Synthetic method of enzalutamide intermediate 4-amino-2-trifluoromethyl benzonitrile

Abstract

The invention discloses a synthetic method of an enzalutamide intermediate 4-amino-2-trifluoromethyl benzonitrile, which comprises the following steps: by taking a compound in a formula (II) as a raw material, dissolving the compound in a solvent A together with a free radical source A, a free radical initiator A and a photocatalyst A, and reacting under an illumination condition to obtain a compound III; mixing the compound (III) with acetic acid and tert-butyl nitrite, reacting in the absence of a solvent or a solvent B, and then adding tert-butyl isonitrile for reacting to obtain a compound (IV); and dissolving the compound (IV), a ligand C, organic alkali and nickel hexammine chloride in a solvent C, and reacting under the illumination condition to obtain the target product 4-amino-2-trifluoromethyl benzonitrile as shown in the formula (I). The reaction process is as follows: the substituent X in the formula is chlorine or bromine. According to the method, 4-bromoaniline or 4-chloro-aniline which is low in price and easy to obtain is taken as a starting raw material, and trifluoromethyl is directly introduced into a benzene ring by adopting photocatalytic free radical trifluoromethylation, so that the method conforms to the green chemical principle, and amino protection and deprotection steps are avoided.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, specifically relating to a method for synthesizing 4-amino-2-trifluoromethylbenzonitrile, an enzalutamide intermediate. Background Technology

[0002] Enzalutamide is used to treat advanced castration-resistant prostate cancer in men that has spread or relapsed. Its efficacy lies in blocking androgen binding to androgen receptors and preventing nuclear translocation of the ligand-receptor complex and recruitment of co-activators. The key intermediate of enzalutamide, 4-amino-2-trifluoromethylbenzonitrile (I), has the following structural formula:

[0003]

[0004] Currently disclosed existing technologies indicate that the main synthetic methods for 4-amino-2-trifluoromethylbenzonitrile (I) include:

[0005] 1) In 2006, patent CN1810775A reported a synthetic method for preparing 4-amino-2-trifluoromethylbenzonitrile. Using o-trifluoromethylfluorobenzene as the main raw material, the target product was obtained through a three-step synthesis method of bromination, cyano nucleophilic substitution, and ammonolysis. The synthetic route is as follows:

[0006]

[0007] This route consists of three steps. In the first step, bromination, the excessive use of glacial acetic acid and concentrated sulfuric acid increases the burden of post-processing. The second step, cyano nucleophilic substitution, requires the use of highly toxic cuprous cyanide, posing a safety risk. The third step, ammonolysis substitution, requires the use of liquid ammonia under high pressure and closed conditions. The high-temperature reaction at 160°C consumes a lot of energy and has high requirements for equipment. The overall process has defects such as many toxic reagents, large solvent consumption, and harsh reaction conditions, which are not conducive to industrial production.

[0008] 2) In 2012, patent CN102875414A reported a method for preparing 4-amino-2-trifluoromethylbenzonitrile. Using o-chlorotrifluorotoluene as a raw material, the target product was obtained via nitration, cyano nucleophilic substitution, and nickel catalysis. The synthetic route is as follows:

[0009]

[0010] This process involves three steps. The first step, nitration, uses large amounts of concentrated sulfuric acid and nitric acid, posing significant safety risks. The second step, cyano nucleophilic substitution, still uses highly toxic cuprous cyanide and requires large amounts of DMF solvent and high-temperature reflux conditions, presenting both safety risks and high energy consumption. The third step, hydrogenation reduction, uses high-pressure hydrogen (0.3-0.8 MPa) and large amounts of Raney nickel, resulting in significant operational risks. The entire process still faces challenges related to the use of toxic reagents, high-pressure operation risks, and complex waste acid treatment.

[0011] 3) In 2021, patent CN110862334A reported a reaction of m-aminotrifluorotoluene as a starting material with ethyl formate under reflux conditions catalyzed by zinc chloride to produce 4-amino-2-trifluoromethylbenzaldehyde. Subsequently, the obtained 4-amino-2-trifluoromethylbenzaldehyde and ammonium bisulfate were added to toluene, with acetic acid added as a catalyst, and reacted under reflux conditions to produce the target product 4-amino-2-trifluoromethylbenzonitrile. The synthetic route is as follows:

[0012]

[0013] This route involves two steps. The starting material, meta-aminotrifluorotoluene, is relatively expensive. The intermediate product from the first step, 4-amino-2-trifluoromethylbenzaldehyde, has a strong, irritating odor, impacting the environment and human health. Although this reaction avoids highly toxic cyanide, it suffers from drawbacks such as high raw material costs.

[0014] Therefore, it is necessary to develop a more convenient and economical synthesis process for 4-amino-2-trifluoromethyl-benzonitrile. Summary of the Invention

[0015] To address the aforementioned problems in existing technologies, this invention aims to provide a more convenient and economical method for synthesizing 4-amino-2-trifluoromethylbenzonitrile, an enzalutamide intermediate suitable for industrial production, avoiding highly toxic and hazardous formulations.

[0016] To achieve the above objectives, the present invention adopts the following technical solution:

[0017] A method for synthesizing 4-amino-2-trifluoromethylbenzonitrile, an enzalutamide intermediate, includes the following steps: 1) using a compound as shown in formula (II) as a raw material, dissolving it in solvent A with a free radical source A, a free radical initiator A and a photocatalyst A, and reacting it under light conditions to obtain compound (III);

[0018] 2) Compound (Ⅲ) was first mixed with acetic acid and tert-butyl nitrite and reacted under solvent-free or solvent B conditions. Then tert-butylisocyanate was added to react and compound (Ⅳ) was obtained.

[0019] 3) Compound (Ⅳ) was dissolved in solvent C with ligand C, organic base and hexaammine nickel chloride, and reacted under light to obtain the target product 4-amino-2-trifluoromethylbenzonitrile shown in formula (Ⅰ);

[0020] The reaction process is as follows:

[0021]

[0022] The substituent X in the formula is chlorine or bromine.

[0023] Further, in step 1), the free radical source A is selected from one or a combination of 1-(trifluoromethyl)-1,2-benzyl-3(1H)-one, sodium trifluoromethylsulfinate, trifluoromethyliodine, trifluoromethyllanthanum, and trifluoromethylhydrazine; the free radical initiator A is selected from one or a combination of ferrous trifluoromethanesulfonate, copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, and yttrium trifluoromethanesulfonate; the photocatalyst A is selected from one or a combination of ruthenium tripyridine chloride, benzophenone, 9-thioxanone, 9-trimethylbenzene-10-methylacridine perchlorate, and fluorescein; and the solvent A is selected from one or a combination of ethanol, methanol, dichloromethane, N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide.

[0024] Furthermore, solvent B in step 2) is selected from acetonitrile.

[0025] Further, in step 3), the ligand C is selected from one or a combination of 4,4'-dimethyl-2,2'-bipyridine, 2-amidinylpyridine hydrochloride and 1,10-phenanthroline; the solvent C is selected from one or a combination of methanol, dichloroethane, N,N-dimethylformamide, acetonitrile and dimethyl sulfoxide; and the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0026] Further, in step 1), the volume of solvent A is 1-8 mL / g based on the mass of the compound shown in formula (II); the molar ratio of the compound shown in formula (II), free radical source A, free radical initiator A and photocatalyst A is 1:1.2-3.0:0.01-0.3:0.01-0.15.

[0027] Furthermore, the reaction process under light conditions in step 1) is carried out by stirring at 20-90°C for 6-36 hours under 380-490nm light.

[0028] Furthermore, in step 2), the molar ratio of compound (Ⅲ), acetic acid and tert-butyl nitrite is 1:0.5-3.0:0.5-3.0.

[0029] Further, in step 2), compound (Ⅲ) is reacted with acetic acid and tert-butyl nitrite at 0-10°C for 10-60 minutes with stirring. Then, tert-butylisocyanate is added and the temperature is raised to 20-90°C for 2-12 hours to obtain compound (Ⅳ).

[0030] Further, in step 3), the molar ratio of compound (Ⅳ), hexaamminenickel chloride, ligand C and organic base is 1:0.2-3.0:0.01-0.1:0.1-3.0.

[0031] Furthermore, in step 3), the light irradiation reaction conditions are: under irradiation of 380–390 nm, stirring reaction at 70–90 °C for 5–15 hours.

[0032] The beneficial effects of this invention are as follows:

[0033] 1) Using inexpensive and readily available 4-bromoaniline or 4-chloroaniline as starting materials, photocatalytic free radical trifluoromethylation is used to directly introduce trifluoromethyl groups into the benzene ring, which conforms to the principles of green chemistry and avoids the protection and deprotection steps of the amino group; 2) The cyanoation is achieved by using tert-butyl nitrite / tert-butylisocyanate system instead of highly toxic cuprous cyanide, thus avoiding the risk of hydrogen cyanide generation.

[0034] 3) The reaction avoids a high-pressure closed system and flammable and explosive nitration reaction, which significantly improves safety, avoids the use of high-risk reagents such as bromine and cuprous cyanide, and produces no bromine- or cyanide-containing wastewater;

[0035] 4) In the photocatalytic ammonolysis reaction, nickel hexaammine chloride is used instead of ammonia water as the ammonia source, which effectively avoids the corrosive and irritating problems of ammonia water. The catalyst nickel hexaammine chloride can be recycled, and the amount of waste emissions is reduced by more than 50%. Detailed Implementation

[0036] The present invention will be further described below with reference to specific embodiments. The content described in these embodiments is merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of the present invention should not be regarded as limited to the specific forms stated in the embodiments.

[0037] Example 1: Preparation of hexaamminenickel chloride

[0038] The preparation of hexaamminenickel chloride is described in Angew. Chem. Int. Ed. 2024, 63, e202314355. Hexaamminenickel chloride is a purple solid that can be obtained by reacting nickel chloride with ammonia at room temperature with stirring. After the reaction is complete, excess ammonia is added to the remaining reaction solution to obtain a purple crystalline precipitate. The product can be recovered by filtration, with an average recovery rate of 85%.

[0039] Take a 200mL three-necked flask, add NiCl2 (100mmol, 12.9g), NH4Cl (300mmol, 15.9g) and 60mL ammonia water, stir and react for 3 hours at 0-5℃. After the reaction is complete, filter the precipitate and remove the solvent under vacuum to obtain a purple powder, which is hexaammine nickel chloride (22.4g, yield 97%).

[0040] Spectral characterization of hexaamminenickel chloride:

[0041] Elemental Analysis:C l2 H 18 N6Ni(230.0323):calcd.H,7.83;N,36.26;foundH7.84,N 36.25.

[0042] Example 2: Preparation of 2-amino-5-bromotrifluorotoluene(III)

[0043] Take a 500 mL quartz photoreactor, add 4-bromoaniline (100 mmol, 17.0 g), sodium trifluoromethanesulfinate (150 mmol, 23.4 g), free radical initiator Fe(OTf)₂ (10 mmol, 3.5 g), photocatalyst Ru(bpy)Cl₂ (1 mmol, 0.62 g), and 80 mL MeCN. Stir and slowly heat to 40-50 °C. Under nitrogen protection, stir and react for 24 h under a 25 W, 440 nm blue light lamp. After the reaction is complete, concentrate under reduced pressure to recover acetonitrile and cool to room temperature. Slowly pour the concentrated reaction solution into ice water and adjust the pH to 7-8 with saturated NaHCO₃ solution. Then, extract with dichloromethane, concentrate under reduced pressure to recover dichloromethane, and obtain a pale yellow oily liquid product, which is compound (Ⅲ) (21.8 g, yield 91%).

[0044] Spectral characterization of compound (Ⅲ):

[0045] 1 H NMR (400MHz, DMSO-d6) δ7.42(d,J=2.3Hz,1H),7.26(dd,J=8.7,2.2Hz,1H),6.70(d,J=8.7Hz,1H),3.84(s,2H). 13 C NMR(100MHz,DMSO-d6)δ143.08,132.79,126.33(CF, 3 J C-F (J=5.4Hz), 124.11(CF, 1 J C-F ,J=265.7Hz),122.32,118.45,114.76(CF,2 J C-F (J = 30.8 Hz). 19 F NMR (376MHz, DMSO-d6): δ-63.21(s).

[0046] Example 3: Preparation of 4-bromo-2-(trifluoromethyl)benzonitrile (IV)

[0047] Take a 200 mL round-bottom reaction flask, add 2-amino-5-bromotrifluorotoluene (100 mmol, 24.0 g), acetic acid (120 mmol, 7.2 mL), tert-butyl nitrite (120 mmol, 12.3 g), and 10 mL of acetonitrile. Stir the mixture at 0–5 °C for 30 minutes, then add tert-butylisocyanate (120 mmol, 9.9 g), and slowly heat to 50 °C for 3 hours. Stop the reaction when no more gas is emitted. After the reaction is complete, recover the solvent under reduced pressure, add 150 mL of water and 100 mL of ethyl acetate, allow to stand to separate the layers and remove the aqueous phase, then dry with anhydrous sodium sulfate. Concentrate the organic layer under reduced pressure until dry to obtain a brown oily substance, which is compound (Ⅳ) (23.3 g, yield 93%).

[0048] Spectral characterization of compound (Ⅳ):

[0049] 1 H NMR (400MHz, DMSO-d6) δ7.61(d,J=8.6Hz,1H),7.01(d,J=2.2Hz,1H),6.82(dd,J=8.6,2.3Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ153.5,136.7,132.8(d, 3 J C-F =29.29Hz), 123.3(d, 1 J C-F =274.7Hz),117.8,115.9,117.2(d, 2 J C-F =5.1Hz), 111.2. 19 F NMR(376MHz,DMSO-d6)δ-63.21(s).

[0050] Example 4: Preparation of 4-amino-2-trifluoromethylbenzonitrile (I)

[0051] Take a 500 mL quartz photoreactor, add 4-bromo-2-(trifluoromethyl)benzonitrile (100 mmol, 25.0 g), 4,4'-dimethyl-2,2'-bipyridine (1 mmol, 0.18 g), and 50 mL DMSO solvent, then add [Ni(NH3)6]Cl2 (20.0 mmol, 3.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (100 mmol, 15.2 g). Irradiate the reaction mixture with a (9W, 390 nm) LED UV lamp at 80-90 °C for 5 h. After the reaction is complete, filter the reaction solution to obtain a recoverable purple solid [Ni(NH3)6]Cl2; then recover the solvent under reduced pressure, concentrate to dryness under reduced pressure, and recrystallize the residue with ethyl acetate (5 mL) and petroleum ether (50 mL) to obtain the target compound (Ⅰ) (17.8 g, yield 96%). The product is a white solid with a melting point of 63 °C.

[0052] Spectral characterization of compound (Ⅰ):

[0053] 1 H NMR (400MHz, DMSO-d6) δ7.61(d,J=8.6Hz,1H),7.01(d,J=2.2Hz,1H),6.82(dd,J=8.6,2.3Hz,1H),6.67(s,2H). 13 C NMR (101MHz, DMSO-d6)δ

[0054] 153.5, 136.7, 132.8 (d, 3 J C-F =29.29Hz), 123.3(d, 1 J C-F =274.7Hz),117.8,115.9,117.2(d, 2 J C-F =5.1Hz), 111.2. 19 F NMR(376MHz,DMSO-d6)δ-63.21(s).

[0055] Examples 5-28: Preparation of 2-amino-5-bromotrifluorotoluene(III) under different conditions

[0056] The preparation process of each embodiment is the same as that of Example 2, except that certain reaction conditions are changed (such as the type of free radical source (a), the molar ratio of compound (II) to free radical source (a), free radical initiator (b) and photocatalyst (c), reaction temperature, etc.). The specific changes in reaction conditions and corresponding reaction effects of each embodiment are shown in Tables 1-6 below.

[0057] Table 1. Effects of different feed ratios on reaction results

[0058]

[0059]

[0060] As can be seen from Table 1, comparing Example 2 and Example 5, it can be found that the reaction yield decreases with the excessive addition of the free radical source, while the appropriate increase of free radical initiator A and photocatalyst A can effectively improve the reaction yield.

[0061] Table 2. Effects of different free radical sources on the reaction effect

[0062]

[0063] As can be seen from Table 2, under certain conditions, sodium trifluoromethyl sulfinate is the most effective choice as a free radical source.

[0064] Table 3. Effects of different free radical initiators on the reaction effect

[0065]

[0066]

[0067] As can be seen from Table 3, under certain conditions, Fe(OTf)2 is the most effective free radical initiator.

[0068] Table 4. Effects of different photocatalysts A on the reaction efficiency

[0069]

[0070] As can be seen from Table 4, under certain operating conditions, the reaction yield is best when terpyridine ruthenium chloride is selected as the catalyst.

[0071] Table 5. Effects of different reaction solvents A on the reaction effect

[0072]

[0073] As can be seen from Table 5, the choice of different solvents also affects the reaction yield. Under certain conditions, acetonitrile is the best solvent for the reaction yield.

[0074] Table 6. Effects of different reaction temperatures and light wavelengths on the reaction results.

[0075]

[0076]

[0077] As can be seen from Table 6, comparing Examples 2, 27 and 28, a suitable wavelength is beneficial to improving the reaction yield; if the reaction temperature is too low, it will affect the reaction yield.

[0078] Examples 29-40: Preparation of 4-bromo-2-(trifluoromethyl)benzonitrile (IV) under different conditions

[0079] The preparation methods of each embodiment are the same as those of Example 3, except that certain reaction conditions are changed (the molar ratio of compound (Ⅲ) to acetic acid (d) and tert-butyl nitrite (e), the reaction temperature, etc.). The specific changes in reaction conditions and the corresponding reaction effects of each embodiment are shown in Tables 7-9 below.

[0080] Table 7. Effects of different feed ratios on reaction efficiency

[0081]

[0082] As can be seen from Table 7, too little acetic acid and tert-butyl nitrite will reduce the reaction yield, while too much acetic acid and tert-butyl nitrite will not affect the reaction yield.

[0083] Table 8. Effects of different reaction solvents B on the reaction effect

[0084]

[0085] As can be seen from Table 8, choosing a suitable reaction solvent (acetonitrile) or a solvent-free reaction can yield better reaction yields.

[0086] Table 9. Effects of different reaction temperatures and reaction times on the reaction outcome.

[0087]

[0088] As can be seen from Table 9, a reaction temperature that is too low will reduce the reaction yield.

[0089] Examples 41-58: Preparation of 4-amino-2-trifluoromethylbenzonitrile (I) under different reaction conditions

[0090] The preparation methods of each embodiment are the same as those of Example 4, except that certain reaction conditions are changed (such as the molar ratio of compound (Ⅳ) to hexaamminenickel chloride (f), organic base (g), ligand (h), type of ligand (g), type of photocatalyst (h), organic solvent C, and different reaction temperatures, visible light wavelengths, etc.). The specific changes in reaction conditions and corresponding reaction effects of each embodiment are shown in Tables 10-14 below.

[0091] Table 10 Effect of different feed ratios on reaction results

[0092]

[0093] Table 11 Effects of different ligands C on the reaction effect

[0094]

[0095]

[0096] As can be seen from Table 11, under certain conditions, the reaction yield is optimal when d-Mebpy is used as the ligand.

[0097] Table 12 Effects of different reaction solvents C on the reaction effect

[0098]

[0099] Table 13 Effects of different reaction times and light wavelengths on reaction results

[0100]

[0101]

Claims

1. A method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile, characterized in that, Includes the following steps: 1) Using the compound shown in formula (II) as a raw material, free radical source A, free radical initiator A and photocatalyst A are dissolved in solvent A and reacted under light conditions to obtain compound (III); 2) Compound (Ⅲ) was first mixed with acetic acid and tert-butyl nitrite and reacted under solvent-free or solvent B conditions. Then tert-butylisocyanate was added to react and compound (Ⅳ) was obtained. 3) Compound (Ⅳ) was dissolved in solvent C with ligand C, organic base and hexaammine nickel chloride, and reacted under light to obtain the target product 4-amino-2-trifluoromethylbenzonitrile shown in formula (Ⅰ); The reaction process is as follows: The substituent X in the formula is chlorine or bromine.

2. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 1, characterized in that, In step 1), the free radical source A is selected from one or a combination of 1-(trifluoromethyl)-1,2-benzyl-3(1H)-one, sodium trifluoromethyl sulfinate, trifluoromethyl iodine, trifluoromethyl lanthanum, and trifluoromethyl hydrazine; the free radical initiator A is selected from one or a combination of ferrous trifluoromethanesulfonate, copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, scandium trifluoromethanesulfonate, and yttrium trifluoromethanesulfonate; the photocatalyst A is selected from one or a combination of ruthenium tripyridine chloride, benzophenone, 9-thioxanone, 9-trimethylbenzene-10-methylacridine perchlorate, and fluorescein; and the solvent A is selected from one or a combination of ethanol, methanol, dichloromethane, N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide.

3. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 1, characterized in that, Solvent B in step 2) is selected from acetonitrile.

4. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 1, characterized in that, In step 3), the ligand C is selected from one or a combination of 4,4'-dimethyl-2,2'-bipyridine, 2-amidinylpyridine hydrochloride and 1,10-phenanthroline; the solvent C is selected from one or a combination of methanol, dichloroethane, N,N-dimethylformamide, acetonitrile and dimethyl sulfoxide; and the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

5. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 2, characterized in that, In step 1), the volume of solvent A is 1-8 mL / g based on the mass of the compound shown in formula (II); the molar ratio of the compound shown in formula (II), free radical source A, free radical initiator A and photocatalyst A is 1:1.2-3.0:0.01-0.3:0.01-0.

15.

6. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 2, characterized in that, The reaction process under light conditions in step 1) is to stir the reaction at 20-90℃ for 6-36 hours under 380-490nm light.

7. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 3, characterized in that, In step 2), the molar ratio of compound (Ⅲ), acetic acid and tert-butyl nitrite is 1:0.5-3.0:0.5-3.

0.

8. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 3, characterized in that, In step 2), compound (Ⅲ) is reacted with acetic acid and tert-butyl nitrite at 0-10°C for 10-60 minutes with stirring. Then, tert-butylisocyanate is added and the temperature is raised to 20-90°C for 2-12 hours to obtain compound (Ⅳ).

9. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 4, characterized in that, In step 3), the molar ratio of compound (Ⅳ), hexaamminenickel chloride, ligand C and organic base is 1:0.2-3.0:0.01-0.1:0.1-3.

0.

10. The method for synthesizing the enzalutamide intermediate 4-amino-2-trifluoromethylbenzonitrile as described in claim 4, characterized in that, In step 3), the light reaction conditions are: under 380–390 nm light and at 70–90 °C, stirring reaction for 5–15 hours.

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