.04,126.77,60.82,44.52,42.44,20.02.

[0098]

[0099] The denitroso step was carried out according to the conditions A in the general procedure for synthesizing the denitroso product in the steps of the synthesis example to obtain clobenzylrexate (4c) as a colorless liquid.

[0100] 1 H NMR (400 MHz, CDCl 3 )δ7.32-7.25(m,4H),7.23-7.13(m,5H),3.95-3.80(m,2H),2.92(h,J=6.3Hz,1H), 2.77(dd,J=13.3,7.2Hz,1H), 2.66(dd,J=13.3,6.4Hz,1H), 1.12(d,J=6.3Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ139.30,137.70,133.77,130.12,129.48,129.28,128.39,128.24,126.76,126.22,53.69,48.88,43.65,20.24.HRMS(ESI)Calcd forC 16 H 19 ClN[M+H] + 260.1201, found 260.1203.

[0101] Example 3 Synthesis of Mephentermine

[0102]

[0103] Using N,2-dimethyl-2-propylamine and iodobenzene as starting materials (using silver tetrafluoroborate), the palladium-catalyzed β-C(sp3)-H arylation step was carried out according to the procedure of the synthesis example. After purification by automated flash column chromatography (n-pentane / ethyl acetate = 95 / 5), N-methyl-N-(2-methyl-1-phenylpropan-2-yl)nitrosamide (4d-1) (the cis isomer is the only isomer) was obtained as a light brown oil (82%).

[0104] 1 H NMR (400 MHz, CDCl 3)δ7.25-7.23(m,3H),7.01(dd,J=7.8,1.7Hz,2H),3.03(s,2H),3.00(s,3H),1.54(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ130.44,130.25,128.26,126.91,63.93,46.92,28.87,26.65.HRMS(ESI)Calcd for C 11 H 16 ON 2 Na[M+H] + 215.1155, found 215.1155.

[0105]

[0106] The denitroso step was carried out according to the conditions B in the general procedure for synthesizing the denitroso product in the steps of the synthesis example to obtain toluenebutylamine (4d) as a colorless liquid.

[0107] 1 H NMR (400 MHz, CDCl 3 )δ7.34-7.29(m,2H),7.28-7.22(m,1H),7.20-7.16(m,2H),3.49(s,1H),2.73(s,2H),2.42(s,3H),1.09(s,6H). 13 CNMR (101MHz, CDCl 3 )δ138.18,130.41,128.02,126.18,53.35,46.25,28.68,26.10.HRMS(DART)Calcd for C 11 H 18 N[M+H] + 164.1434, found 164.1433.

[0108] Example 4 Synthesis of Prenylamine

[0109]

[0110] Using N-isopropyl-3,3-diphenylpropan-1-amine and iodobenzene as starting materials (using silver tetrafluoroborate), the palladium-catalyzed β-C(sp3)-H arylation step was carried out according to the steps of the synthesis example. After purification by automated flash column chromatography (n-pentane / ethyl acetate = 96 / 4), N-(3,3-diphenylpropyl)-N-(1-phenylpropan-2-yl)nitrosamide (4e-1) (cis:trans = 5.6:1) was obtained as a light brown oil (72%).

[0111] 1 H NMR (400 MHz, CDCl 3 )δ7.36-7.18(m,13H),7.15-7.09(m,2H),5.03(h,J=7.3Hz,0.15H),4.57(h,J=6.9Hz,0.85H),4.02(t,J=7.8Hz,0.15H),3 .86(td,J=7.8,4.5Hz,1.15H),3.42(ddd,J=13.1,10.7,5.1Hz,0.85H),3.25(ddd,J=13.1,10.8,5.1Hz,0.85H),3.12(dd, J=13.7,8.0Hz,0.85H),2.97-2.85(m,1H),2.64(dd,J=13.6,8.2Hz,0.15H),2.57-2.46(m,0.30H),2.16(dddd,J=12.9,10 .8,7.7,5.1Hz,0.85H),1.99(dddd,J=13.3,10.7,8.3,5.1Hz,0.85H),1.44(d,J=6.8Hz,2.50H),1.15(d,J=6.9Hz,0.50H). 13 C NMR (101 MHz, CDCl 3 )δ143.52,143.48,137.47,137.34,129.07,128.84,128.69,128.67,128.61,128.56,128.52,127.69,127.62,127.59,126.80,126.7 2,126.59,126.52,126.48,61.42,49.25,48.63,43.38,42.10,39.22,35.56,31.47,31.40,30.10,19.88,16.33.HRMS(DART)Calcdfor C 24 H 27 ON 2 [M+H] + 359.2118, found 359.2115.

[0112]

[0113] The denitroso step was carried out according to the conditions B in the general procedure for the synthesis of the denitroso product in the procedure of the synthesis example to obtain prenylamine (4e) as a colorless liquid (quantitative).

[0114] 1 H NMR (400 MHz, CDCl 3 )δ7.33-7.22(m,7H),7.20-7.13(m,8H),3.89(t,J=7.9Hz,1H),2.84(p,J =6.4Hz,1H),2.74-2.46(m,4H),2.30-2.15(m,2H),1.01(d,J=6.2Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ144.57,144.48,139.24,129.29,128.43,128.41,127.73,127.72,126.23,126.16,54.48,48.85,45.24,43.34,35.50,19.90.HRMS(DART)Calcd forC 24 H 28 N[M+H] + 330.2216, found 330.2213.

[0115] Example 5 Gram-scale reaction for drug synthesis

[0116] A magnetic stirrer was added to a 250 ml round-bottom flask, and N,2-dimethyl-2-propylamine (10 mmol) and isoamyl nitrite (15 mmol, 1.5 equivalents) were charged under a nitrogen atmosphere. The reaction mixture was stirred at 60 ° C for 24 hours and then purified by column chromatography to obtain a pure N-nitrosamine intermediate with a conversion rate of 96%. N-nitrosamine, palladium acetate (0.25 mmol), ligand (0.175 mmol), silver tetrafluoroborate (20 mmol, 2.0 equivalents), iodobenzene (18 mmol, 1.8 equivalents) and hexafluoroisopropanol (50 ml) were added to a 250 ml round-bottom flask. The reaction mixture was refluxed under a nitrogen atmosphere and stirred at 100 ° C for 48 hours. After cooling to room temperature, the reaction mixture was diluted with 10 ml of ethyl acetate and then filtered through a silica gel pad. The filtrate was concentrated under reduced pressure and then purified by silica gel flash column chromatography. After purification by automated flash column chromatography (n-pentane / ethyl acetate = 95 / 5), N-methyl-N-(2-methyl-1-phenylpropan-2-yl)nitrosamide (4d-1) was obtained with a yield of 61%.

[0117] A stirring bar was added to a 250 ml Schlenk flask, and β-arylation product (6.2 mmol), Raney nickel (50 mmol) and dry methanol (100 ml) were loaded. The flask was sealed with a rubber septum and filled with hydrogen through five vacuum / backfill cycles, during which the reaction mixture was vigorously stirred. A hydrogen balloon was then connected to the flask as a hydrogen source, and hydrogen needed to be replenished after the hydrogen in the balloon was consumed. The reaction was allowed to proceed at room temperature for 36 hours. The solution was then filtered through a diatomaceous earth plug, washed with a saturated saline solution, and dried over sodium sulfate. The solvent was then removed by distillation under reduced pressure, and toluene butylamine (4d) was obtained without further purification, and the yield was 99%.

[0118] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for synthesizing β-arylethylamine drugs, characterized in that: The steps include: S1, reacting a mixed raw material containing a secondary amine compound and a nitrosation reaction solvent to obtain a nitrosamine compound; S2, reacting a mixture containing a nitrosamine compound, an aryl iodide, an oxidant, a catalyst, and a solvent with II to obtain an arylethylamine drug precursor; S3, removing the nitroso group from the arylethylamine drug precursor to obtain the β-arylethylamine drug; The β-arylethylamine drug has a structure shown in Formula I-a6: Among them, R1 is selected from one of methyl, ethyl, isopropyl and isobutyl, and R3 is selected from one of hydrogen, chlorine and trifluoromethyl.

2. The synthesis method according to claim 1, characterized in that The secondary amine compound is selected from one of the structures shown in formula I-a1: Wherein, R1 and R2 are independently selected from one of methyl, ethyl, isopropyl and isobutyl.

3. The synthesis method according to claim 1, characterized in that The nitrosation reaction solvent is selected from at least one of isoamyl nitrite and tert-butyl nitrite.

4. The synthesis method according to claim 1, characterized in that The aryl iodide is selected from one of the structures shown in formula I-a4: Wherein, R3 is selected from one of hydrogen atom, chlorine and trifluoromethyl.

5. The synthesis method according to claim 1, characterized in that The molar ratio of the secondary amine compound to the nitrosation reaction solvent is 1:1-2; Preferably, the molar ratio of the nitrosamine compound to the aryl iodide is 1:1 to 5; Preferably, the molar ratio of the nitrosamine compound to the oxidant is 1:1-5.

6. The synthesis method according to claim 1, characterized in that The oxidant is selected from at least one of silver tetrafluoroborate, silver trifluoroacetate, silver hexafluoroantimonate, and silver acetate; Preferably, the catalyst comprises a metal catalyst and an organic hydroxypyridine-amide-ester catalyst; Preferably, the metal catalyst is selected from a palladium catalyst; Preferably, the organic hydroxypyridine-amide-ester catalyst is selected from (5-nitro-6-oxo-1,6-dihydropyridine-2-carbonyl)glycine methyl ester.

7. The synthesis method according to claim 6, characterized in that The molar ratio of the nitrosamine compound to the metal catalyst is 1:0.01-0.1; Preferably, the molar ratio of the nitrosamine compound to the organic hydroxypyridine-amide-ester catalyst is 1:0.01-0.

1.

8. The synthesis method according to claim 1, characterized in that The conditions of the reaction I and reaction II independently include: the reaction temperature is 60° C. to 120° C., and the reaction time is 8 h to 48 h.

9. The synthesis method according to claim 1, characterized in that The step of removing the nitroso group from the arylethylamine drug precursor is selected from at least one of condition A and condition B; Condition A comprises: stirring a mixture containing an arylethylamine drug precursor and a nitroso reduction catalyst A under acidic conditions; Condition B comprises: vigorously stirring a mixture containing an arylethylamine drug precursor, a nitroso reduction catalyst B, and methanol in a reducing atmosphere.

10. The synthesis method according to claim 9, characterized in that Condition A specifically comprises: stirring a mixture containing an arylethylamine drug precursor, copper chloride, and concentrated hydrochloric acid under acidic conditions; Preferably, condition B specifically includes: vigorously stirring a mixture containing an arylethylamine drug precursor, Raney nickel and methanol in a reducing atmosphere.

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