JP7031858B2 - Method for producing primary amine compound - Google Patents

Description

The present invention relates to pharmaceuticals, pesticides, cosmetics, fragrances, synthetic fibers and methods for producing primary amine compounds useful as raw materials thereof.

As a method for synthesizing an amine compound from a ketone compound, a method is known in which ketooxime is prepared from a ketone compound, converted into an amide compound by Beckmann rearrangement, and then converted into an amine compound by hydrolysis (Non-Patent Document 1). ). However, when synthesizing an amide compound from a ketone compound, it is necessary to separately prepare ketooxime and then isolate it, which causes a problem that it takes time and effort. In addition, high temperature and strong acid conditions are required when synthesizing an amide compound from ketooxime by Beckmann rearrangement.

On the other hand, there is known a method of oxidizing a ketone compound to a carboxylic acid and then converting it into an amine compound by Curtius rearrangement using sodium azide (Non-Patent Document 2). However, it is necessary to use highly toxic sodium azide.

G. Bourgery, P.M. Doster, A. Lacour, M. et al. Langloison, B. et al. Paulrias, J. et al. Tissne-Versailles, J. Mol. Med. Chem. 1981, 24, 159-167. S. A. Munk, D.M. A. Harcourt, P.M. N. Arasingham, J. Mol. A. Burke, A. B. Kharlamb, C.I. A. Manlapaz, E. et al. U. Padillo, D.I. Roberts, E.I. Runde, L.M. Williams, L.M. A. Whoeler, M.D. E. Garst, J.M. Med. Chem. 1997, 40, 18-23.

An object of the present invention is to provide a simple method for producing a primary amine compound, which does not require complicated procedures and does not require the use of highly toxic sodium azide or the like.

The present inventor aims to synthesize a direct primary amine compound from a ketone compound, transoxime to a ketone using a tosylic acid monohydrate as a catalyst, and perform Beckmann rearrangement and alcoholic decomposition. The present invention has been completed by finding a method for producing an amine compound. The acid catalyst and alcohol cause an oxime transfer from the oxime compound as the reactant to the ketone compound as the raw material, and then the primary amine compound is synthesized by the additional decomposition of the rearrangement produced by the Beckmann rearrangement and the alcohol. To.

That is, the present invention relates to a method for producing a primary amine compound, which comprises a step of reacting a ketone compound and an oxime compound in the presence of an alcohol and an acid catalyst.

The acid catalyst is preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, tosylic acid monohydrate, trifluoromethanesulfonic acid, or boron trifluoride diethyl ether complex.

The alcohol is preferably methanol, ethanol, or 1-propanol.

The oxime compound is preferably an O-benzenesulfonyl-acetohydroxamic acid ester derivative.

In the present invention, the corresponding primary amine compound can be synthesized from the ketone compound in a one-step reaction only by reacting the ketone compound and the oxime compound with alcohol in the presence of an acid catalyst. The obtained primary amine compounds are useful as pharmaceuticals, pesticides, cosmetics, fragrances, synthetic fibers and their raw materials.

The method for producing a primary amine compound of the present invention is characterized by comprising a step of reacting a ketone compound and an oxime compound in the presence of an alcohol and an acid catalyst. An oxygen-substituted stable oxime compound is regarded as an oxygen-substituted hydroxylamine equivalent, and a primary amine compound is produced from a ketone compound under simple and mild conditions. The transoximation reaction from ethyl acetohydroxamate oxygen-substituted with a Bronsted acid catalyst to a ketone compound proceeds, oxygen-substituted ketooxime is synthesized, and the ketooxime intermediate undergoes Beckmann rearrangement by an acid catalyst. It chemically reacts with the primary amine compound by alcohol decomposition with the generated rearrangement and alcohol.

The ketone compound is not particularly limited as long as it has a carbonyl group, and is, for example, acetophenone such as acetophenone, 1-acetophenone, 2-acetophenone, 6-methoxy-2-acetonaphthone, 2-methylacetophenone, 3-methylacetophenone, 4-methyl. Methylacetophenone such as acetophenone, methoxyacetophenone such as 4-methoxyacetophenone and trimethoxyacetophenone, chloroacetophenone such as 4-chloroacetophenone, chloroacetophenone such as 4-bromoacetophenone and 2-bromoacetophenone, and nitroacetophenone such as 4-nitroacetophenone. , Trifluoromethylacetophenone such as 4-trifluoromethylacetophenone, ethylphenylketone, nitroacetophenone such as 4-nitroacetophenone, methylphenonetylketone, benzophenone, cyclododecanone, propiophenone, isobutyrophenone, 2-acetylthiophene Examples include acetylthiophenone such as, and dodecanone such as 2-dodecanone. Of these, acetaminophens having an electron-donating substituent on the aromatic ring are preferable in terms of reactivity.

（式中、Ｒ^１はＨ、ＣＦ_３、または、ＯＣＨ_３であり、Ｒ^２はＣＨ_３、Ｃ_２Ｈ_５、または、Ｃ_３Ｈ_７である。）
で表されるＯ－ベンゼンスルホニル－アセトヒドロキサム酸エステル誘導体、Ｏ－４－トリフルオロメチルベンゼンスルホニル－アセトヒドロキサム酸エステル誘導体、Ｏ－ジフェニルホスフィニル－アセトヒドロキサム酸エステル誘導体などが挙げられる。なかでも、反応収率の点で、上記化学式で表されるＯ－ベンゼンスルホニル－アセトヒドロキサム酸エステル誘導体、Ｏ－４－トリフルオロメチルベンゼンスルホニル－アセトヒドロキサム酸エステル誘導体が好ましい。 The oxime compound is not particularly limited as long as it has a structure represented by> C = N—OH, and is, for example, the following chemical formula.

(In the equation, R ¹ is H, CF ₃ , or OCH ₃ , and R ² is CH ₃ , C ₂ H ₅ , or C ₃ H _7. )
Examples thereof include O-benzenesulfonyl-acetohydroxamic acid ester derivative represented by, O-4-trifluoromethylbenzenesulfonyl-acetohydroxamic acid ester derivative, O-diphenylphosphinyl-acetohydroxamic acid ester derivative and the like. Of these, the O-benzenesulfonyl-acetohydroxamic acid ester derivative represented by the above chemical formula and the O-4-trifluoromethylbenzenesulfonyl-acetohydroxamic acid ester derivative are preferable in terms of reaction yield.

Alcohol is not particularly limited, and examples thereof include methanol, ethanol, propanol, butanol, and isobutanol. Of these, methanol, ethanol and 1-propanol are preferable in terms of reactivity.

Alcohol can also be used as a solvent and may be used in combination with other organic solvents such as methylene chloride, chloroform, hexane, toluene, diethyl ether, hexane, toluene, acetonitrile, methanol, tetrahydrofuran, ethyl acetate, acetone, dimethylformaldehyde and the like. You can also. It is preferable that water is absent.

The acid catalyst is not particularly limited, and includes not only the acid itself but also its metal salt. For example, hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, tosylic acid monohydrate, trifluoromethanesulfonic acid, bistrifluoromethanesulfonimide, boron trifluorodiethyl ether complex, scandium trifluoromethanesulfonic acid (III), trifluo. Examples thereof include iron lomethanesulfonate (III), copper trifluoromethanesulfonate (II), bismuth trifluoromethanesulfonate (III), titanium tetrachloride, iron trichloride and the like. Of these, hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, tosylic acid monohydrate, trifluoromethanesulfonic acid, and boron trifluoride diethyl ether complex are preferable in terms of reaction time.

The amount of the oxime compound added to the ketone compound is preferably 1 to 10 mol, more preferably 1 to 2 mol, per 1 mol of the ketone compound. Below 1 mol, the reaction tends to be incomplete.

The amount of the acid catalyst added is preferably 0.0025 to 1 mol, more preferably 0.025 to 0.10 mol, based on 1 mol of the ketone compound. If it is less than 0.0025 mol, the amine compound is not produced, so that the reaction tends to be slowed down. Even if it exceeds 1 mol, the effect of promoting the reaction is small and tends to impair economic efficiency.

The reaction temperature is not particularly limited, but is preferably 0 to 40 ° C, more preferably 20 to 30 ° C. Below 0 ° C., the yield of the amide compound decreases and the reaction tends to be incomplete. Even if the temperature exceeds 40 ° C., the improvement in yield is small and the energy consumption tends to increase. The reaction time is also not particularly limited, but is preferably 1 to 48 hours, more preferably 24 to 48 hours. The reaction tends to be incomplete in less than an hour. Even if it exceeds 48 hours, the improvement in yield is small and tends to consume only time.

The amide compound obtained by the production method of the present invention is useful as pharmaceuticals, pesticides, cosmetics, fragrances, synthetic fibers and raw materials thereof.

Hereinafter, examples of the present invention will be described, but the present invention is not limited to the following examples.

Synthesis Example 1 Synthesis of ethyl O-benzenesulfonyl-acetohydroxamic acid (Compound 2a) Ethyl acetohydroxamic acid (200 mg, 1.94 mmol, 1. 0 eq.), Benzene sulfonyl chloride (0.33 mL, 2.62 mmol, 1.35 eq.), Triethylamine (0.39 mL, 2.81 mmol, 1.45 eq.), And tetrahydrofuran (6.4 ml, 0.30 M). , Stirred at room temperature for 1 hour. Then, the reaction was stopped with a saturated aqueous solution of ammonium chloride, tetrahydrofuran was distilled off under reduced pressure, extraction was performed using diethyl ether (20 mL × 3 times), the organic phase was washed with saturated brine, and dried over sodium sulfate. did. Sodium sulfate was filtered off by cotton plug filtration, the solvent was distilled off under reduced pressure, and NMR (CDCl ₃ ) was measured. Purified by silica gel column chromatography (Kanto Chemical silica gel 60 (40-50 μm), hexane / ethyl acetate = 95/5), 376 mg (yield 80) of white ethyl O-benzenesulfonyl-acetohydroxamate (compound 2a) was added. %)Obtained. The NMR data of compound 2a is as follows.

2a: ¹ H-NMR (400Hz, CDCl ₃ ) δ1.22 (t, J = 7.1Hz, 3H), 2.02 (s, 3H), 3.97 (q, J = 7.1Hz, 2H) , 7.54 (d, J = 7.5Hz, 2H), 7.67 (d, J = 7.5Hz, 1H), 7.97 (d, J = 7.5Hz, 2H); ¹³ C-NMR (CDCl ₃ , 100 MHz) δ14.8, 15.8, 64.7, 129.6, 134.6, 136.3, 170.8.

Example 1 Synthesis of 6-methoxy-2-naphthylamine (Compound 3a) 6'-methoxy-2'-acetonafton (100 mg, 0.50 mmol) in a test tube (with a stirrer) at room temperature and an argon atmosphere. , 1.0 eq.), Tosylic acid monohydrate (4.8 mg, 0.0250 mmol, 5.0 mol%), methanol (0.50 mL, 1.0 M), ethyl O-benzenesulfonyl-acetohydroxamate (146 mg). , 0.60 mmol, 1.2 eq.) Was added, and the mixture was stirred at room temperature for 24 hours. Then, 3 ml of saturated aqueous sodium hydrogen carbonate solution was added, the mixture was stirred for 10 minutes, and extraction was performed 3 times with 10 mL of ethyl acetate. The collected organic phase was washed with saturated brine and dried over sodium sulfate. Then, sodium sulfate was removed, the solvent was distilled off under reduced pressure, and NMR was measured. Purified by silica gel column chromatography (manufactured by Kanto Chemical Co., Inc., silica gel 60 (40-50 μm), toluene / hexane = 9/1), and white 6-methoxy-2-naphthylamine (compound 3a) was 77.9 mg (compound 3a). Yield 90%) was obtained.

The NMR data of compound 3a is as follows.
^{1 1} H-NMR (CDCl ₃ , 400 MHz, ppm) δ7.55 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.07-7.02 (d, J = 8.5 Hz, 1H) m, 2H), 6.93-6.90 (m, 2H), 3.83 (s, 3H), 3.69 (br, 2H)
¹³ C-NMR (CDCl ₃ , 100 MHz, ppm) δ155.5, 142.4, 130.3, 128.7, 128.0, 127.4, 119.0, 118.8, 109.3, 106. 2,55.4
LC-MS (ESI, positive) m / z calcd for C ₁₁ H ₁₂ NO ⁺ [M + H]: 174.09, found 174.10.

The primary amine compounds synthesized using the present invention are shown in Table 1 below.

The reaction proceeded with a particularly high yield for aromatic ketones. Good reactivity was also shown for the position of the substituent and the sterically large naphthalene ring. In the case of an electron-donating substituent as an electronic property, a high yield can be obtained, but in the case of an electron-withdrawing substituent, dislocation does not proceed easily and heating is required. The reaction also proceeds with the chain aliphatic ketone. Compound 3c is also a useful substance that can be used as a raw material for organic electronic devices.

Example 2
Table 2 shows the results of examining various catalysts in the reaction for synthesizing 2-naphthylamine from 2-acetonafton. Since entry1 does not use an acid catalyst, it corresponds to a comparative example, and the primary amine compound could not be synthesized without the acid catalyst. On the other hand, as catalysts, hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), methanesulfonic acid (MsOH), camphorsulfonic acid (CSA), tosylic acid monohydrate (TsOH · _H2O ), trifluoromethanesulfonic acid. Using (TfOH), a boron trifluoride diethyl ether complex (BF ₃ , Et ₂ O), a primary amine compound could be synthesized in high yield.

Example 3
Table 3 shows the results of examining various solvents in the reaction for synthesizing 2-naphthylamine from 2-acetonafton. Since entry4 does not use alcohol, it corresponds to a comparative example, and the primary amine compound could not be synthesized in the absence of alcohol. On the other hand, when methanol, ethanol, or 1-propanol was used as the alcohol, the primary amine compound could be synthesized in high yield.

According to the present invention, the corresponding primary amine compound can be synthesized from the ketone compound in a one-step reaction. The obtained primary amine compounds are useful as pharmaceuticals, pesticides, cosmetics, fragrances, synthetic fibers and their raw materials.

Claims (3)

A method for producing a primary amine compound, which comprises a step of directly synthesizing a primary amine compound by reacting a ketone compound and an oxime compound in the presence of an alcohol and an acid catalyst.
The acid catalyst is a metal salt of hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, tosylic acid monohydrate, trifluoromethanesulfonic acid, bistrifluoromethanesulfonicimide, boron trifluoride diethyl ether complex, trifluoromethanesulfonic acid. , Titanium tetrachloride, or iron trichloride ,
The oxime compound has the following chemical formula

(In the equation, R ¹ is H, CF ₃ , or OCH ₃ , and R ² is CH ₃ , C ₂ H ₅ , or C ₃ H _7. )
A method for producing a primary amine compound , which is an O-benzenesulfonyl-acetohydroxamic acid ester represented by . The primary amine compound according to claim 1, wherein the acid catalyst is hydrochloric acid, sulfuric acid, methanesulfonic acid, camphorsulfonic acid, tosylic acid monohydrate, trifluoromethanesulfonic acid, or boron trifluoride diethyl ether complex. Manufacturing method. The method for producing a primary amine compound according to claim 1 or 2, wherein the alcohol is methanol, ethanol, or 1-propanol.