Cracking method of phenylethylamine compound

Abstract

The invention provides a cracking method of a phenylethylamine compound, and relates to the technical field of organic chemistry. The cracking method provided by the invention comprises the following steps: in an oxygen-containing environment, a solvent environment and the participation of organic alkali, enabling a phenylethylamine compound to react at 20-40 DEG C for 2-5 hours, then breaking a carbon-nitrogen bond, and preparing a cracking product. According to the method, transition metal does not need to be used as a catalyst, meanwhile, cracking deprotection can be conducted on the phenylethylamine compound at the mild reaction temperature, the method is environmentally friendly, and the operation process is simple and safe.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and in particular to a cracking method of phenylethylamine compounds. Background Art

[0002] Amine compounds are very effective drug functional groups with extremely important physiological and biological activities. For example, proteins, nucleic acids, many hormones, antibiotics and alkaloids are complex derivatives of amines. Most drugs currently used in clinical practice are amines or amine derivatives. However, since amine compounds are sensitive to oxidants and bases, the protection and deprotection of amines have become indispensable means in organic synthesis.

[0003] Arylalkylamines are one of the most commonly used amine protecting groups due to their high chemical stability under various reaction conditions. To date, many reagents or reagent combinations have been developed for the deprotection of aralkylamines, such as protonic acids, Lewis acids, nucleophiles, oxidants, reducing agents, and transition metal catalysts. However, these reagents often require harsh reaction conditions and the use of relatively expensive transition metals as catalysts to deprotect aromatic amine compounds. Therefore, there is an urgent need to provide a solution to improve the above problems. Summary of the Invention

[0004] The present invention aims to provide a method for cracking phenylethylamine compounds, which does not require the use of transition metals as catalysts and can crack and deprotect phenylethylamine compounds at a relatively mild reaction temperature. The method is environmentally friendly and has a simple and safe operation process.

[0005] The present invention provides a cracking method for phenylethylamine compounds, comprising: reacting the phenylethylamine compounds at 20° C.-40° C. for 2 h-5 h in an oxygen-containing environment, a solvent environment, and the presence of an organic base, thereby breaking the carbon-nitrogen bond and obtaining a cracking product.

[0006] Optionally, the phenethylamine compound includes one of a phenethylamine compound and an indoline compound.

[0007] Optionally, the phenethylamine compound further includes a phenethylamide compound.

[0008] Optionally, the structural formula of the phenethylamine compound is as shown in Formula I:

[0009]

[0010] Among them, R 1 With R 2 are independently hydrogen, C1 to C 40 Fatty groups, C4 to C 40aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

[0011] Optionally, the structural formula of the phenethylamide compound is as shown in Formula II:

[0012]

[0013] Among them, R 3 With R 4 are independently hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

[0014] Optionally, the structural formula of the indoline compound is as shown in Formula III:

[0015]

[0016] Among them, R 5 is hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

[0017] Optionally, the C1 to C 40 The aliphatic group includes one of methyl, ethyl, propyl, isopropyl, butyl and benzyl.

[0018] Optionally, the C4 to C 40 The aromatic group includes one of a pyridine derivative, a phenyl group, a substituted phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

[0019] Optionally, the halogen includes one of fluorine, chlorine, bromine and iodine.

[0020] Optionally, the cleavage products of the phenethylamine compound include styrene compounds and amine compounds.

[0021] Optionally, the cleavage products of the phenethylamide compound include styrene compounds and amide compounds.

[0022] Optionally, the cleavage products of the indoline compound include o-aminostyrene compounds.

[0023] Optionally, the reaction formula for cracking the phenethylamine compound is:

[0024]

[0025] Optionally, the reaction formula for cracking the phenethylamide compound is:

[0026]

[0027] Optionally, the reaction formula for cleaving the indoline compound is:

[0028]

[0029] Optionally, the solvent environment includes one of dimethyl sulfoxide and N,N-dimethylformamide.

[0030] Optionally, the organic base includes one of t-BuONa and t-BuOK.

[0031] Optionally, the oxygen concentration in the oxygen-containing environment is 10%-100%.

[0032] Optionally, the molar ratio of the organic base to the phenylethylamine compound is (2-6):1.

[0033] Alternatively, the phenylethylamine compound is reacted at 20° C.-40° C. for 2 h-5 h, then quenched, extracted, and separated by column chromatography to obtain a cleavage product. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs.

[0035] The present invention provides a method for cracking phenylethylamine compounds, comprising reacting the phenylethylamine compounds at 20°C-40°C for 2-5 hours in an oxygen-containing environment, a solvent environment, and the presence of an organic base, followed by cleavage of the carbon-oxygen bond to produce a cracking product. The present invention eliminates the need for a transition metal catalyst and can perform cracking and deprotection of the phenylethylamine compounds at relatively mild reaction temperatures, making it environmentally friendly and simple and safe to operate.

[0036] Specifically, the phenylethylamine compounds include one of phenylethylamine compounds and indoline compounds. In addition, the phenylethylamine compounds also include phenylethylamide compounds. In fact, the cleavage method provided by the present invention has good applicability to different types of reaction substrates and can break the carbon-nitrogen bond in a relatively mild system without the need for a transition metal catalyst.

[0037] In some embodiments, the cleavage reaction is performed in a solvent environment comprising dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (N,N-DMF), an organic base comprising t-BuONa or t-BuOK, and an oxygen concentration within the oxygen environment ranging from 10% to 100%. In practice, the organic base / solvent / oxygen environment system allows for efficient cleavage of phenylethylamine compounds containing C-N bonds.

[0038] Specifically, the cleavage reaction can be carried out in an air atmosphere, and the efficiency of the cleavage reaction is higher in an air atmosphere than in an oxygen atmosphere or an inert atmosphere. In addition, the molar ratio of the organic base to the phenylethylamine compound in the solvent environment is (2-6):1.

[0039] In some embodiments, the phenylethylamine compound is reacted at 20°C-40°C for 2-5 hours, then quenched, extracted, and separated by column chromatography to obtain a cleavage product. In practice, a relatively large amount of water can be added to the reaction system during quenching. Furthermore, after quenching, multiple extractions can be performed with ethyl acetate. The combined extracts are then washed with sodium chloride solution, dehydrated, concentrated under reduced pressure, and purified by silica gel column chromatography.

[0040] Furthermore, the structural formula of the phenethylamine compound is shown in Formula I below:

[0041]

[0042] Among them, R 1 With R 2 are independently hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

[0043] Furthermore, the structural formula of the phenethylamide compound is shown in Formula II:

[0044]

[0045] Among them, R 3 With R 4 are independently hydrogen, C1 to C 40 Fatty groups, C4 to C40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

[0046] Furthermore, the structural formula of the indoline compound is shown in Formula III:

[0047]

[0048] Among them, R 5 is hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

[0049] In fact, C1 to C 40 The aliphatic group includes one of methyl, ethyl, propyl, isopropyl, butyl, benzyl, C4 to C 40 The aromatic group includes one of a pyridine derivative, a phenyl group, a substituted phenyl group, a 1-naphthyl group, and a 2-naphthyl group, and the halogen includes one of a fluorine group, a chlorine group, a bromine group, and an iodine group.

[0050] Specifically, the cleavage products of the phenylethylamine compounds include styrene compounds and amine compounds, and the reaction formula during the cleavage is:

[0051]

[0052] Specifically, the cleavage products of the phenylethylamide compounds include styrene compounds and amide compounds, and the reaction formula during the cleavage is:

[0053]

[0054] Specifically, the cleavage products of the indoline compounds include o-aminostyrene compounds, and the reaction formula during the cleavage is:

[0055]

[0056] Example 1

[0057] This embodiment 1 provides a method for cracking phenylethylamine compounds, comprising the following steps:

[0058] S1. Add 0.8 mmol (76.9 mg) of sodium tert-butoxide, 0.2 mmol of phenylethyl arylamine, and 2 mL of DMSO into a 25 mL reaction tube and stir the reaction at 30°C in a dry air atmosphere for 4 h to fully break the carbon-nitrogen bond.

[0059] S2. After adding 10 mL of deionized water to the reaction system of step S1 for quenching, extraction was performed with 5 mL of ethyl acetate and repeated three times, and the extracts were combined to obtain an organic phase. The organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, the organic phase was purified by silica gel column chromatography to obtain cleavage products of styrene and aniline.

[0060] Wherein, the reaction formula in Example 1 is:

[0061]

[0062] Example 2 to Example 9

[0063] Examples 2 to 9 provide a method for cracking a phenylethylamine compound, respectively. The difference from Example 1 is that the type of phenylethylamine compound and the reaction time are shown in Table 1 below.

[0064] Table 1 Phenylethylamine compounds, reaction time, cleavage products and yields

[0065]

[0066]

[0067] The nuclear magnetic resonance characterization of the pyrolysis product styrene in Examples 1 to 8 is as follows: 1 H NMR(400MHz, CDCl3)δ:7.19(d,J=8.0Hz,2H),7.10(t,J=8.0Hz,2H),7.02(t,J=8.0Hz ,2H),6.50(dd,J=12.0,20.0Hz,1H),5.53(d,J=16.0Hz,1H),5.02(d,J=16.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ: 136.7, 136.0, 127.6, 126.9, 125.3, 112.9.

[0068] The nuclear magnetic resonance characterization of the cleavage product aniline in Example 1 is as follows: 1 H NMR (400MHz, CDCl3): δ7.12 (t, J = 10.0Hz, 2H), 6.73 (t, J = 10.0Hz, 1H), 6.63 (d, J = 11.2Hz, 2H), 3.53 (s, 2H) ppm. 13 C NMR (100MHz, CDCl3): δ146.4, 129.0, 118.0, 114.8ppm.

[0069] The nuclear magnetic resonance characterization of the cleavage product p-nitroaniline in Example 2 is as follows:1 H NMR (300MHz, CDCl3): δ7.07 (d, J = 9.0 Hz, 2H), 5.63 (d, J = 9.0 Hz, 2H), 3.37 (s, 2H) ppm. 13 CNMR (100MHz, CDCl3): δ153.6,140.3,127.5,114.5ppm.

[0070] The nuclear magnetic resonance characterization of the cleavage product p-aminoacetophenone in Example 3 is as follows: 1 H NMR (400MHz, CDCl3): δ7.61 (d, J = 8.4Hz, 2H), 6.45 (d, J = 8.4Hz, 2H), 3.91 (s, 2H), 2.30 (s, 3H) ppm. 13 C NMR (100MHz, CDCl3): δ197.7,152.2,131.9,129.0,114.8,27.2ppm.

[0071] The nuclear magnetic resonance characterization of the cleavage product p-bromoaniline in Example 4 is as follows: 1 H NMR (300MHz, CDCl3): δ7.03 (d, J = 6.6 Hz, 2H), 6.36 (d, J = 6.6 Hz, 2H), 3.45 (s, 2H) ppm. 13 C NMR (100MHz, CDCl3): δ144.5, 131.1, 115.8, 109.3ppm.

[0072] The nuclear magnetic resonance characterization of the cleavage product p-anisidine in Example 5 was as follows: 1 H NMR (400MHz, CDCl3): δ6.55(d,J=8.8Hz,2H), 6.45(d,J=8.8Hz,2H), 3.54(s,3H), 3.21(s,2H)ppm. 13 C NMR (100MHz, CDCl3): δ151.9, 139.0, 115.5, 113.9, 54.9ppm.

[0073] The nuclear magnetic resonance characterization of the cleavage product 1-naphthylamine in Example 6 is as follows: 1 H NMR (400MHz, CDCl3): δ7.64 (t, J = 2.4Hz, 2H), 7.29-7.26 (m, 2H), 7.17-7.10 (m, 2H), 6.60 (d, J = 6.8Hz, 1H), 3.51 (s, 2H) ppm. 13C NMR (100MHz, CDCl3): δ141.1,133.5,127.6,125.4,124.9,123.9,122.7,119.9,118.0,108.7ppm.

[0074] The nuclear magnetic resonance characterization of the cleavage product 2-methylpyridinamine in Example 7 is as follows: 1 H NMR (300MHz, CDCl3): δ8.25 (d, J = 4.2Hz, 1H), 7.63-7.51 (m, 1H), 6.84-6.80 (dd, J = 5.1, 6.3Hz, 1H), 6.68 (d, J = 8.1Hz, 1H), 4.59 (br-s, 2H) ppm. 13 C NMR (75MHz, CDCl3): δ159.6, 149.0, 138.7, 114.8, 109.6ppm.

[0075] The nuclear magnetic resonance characterization of the cleavage product benzamide in Example 8 is as follows: 1 H NMR (DMSO, 400MHz): δ (ppm) 7.79 (s, 1H), 7.71-7.68 (m, 2H), 7.34-7.30 (m, 1H), 7.27-7.23 (m, 2H), 7.18 (s, 1H); 13 C NMR (DMSO, 100MHz): δ (ppm) 167.0, 133.3, 130.2, 127.2, 126.5.

[0076] The nuclear magnetic resonance characterization of the cleavage product o-aminostyrene in Example 9 was as follows: 1 H NMR (400MHz, CDCl3) δ (ppm) 7.30 (d, J = 7.6Hz, 1H), 7.30 (t, J = 7.6Hz, 1H), 7.01-6.96 (m, 2H),6.89(d,J=7.9Hz,1H),5.84(d,J=17.5Hz,1H),5.53(d,J=11.8Hz,1H),3.92(s,2H); 13 C NMR (101MHz, CDCl3) δ (ppm) 144.57, 133.65, 129.69, 128.26, 125.03, 119.88, 117.03, 116.67.

[0077] While the embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations of these embodiments are possible. However, it should be understood that such modifications and variations are within the scope and spirit of the present invention as set forth in the claims. Furthermore, the invention described herein is susceptible to other embodiments and may be practiced or implemented in a variety of ways.

Claims

1. A method for cracking phenylethylamine compounds, characterized in that: include: In an oxygen-containing environment, a solvent environment and the participation of an organic base, a phenylethylamine compound is reacted at 20° C.-40° C. for 2 h-5 h, and then the carbon-nitrogen bond is broken to obtain a cleavage product.

2. The cracking method according to claim 1, wherein: The phenethylamine compound includes one of a phenethylamine compound and an indoline compound; preferably, the phenethylamine compound also includes a phenethylamide compound.

3. The cracking method according to claim 2, wherein: The structural formula of the phenethylamine compound is shown in Formula I: Among them, R 1 With R 2 are independently hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group; Preferably, the structural formula of the phenethylamide compound is as shown in Formula II: Among them, R 3 With R 4 are independently hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group; And / or, the structural formula of the indoline compound is as shown in Formula III: Among them, R 5 is hydrogen, C1 to C 40 Fatty groups, C4 to C 40 aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxyl group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group.

4. The cracking method according to claim 3, wherein: The C1 to C 40 The aliphatic group includes one of methyl, ethyl, propyl, isopropyl, butyl and benzyl; and / or the C4 to C 40 The aromatic group includes one of a pyridine derivative, a phenyl group, a substituted phenyl group, a 1-naphthyl group, and a 2-naphthyl group; and / or the halogen includes one of a fluorine group, a chlorine group, a bromine group, and an iodine group.

5. The cracking method according to claim 2, wherein: The cleavage products of the phenethylamine compound when cleaved include styrene compounds and amine compounds. Preferably, the cleavage products of the phenethylamide compound when cleaved include styrene compounds and amide compounds; When the indoline compound is cracked, the cracking products include o-aminostyrene compounds.

6. The cracking method according to claim 2, wherein: The reaction formula when the phenethylamine compound is cracked is: Preferably, the reaction formula for cracking the phenethylamide compound is: The reaction formula when the indoline compound is cracked is:

7. The cracking method according to claim 1, wherein: The solvent environment includes one of dimethyl sulfoxide and N,N-dimethylformamide; and / or the organic base includes one of t-BuONa and t-BuOK; and / or the oxygen concentration in the oxygen-containing environment is 10%-100%; and / or the molar ratio of the organic base to the phenylethylamine compound is (2-6):

1.

8. The cracking method according to claim 1, characterized in that The phenylethylamine compound is reacted at 20° C.-40° C. for 2 h-5 h, then quenched, extracted, and separated by column chromatography to obtain a cleavage product.

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