A preparation method of β-aminosulfone and its derivatives

Abstract

The invention discloses a method for preparing β-aminosulfone and its derivatives, and belongs to the technical field of organic synthesis. Compound 1 and compound 2 are used as raw materials, and light is irradiated in the presence of a photocatalyst in an organic solvent to obtain β-aminosulfone and its derivative 3; then, in the presence of acetic acid, it is reacted with compound 5 to obtain Apremilast and its analog 4. The invention adopts a photocatalytic coupling reaction under normal pressure to synthesize Apremilast intermediates and its analogs, and has the advantages of simple synthesis process, easy operation, significantly improved synthesis yield, low environmental pollution, green environmental protection, etc., and the product has broad application prospects and market demand.

Description

Technical Field

[0001] The invention relates to a preparation method of beta-amino sulfone and derivatives thereof, belonging to the technical field of organic synthesis. Background Art

[0002] β-Aminosulfone compounds are of great value and are widely found in various drugs, agrochemicals and natural products. For example, Apremilast, a phosphodiesterase 4 (PDE4) inhibitor used to treat active psoriatic arthritis, achieved full-year sales of $2.249 billion in 2021.

[0003] At present, the classic methods for synthesizing β-aminosulfones include: aza-Michael addition and cycloaddition of alkenyl sulfones, stereoselective addition of imines or their equivalents to sulfone compounds under alkaline conditions, and asymmetric hydrogenation of β-aminovinyl sulfones. However, these methods are usually cumbersome and have limited functional group tolerance, and are not suitable for the preparation of diverse β-aminosulfone compounds. Olefin difunctionalization is a simple and universal method for synthesizing ortho-difunctional groups. Due to the abundance and availability of sulfonyl radical precursors, difunctionalization reactions involving sulfonyl radicals have been widely studied for the synthesis of β-functional substituted sulfone compounds. However, there are limited reports on the synthesis of β-aminosulfones, which stems from the fact that fewer nitrogen-containing nucleophiles are compatible with oxidative conditions in the radical polar cross-linking tandem strategy. In the reaction involving diradicals, only the special substrate reaction of 1,2-aminosulfonylation of styrene with sodium sulfonate and aromatic amines cannot achieve the synthesis of a wide spectrum of β-aminosulfone compounds. The reaction equation is as follows:

[0004]

[0005] The above reactions use hazardous reagents, additional oxidizing or reducing agents, and have a narrow substrate range. Different functional groups in the molecules of β-aminosulfone compounds have a significant impact on their biological properties, and structural diversity is the basis for expanding the biologically relevant chemical space. Therefore, it is still a challenge to develop efficient and green synthesis of structurally rich β-aminosulfone compounds. Summary of the invention

[0006] In order to overcome the above technical defects, the present invention provides a safe, green and efficient preparation method of β-aminosulfone and its derivatives. Compound 1 and compound 2 are used as raw materials, and light is reacted in the presence of a photocatalyst in an organic solvent to obtain β-aminosulfone and its derivative 3; then, in the presence of acetic acid, it reacts with compound 5 to obtain Apremilast and its analogs 4. The present invention uses a photocatalytic diradical coupling reaction at room temperature and pressure to synthesize Apremilast intermediates and analogs, which has the advantages of simple synthesis process, easy operation, significantly improved synthesis yield, low environmental pollution, and green environmental protection.

[0007] The preparation method of β-aminosulfone and its derivatives described in the present invention comprises the following steps: using compound 1 and compound 2 as raw materials, and subjecting them to light irradiation reaction in the presence of a photocatalyst in an organic solvent to obtain β-aminosulfone and its derivative 3; the reaction equation is expressed as follows:

[0008]

[0009] Where: R 1 R is selected from C1-C20 straight-chain alkyl, C1-C20 branched-chain alkyl, phenyl, C1-C20 branched-chain alkoxy, aromatic heterocycle, and aryl with electron-withdrawing or electron-donating group; 2 is selected from C1-C20 straight chain alkyl, C1-C20 branched chain alkyl, C1-C20 straight chain alkoxy, C1-C20 branched chain alkoxy, hydrogen, halogen, nitro, amino; R 3 is selected from C1-C20 straight chain alkyl, C1-C20 branched chain alkyl, C1-C20 straight chain alkoxy, C1-C20 branched chain alkoxy, hydrogen, halogen, nitro, amino; R 4 is selected from C1-C20 straight-chain alkyl, C1-C20 branched-chain alkyl, C1-C20 straight-chain alkoxy, C1-C20 branched-chain alkoxy, phenyl, aromatic heterocycle, aryl with electron-withdrawing or electron-donating group, trifluoromethyl, hydrogen, ester group, nitrile group, acyl group; R 5 is selected from C1-C20 straight-chain alkyl, C1-C20 branched-chain alkyl, C1-C20 straight-chain alkoxy, C1-C20 branched-chain alkoxy, phenyl, aromatic heterocycle, aryl with electron-withdrawing or electron-donating group, trifluoromethyl, hydrogen, ester group, nitrile group, acyl group; R 6 Selected from hydrogen, C1-C6 alkyl.

[0010] Furthermore, in the above technical solution, the R 1 is selected from 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 4-nitrilephenyl, tetramethylpyridine, cyclopropane, etc.; halogen is selected from bromine; R 4 is selected from 4-tert-butylphenyl, 4-methoxyphenyl, pyridine, 4-ethylphenyl, biaryl, etc.; R 5 Selected from 4-tert-butylphenyl, 4-methoxyphenyl, pyridine, 4-ethylphenyl, biaryl and the like.

[0011] Further, in the above technical scheme, the photocatalyst is selected from (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 9-thioxanthone, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 9,10-anthraquinone, 3,4,5,6-tetrakis(3,6-di-tert-butyl-9-carbazolyl)-terephthalonitrile or fac-Ir(2-phenylpyridyl)3.

[0012] Furthermore, in the above technical solution, the molar ratio of compound 1, compound 2 and photocatalyst is 1.2-1.6:1:0.01-0.05.

[0013] Furthermore, in the above technical solution, the organic solvent is selected from acetone, acetonitrile, dichloromethane, tetrahydrofuran, methanol, toluene, ethyl acetate or N,N-dimethylformamide, preferably ethyl acetate.

[0014] Furthermore, in the above technical solution, the wavelength range of the light reaction is 390-456nm.

[0015] Furthermore, in the above technical solution, the reaction temperature is 30-60°C, preferably 40°C.

[0016] The present invention also provides a method for synthesizing Apremilast and its analog 4, comprising the following steps: using the above method to obtain β-aminosulfone and its derivative 3A, and then reacting the obtained product 3A with compound 5 in the presence of acetic acid to obtain Apremilast and its analog 4; the reaction equation is expressed as follows:

[0017]

[0018] Where: R 7 -R 9 Each is independently selected from H, C1-C20 straight-chain alkyl, C1-C20 branched-chain alkyl, phenyl, aromatic heterocyclic ring, methoxy, and ethoxy.

[0019] Beneficial effects of the invention:

[0020] The present invention uses a photocatalytic coupling reaction under normal pressure to synthesize apremilast intermediates and analogs thereof, and has the advantages of simple synthesis process, easy operation, significantly improved synthesis yield, low environmental pollution, green environmental protection, etc. At the same time, the product has broad application prospects and market demand. DETAILED DESCRIPTION

[0021] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. It should be understood by those skilled in the art that the following specific description is illustrative rather than restrictive, and should not be used to limit the scope of protection of the present invention.

[0022] Condition optimization experiment

[0023] 1. Photocatalyst screening:

[0024] Add a magnetic stirrer to the dry reaction bottle, fill with argon protection, add photocatalyst, N-diphenylmethylene-4-methylbenzenesulfonamide (0.15mol, 50.3mg) and styrene (0.1mol, 10.4mg) in sequence, then add 1mL of ethyl acetate to dissolve, and fill with argon protection. After sealing, illuminate under the light source of the photocatalyst excitation wavelength, the light source is about 6cm away from the reaction bottle, the fan is cooled, and the temperature is controlled at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain β-aminosulfone compound. The screening results are as follows:

[0025]

[0026]

[0027] Various photocatalysts were used to catalyze the above reaction, including (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, 9-thioxanthone, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, 9,10-anthraquinone, 3,4,5,6-tetrakis(3,6-di-tert-butyl-9-carbazolyl)-terephthalonitrile, and fac-Ir(2-phenylpyridyl)3, and the catalytic reaction was carried out at room temperature. Among them, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate and 9-thioxanthone had better yields of 74% and 71%, respectively. Then the temperature was raised to 40°C and the yields reached 85% and 81%, respectively.

[0028] 2. Solvent screening:

[0029] Add a magnetic stirrer to the dry reaction bottle, fill with argon protection, add 9-thioxanthone (0.05mol, 1.1mg), N-diphenylmethylene-4-methylbenzenesulfonamide (0.15mol, 50.3mg) and styrene (0.1mol, 10.4mg) in sequence, add 1mL solvent to dissolve, and fill with argon protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is cooled to control the temperature at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain β-aminosulfone. The screening results are as follows:

[0030]

[0031]

[0032] Various solvents were used to catalyze the above reaction at the same concentration (0.1 M). Ethyl acetate had the best yield (85%). Acetonitrile, dichloroethane, tetrahydrofuran, toluene, acetone, N,N-dimethylformamide, etc. can also be used, but the methanol yield is not good and is not suitable for use.

[0033] Example 1

[0034]

[0035] Add a magnetic stirrer to a dry reaction bottle, fill with argon for protection, add 9-thioxanthone (0.05mol, 1.1mg), N-(diphenylmethylene)methanesulfonamide (0.15mol, 38.9mg), 2-ethoxy-1-methoxy-4-vinylbenzene (0.1mol, 17.8mg) in sequence, add 1mL of ethyl acetate to dissolve, and fill with argon for protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is cooled to control the temperature at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 27.5mg of the product. 1H NMR (500MHz, CDCl3): δ=7.69–7.68(m,2H),7.42–7.33(m,6H),7.01–6.99(m,2H),6.76(d,J=8.3Hz,1H),6.70(dd,J=8.3,2.0Hz,1H),6.59(d,J=2 .0Hz,1H),4.95(dd,J=9.3,3.1Hz,1H),4.02–3.97(m,2H),3.91–3.84(m, 1H),3.84(s,3H),3.30–3.26(m,1H),2.88(s,3H),1.43(t,J=7.0Hz,3H). 13 C NMR (125MHz, CDCl3): δ=170.3,148.8,148.4,139.0,136.1,134.2,130.8,128.8,128.6,128 .5,128.4,127.6,119.2,111.7,111.5,64.4,63.4,61.4,56.0,43.3,14.9.HRMS(m / z):[M+H] + Calculate for C 25 H 28 NO4S + 438.1734, found 438.1749.

[0036] Example 2

[0037]

[0038] Add a magnetic stirrer to a dry reaction bottle, fill with argon protection, add 9-thioxanthone (0.05mol, 1.1mg), N-diphenylmethylene-4-methylbenzenesulfonamide (0.15mol, 50.3mg), 4-fluorostyrene (0.1mol, 12.2mg) in sequence, add 1mL of ethyl acetate to dissolve, and fill with argon protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is cooled to control the temperature at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 36.7mg of the product. 1H NMR (500MHz, CDCl3): δ=7.64(d,J=8.2Hz,2H),7.44–7.34(m,6H),7.27–7.23(m,2H),7.16(d,J=8.0Hz,2H),7.07–7.04(m,2H),6.99(d, J=6.9Hz,2H),6.92–6.89(m,2H),5.00(dd,J=9.1,3.1Hz,1H),4.00(dd,J=14.4,9.1Hz,1H),3.44(dd,J=14.4,3.1Hz,1H),2.34(s,3H). 13 C NMR (125MHz, CDCl3): δ = 169.3, 162.1 (d, J C-F =246.0Hz),144.3,139.2,138.1(d,J C-F =3.4Hz),137.6,136.2,130.5,129.8,128.9,128.6(d,J C-F =8.0Hz),128.5,128.1,127.9,127.8,115.7(d,J C-F =21.4Hz),64.6,60.8,21.7. 19 F NMR (282MHz, CDCl3): δ = -114.54.HRMS (m / z): [M+H] + Calculate for C 28 H 25 FN O2S 458.1585, found 458.1593.

[0039] Example 3

[0040]

[0041] Add a magnetic stirrer to a dry reaction bottle, fill with argon for protection, add 9-thioxanthone (0.05mol, 1.1mg), N-(diphenylmethylene)-5-methylpyridine-2-sulfonamide (0.15mol, 50.4mg), diphenylethylene (0.10mol, 18.1mg) in sequence, add 1.0mL of ethyl acetate to dissolve, fill with argon for protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is used to cool down and control the temperature to 40°C. After 3 hours, add 5.0mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 46.5mg of the product. 1H NMR (500MHz, CDCl3): δ = 8.16 (d, J = 2.0Hz, 1H), 7.53–7.51 (m, 3H), 7.38–7.27 (m,4H),7.19–7.02(m,13H),6.72(d,J=7.4Hz,2H),4.61(s,2H),2.13(s,3H). 13 C NMR (125MHz, CDCl3): δ=168.8,155.2,150.1,147.2,141.5,138.2,137.7,137.0,130.3,12 8.7,127.9,127.8,127.7,127.4,127.4,126.3,122.4,66.4,61.6,18.5.HRMS(m / z):[M+H] + Calculate for C 33 H 29 N2O2S517.1944, found 517.1947.

[0042] Example 4

[0043]

[0044] Add a magnetic stirrer to a dry reaction bottle, fill with argon for protection, add 9-thioxanthone (0.05mol, 1.1mg), N-(diphenylmethylene)-4-(trifluoromethoxy)benzenesulfonamide (0.15mol, 60.8mg), diphenylethylene (0.1mol, 18.1mg) in sequence, add 1mL of ethyl acetate to dissolve, and fill with argon for protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is cooled to control the temperature at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 56.2mg of the product. 1 H NMR (500MHz, CDCl3): δ=7.71–7.69(m,2H),7.49–7.37(m,5H),7.21–7.18(m,1H),7.10–6.97(m,14H),6.67(d,J=7.1Hz,2H),4.40(s,2H). 13 C NMR (125MHz, CDCl3): δ=170.0,152.3(q,J C-F =1.9Hz),147.2,141.6,138.8,138.4,130.8,130.5,128.8,128.2,128.2,127.7,127.5,127.4,127.1,126.5,120.3,120.3(q,JC-F =259.4Hz),65.8,65.7. 19 F NMR (282MHz, CDCl3): δ = -57.48.HRMS (m / z): [M+H] + Calculate for C 34 H 27 F3NO3S 586.1658, found 586.1662.

[0045] Example 5

[0046]

[0047] Add a magnetic stirrer to a dry reaction bottle, fill with argon protection, add 9-thioxanthone (0.05mol, 1.1mg), (diphenylmethylene) methanesulfonamide (0.15mol, 38.9mg), diphenylethylene (0.1mol, 18.1mg) in sequence, add 1mL of ethyl acetate to dissolve, fill with argon protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is cooled to control the temperature at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 37.3mg of the product. 1 H NMR (500MHz, CDCl3): δ=7.72–7.70(m,2H),7.40–7.33(m,7H),7.25–7.19(m, 7H), 7.10 (t, J = 7.7Hz, 2H), 6.62 (d, J = 7.0Hz, 2H), 4.06 (s, 2H), 2.20 (s, 3H). 13 C NMR (125MHz, CDCl3): δ = 169.8, 147.5, 141.7, 138.2, 130.4, 128.7, 128.5, 128.2, 127.8, 127.7, 127.6, 127.5, 127.1, 64.6, 43.1. HRMS (m / z): [M+H] + Calculate for C 28 H 26 NO2S 440.1679, found 440.1693.

[0048] Example 6

[0049]

[0050] Add a magnetic stirrer to a dry reaction bottle, fill with argon for protection, add 9-thioxanthone (0.05mol, 1.1mg), N-diphenylmethylene-4-methylbenzenesulfonamide (0.15mol, 50.3mg), 4-vinylbiphenyl (0.1mol, 18.0mg) in sequence, add 1mL of ethyl acetate to dissolve, and fill with argon for protection. After sealing, illuminate under a 390nm light source, the light source is about 6cm away from the reaction bottle, and the fan is cooled to control the temperature at 40°C. After 3 hours, add 5mL of ethyl acetate to dilute, concentrate under reduced pressure, and directly separate and purify by column chromatography (n-hexane: ethyl acetate = 10:1) to obtain 38.1mg of the product. 1 H NMR (500MHz, CDCl3): δ = 7.65 (d, J = 8.3Hz, 2H), 7.54–7.52 (m, 2H), 7.46–7.40 (m, 9H), 7.38–7.32 (m, 2H), 7.28–7.24 (m, 2H), 7.17–7.1 5(m,4H),7.05(d,J=7.1Hz,2H),5.06(dd,J=9.2,3.0Hz,1H),4.06(dd,J=14.5,9.2Hz,1H),3.52(dd,J=14.5,3.0Hz,1H),2.33(s,3H). 13 C NMR (125MHz, CDCl3): δ=169.2,144.2,141.3,140.7,140.5,137.7,136.3,130.4,129.8,128.9 ,128.8,128.5,128.1,127.9,127.9,127.5,127.5,127.1,64.6,61.3,21.7.HRMS(m / z):[M+H] + Calculate for C 34 H 30 NO2S 516.1992, found 516.2001.

[0051] Example 7

[0052] According to the operation of Examples 1-6, only raw materials 1 and 2 were changed to obtain a series of β-amino sulfones and their derivatives 3. The reaction results are as follows:

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] Comparative Example 1

[0060]

[0061] Add dimethyl sulfoxide (0.8 g, 10.7 mmol) and tetrahydrofuran (70 mL) to a dry reaction bottle, place it in a -70°C dry ice acetone bath, add n-BuLi (2.5 M in hexanes, 4.6 mL, 11.5 mmol) dropwise, and continue stirring at this temperature for 0.5 hours to obtain a dimethyl sulfoxide / butyl lithium solution. Add benzaldehyde (1.9 g, 10.0 mmol) to another reaction bottle and dissolve it in THF (20 mL) and place it at 0°C. Add LiHMDS (1 M in THF, 12 mL) and stir for 15 minutes, then add boron trifluoride-ether solution (2.8 mL, 22 mmol) and continue stirring for 5 minutes. Add the above solution to the dimethyl sulfoxide / butyl lithium reaction bottle at -70°C, and heat the system to room temperature and stir overnight. Then place the system in an ice-water bath, and add potassium carbonate (8 g) and water (50 mL) respectively. The aqueous layer was extracted twice with ethyl acetate (2*20 mL), the organic layers were combined and dried over sodium sulfate. After concentration, MTBE (30 mL) and 4N hydrochloric acid (30 mL) were added respectively and reacted at room temperature for 2 hours. After the reaction, the organic layer was extracted with 4N hydrochloric acid, the aqueous phase was combined, and the pH was adjusted to > 12 with sodium hydroxide solution. Ethyl acetate was added and extracted 3 times (3*50 mL). The organic phases were combined, dried, and spin-dried to obtain a yellow solid product (106.5 mg, 3.9 mmol) with a yield of 39%.

[0062] Comparative Example 2

[0063]

[0064] In a nitrogen-filled dry sealed tube, CuCl (2.0 mg, 0.02 mmol, 10 mol%) and sodium trifluoromethanesulfonate (0.3 mmol, 1.5 eq) were dissolved in a mixed solvent of CH3CN (1.0 mL) and H2O (0.3 mL), and then the olefin substrate (0.2 mmol, 1.0 eq) and TMSN3 (54 μL, 0.4 mmol, 2 eq) were added. The mixture was then stirred at 60 °C for 16 hours. Ethyl acetate (5 mL) was added, and the mixture was washed with NaHCO3 solution (5 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated in vacuo. The crude product was purified by silica gel column chromatography, and the product was obtained by gradient elution with petroleum ether / ethyl acetate. In a nitrogen-filled dry sealed tube, the raw material (1.0 g, 3.34 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (20.0 mL) and H2O (5 mL), and then PPh3 (2.19 g, 8.35 mmol, 2.5 eq) was added. The reaction mixture was stirred at 60°C for 6 hours. After rotary evaporation and concentration, the mixture was extracted with EA and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography with a gradient elution of PE / EA = 5 / 1 to obtain the product (794.2 mg, 2.91 mmol).

[0065] The yields of the above examples are compared as follows:

[0066] Steps (total) Yield % Example 1 1 65 Example 2 1 75 Example 3 1 90 Example 4 1 96 Example 5 1 85 Example 6 1 74 Comparative Example 1 2 39 Comparative Example 2 2 67

[0067] Compared with the comparative example, the present invention only needs to add a photocatalyst and raw materials, the synthesis process is simple, the steps are few, the operation is easy, and the reaction has almost no by-products, the atom economy is high, the environmental pollution is small, and it is green and environmentally friendly. The present invention can ensure that the quality of the entire product is further improved, and has broad application prospects and market demand.

[0068] Example 8

[0069]

[0070] In a 250mL pressure tube equipped with a stirrer, 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl-1,1-diphenylmethylamine (1.84g, 4.2mmol) and AcOH solution (50mL) were added, and after stirring evenly, 3-acetylaminophthalic anhydride (947.3mg, 4.2mmol, 1.1eq) was added, and the reaction tube was sealed. Heat and stir in an oil bath at 120°C for 18h. After the reaction was completed, the solvent was removed by rotary evaporation, and then extracted with ethyl acetate, dried with Na2SO4, filtered, and concentrated in vacuo. The crude mixture was then immediately purified by flash chromatography on silica gel (Pet / EtOAc, 2 / 1, v / v) to obtain the product Apremilast (1.84g, yield 95%), and benzophenone (741.8mg, yield 97%) was recycled.

[0071] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. A method for preparing β-aminosulfone 3, characterized in that: The method comprises the following steps: using compound 1 and compound 2 as raw materials, and subjecting them to light reaction in the presence of a photocatalyst in an organic solvent to obtain β-aminosulfone 3; the reaction equation is as follows: Where: R 1 is methyl, R 2 -R 4 and R 6 is hydrogen, R 5 The organic solvent is ethyl acetate; the reaction temperature is 40°C; the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate or 9-thioxanthone; and the wavelength of the light reaction is 390nm.

2. The method for preparing β-aminosulfone and its derivatives according to claim 1, characterized in that: The molar ratio of the compound 1, the compound 2 and the photocatalyst is 1.2-1.6:1:0.01-0.

05.

3. A method for synthesizing Apremilast 4, characterized in that: The method comprises the following steps: obtaining β-aminosulfone 3 by the method of claim 1 or 2, and then reacting the obtained product 3 with compound 5 in the presence of acetic acid to obtain apremilast 4; the reaction equation is as follows: Where: R 7 is methoxy, R 8 is hydrogen, R 9 It is ethoxy.

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