Preparation method of antitumor drug intermediate 4-(monochlorodifluoromethoxy) aniline

Abstract

The invention discloses a preparation method for synthesizing an antitumor drug intermediate 4-(monochlorodifluoromethoxy) aniline. According to the method, 4-hydroxyaniline is used as an initial raw material, and etherification and chlorination are sequentially performed to prepare a target product. The preparation method has the advantages of easily available raw materials, few side reactions, economy, environmental protection and suitableness for large-scale production, and provides a new intermediate preparation approach for industrial production of anti-tumor drugs such as acanib and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates thereof, and particularly relates to a method for preparing 4-(monochlorodifluoromethoxy)aniline, an intermediate for synthesizing the anti-tumor drug aspergillus. Background Art

[0002] The structure of 4-(chlorodifluoromethoxy)aniline is as follows:

[0003]

[0004] Because this compound contains unique functional groups such as a fluorodichloromethoxy group, it has been widely used in the molecular design of anti-tumor drugs. Recently, a novel BCR-ABL allosteric inhibitor, asciminib, contains a fluorodichloromethoxy group in its molecule. Therefore, 4-(chlorodifluoromethoxy)aniline has become a key intermediate in the preparation of asciminib, making the development and optimization of its preparation methods of great practical significance.

[0005] The preparation of 4-(chlorodifluoromethoxy)aniline has been reported in the literature, mainly including the following:

[0006] Method A: J.Org.Chm.1979,44,2907-1908 reports a method in which p-nitrophenol is used as the starting material, which is converted into p-nitrochlorodifluoromethoxybenzene by reaction with carbon tetrachloride and hydrogen fluoride. The intermediate is then subjected to catalytic hydrogenation to reduce the nitro group to the amino group, thereby producing the target product 4-(chlorodifluoromethoxy)aniline.

[0007]

[0008] Method B: Another preparation method is reported in Eur. J. Org. Chm. 2008, 2875-2880. This method also uses p-nitrophenol as the starting material. It first reacts with thiophosgene to produce thionyl chloride, which then undergoes a substitution reaction with bromine trifluoride to produce p-nitrochlorodifluoromethoxybenzene. This intermediate is then subjected to catalytic hydrogenation to reduce the nitro group to the amino group, yielding the target product, 4-(chlorodifluoromethoxy)aniline.

[0009]

[0010] Method C: Chinese Patent CN104119238 reports a method for converting trichloromethoxy to chlorodifluoromethoxy. Specifically, this method uses trichloromethoxybenzene as the starting material, first undergoing a selective fluorine-chlorine substitution reaction in the presence of hydrogen fluoride, followed by nitration and reduction, to produce the target product, 4-(chlorodifluoromethoxy)aniline.

[0011]

[0012] In addition, the literature J.Am.Chem.Soc. 2023, 145, 23899-23904 describes a novel method for converting phenolic hydroxyl groups in aromatic rings into monochlorodifluoromethoxy groups. This method uses phenyl 4-hydroxybenzoate as a substrate, TMSCF2Cl as a difluorocarbene source, 1-chloromethyl-4-fluoro-1,4-diazobicyclo-2.2.2-octane bis(tetrafluoroborate) salt (Selectfluor) as an oxidant, CuCl as a copper salt catalyst, and nBu4NCl as an additive. The reaction is carried out in NMP / DCM solvent at room temperature for 12 hours to obtain the monochlorodifluoromethoxy product in a 66% yield.

[0013]

[0014] As a novel reaction type for introducing a chlorodifluoromethoxy functional group, this method features a novel design and a simple route, but the catalyst involved is relatively complex. In particular, the reaction has been reported in the literature only for substrates with phenyl carboxylates at the para position. Whether it can be applied to the target product in this case with an amino or nitro group at the para position remains unknown, and further research is needed.

[0015] A comprehensive review of existing preparation methods reveals that, on the one hand, the preparation process requires the use of toxic and hazardous substances such as carbon tetrachloride, thiophosgene, and hydrogen fluoride, and employs high temperature and high pressure reaction conditions. Some reactions also require the use of precious metals and other complex catalysts. These processes place high demands on safety and environmental protection, making them difficult to scale up for industrial production. On the other hand, since most current preparation routes involve the introduction of a chlorodifluoromethoxy functional group followed by nitration and nitro-reduction reactions, side reactions are prone to occur, impacting overall yield and product quality.

[0016] It can be seen from this that although the synthesis method of 4-(chlorodifluoromethoxy)aniline has been studied and reported, based on the existing synthesis technology, selecting readily available industrial raw materials and common unit reactions, striving to shorten the synthesis steps and overcome the influence of side reactions under mild and environmentally friendly reaction conditions, and finding a convenient and fast preparation method has significant practical significance for the industrial production of anti-tumor drugs including aspergillus. Summary of the Invention

[0017] The purpose of the present invention is to overcome the defects of the prior art and provide an improved preparation method of 4-(monochlorodifluoromethoxy)aniline (I) in accordance with the synthesis concept of green chemistry. The preparation method overcomes the safety and environmental protection defects of the existing methods, shortens the reaction process and reduces the occurrence of side reactions by using economically available raw materials and relatively mild reaction conditions, thereby facilitating the quality improvement and industrial production of the product and promoting the economic and technological development of related raw materials.

[0018] In order to achieve the above object, the main technical scheme provided by the present invention is as follows: a preparation method of 4-(chlorodifluoromethoxy)aniline (I),

[0019]

[0020] The preparation method comprises the following steps: etherifying 4-hydroxyaniline (II) and chlorodifluoromethane (III) under alkaline conditions to obtain 4-(difluoromethoxy)aniline (IV); and chlorinating 4-(difluoromethoxy)aniline (IV) and a chlorinating agent in the presence of an initiator to obtain 4-(chlorodifluoromethoxy)aniline (I).

[0021] The reaction route is shown below:

[0022]

[0023] In addition, the present invention also provides the following subsidiary technical solutions:

[0024] The molar ratio of the raw materials 4-hydroxyaniline (II) and monochlorodifluoromethane (III) in the etherification reaction is 1:1-3, preferably 1:1.5-2.5, and more preferably 1:2.

[0025] The base used in the etherification reaction is sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium ethoxide or sodium methoxide, preferably sodium hydroxide.

[0026] The solvent used in the etherification reaction is acetonitrile, ethyl acetate, toluene, diethyl ether, isopropyl ether, dioxane or tetrahydrofuran, preferably tetrahydrofuran.

[0027] The temperature of the etherification reaction is 0-80°C, preferably 30-50°C.

[0028] The chlorinating agent used in the chlorination reaction is chlorine, sulfuryl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride, preferably phosphorus pentachloride or oxalyl chloride.

[0029] The molar ratio of the chlorination reaction raw material 4-(difluoromethoxy)aniline (IV) to the chlorinating agent is 1:1-2, preferably 1:1.5.

[0030] The initiator of the chlorination reaction is azobisisobutylnitrile, azobisisoheptonitrile or dibenzoyl peroxide, preferably azobisisobutylnitrile; the amount of the initiator is 5-15% of the mole number of 4-(difluoromethoxy)aniline (IV), preferably 10%.

[0031] The solvent for the chlorination reaction is tetrahydrofuran, toluene, ether, isopropyl ether or acetonitrile, preferably acetonitrile.

[0032] The temperature of the chlorination reaction is 0-100°C, preferably 70-80°C.

[0033] The present invention relates to a method for preparing 4-(monochlorodifluoromethoxy)aniline (I), an anti-tumor drug intermediate. The method uses 4-hydroxyaniline (II) as a starting material and undergoes two steps of etherification and chlorination. The preparation process has readily available raw materials, few side reactions, is economical and environmentally friendly, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is a hydrogen nuclear magnetic resonance spectrum of the compound of formula I obtained by the preparation method of the present invention;

[0035] Figure 2 is the mass spectrum of the compound of formula I obtained by the preparation method of the present invention. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is further described in detail below in conjunction with several preferred embodiments.

[0037] Example 1:

[0038] 4-Hydroxyaniline (II) (5.5 g, 50 mmol) and sodium hydroxide solution (4 M, 50 mL) were added to a reaction flask under an ice bath. A solution of monochlorodifluoromethane (8.7 g, 100 mmol) in 50 mL of tetrahydrofuran was added dropwise with stirring. The reaction was maintained at 0-5°C for 30 minutes, then the temperature was raised to 35-45°C and allowed to react overnight. Extraction was performed three times with ethyl acetate. The combined organic phases were washed with saturated ammonium chloride solution and dried over anhydrous magnesium sulfate. Filtration and concentration were performed, and the residue was distilled under reduced pressure to obtain 6.5 g of 4-(difluoromethoxy)aniline (IV) as a colorless oily liquid, with a yield of 81.8%. BP was 230-232°C. EI-MS m / z: 160 [M+H] + .

[0039] Example 2:

[0040] Under nitrogen, 4-(difluoromethoxy)aniline (IV) (3.18 g, 20 mmol), azobis(isobutylnitrile) (0.33 g, 2 mmol), and acetonitrile (100 mL) were added to a reaction flask. Oxalyl chloride (3.8 g, 30 mmol) was then added portionwise at room temperature. After addition, the mixture was stirred at 70-80°C for 10-12 hours. TLC confirmed the reaction was complete. The reaction was quenched with water and extracted three times with isopropyl ether. The organic phases were combined and washed sequentially with saturated sodium bicarbonate, saturated brine, and water, dried, and concentrated. The resulting residue was distilled under reduced pressure to yield 2.7 g of 4-(chlorodifluoromethoxy)aniline (I) as a light yellow oily liquid in a yield of 69.3%. bp 244-248°C, EI-MS m / z: 194 [M+H] + .

[0041] Example 3:

[0042] Under nitrogen, 4-(difluoromethoxy)aniline (IV) (3.2 g, 20 mmol), azobis(isobutylnitrile) (0.33 g, 2 mmol), and acetonitrile (100 mL) were added to a reaction flask. Phosphorus pentachloride (6.2 g, 30 mmol) was then added portionwise at room temperature. After addition, the mixture was stirred at 70-80°C for 10-12 hours. TLC confirmed the reaction was complete. The reaction was quenched with water and extracted three times with isopropyl ether. The organic phases were combined and washed sequentially with saturated sodium bicarbonate, saturated brine, and water, dried, and concentrated. The resulting residue was distilled under reduced pressure to afford 2.9 g of 4-(chlorodifluoromethoxy)aniline (I) as a light yellow oily liquid, with a yield of 75.0%, bp 244-248°C, EI-MS m / z: 194 [M+H]. + , 1 H NMR (DMSO-d6) δ 6.98 (dd, J1 = 12.4 Hz, J2 = 3.2 Hz, 2H), 6.59 (m, 2H), 5.32 (s, 2H). The H NMR spectrum and mass spectrum of the compound of formula I are shown in the attached Figure 1 and 2 .

[0043] It should be noted that the above preferred embodiments are merely illustrative of the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit and essence of the present invention are intended to be encompassed within the scope of protection of the present invention.

Claims

1. A method for preparing an anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline, the chemical structure of which is as follows: It is characterized by The preparation method comprises the following steps: 4-hydroxyaniline and chlorodifluoromethane undergo etherification reaction under alkaline conditions to obtain 4-(difluoromethoxy)aniline; and 4-(difluoromethoxy)aniline undergoes chlorination reaction with a chlorinating agent in the presence of an initiator to obtain 4-(chlorodifluoromethoxy)aniline.

2. The method for preparing the anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline according to claim 1, characterized in that The molar ratio of the raw materials 4-hydroxyaniline and chlorodifluoromethane in the etherification reaction is 1:1-3.

3. The method for preparing the anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline according to claim 1, characterized in that The base used in the etherification reaction is sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium ethoxide or sodium methoxide.

4. The method for preparing the anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline according to claim 1, characterized in that The solvent used in the etherification reaction is acetonitrile, ethyl acetate, toluene, diethyl ether, isopropyl ether, dioxane or tetrahydrofuran; and the temperature of the etherification reaction is 0-80°C.

5. The method for preparing the anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline according to claim 1, characterized in that The chlorinating agent used in the chlorination reaction is chlorine, sulfuryl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride; the molar ratio of the raw material 4-(difluoromethoxy)aniline in the chlorination reaction to the chlorinating agent is 1:1-2.

6. The method for preparing the anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline according to claim 1, characterized in that The initiator of the chlorination reaction is azobisisobutylnitrile, azobisisoheptonitrile or dibenzoyl peroxide; the amount of the initiator is 5-15% of the molar number of 4-(difluoromethoxy)aniline.

7. The method for preparing the anti-tumor drug intermediate 4-(chlorodifluoromethoxy)aniline according to claim 1, characterized in that The solvent of the chlorination reaction is tetrahydrofuran, toluene, ether, isopropyl ether or acetonitrile; and the temperature of the chlorination reaction is 0-100°C.

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