| 77.3% |
With monoperoxyphthalic acid; In ethyl acetate; toluene; at 50 - 55℃; for 9.56667h;Product distribution / selectivity; |
Example 1 Synthesis of 4-cyano-N-(2,3-epoxy-2-methylpropionyl)-3-trifluoromethylaniline N-Methacryloyl-4-cyano-3-trifluoromethylaniline (13.8 g, 54 mmol) and ethyl acetate (40 ml) were charged in a 300 ml four-neck flask, and the mixture was heated at 50 C.-55 C. A solution of mono-perphthalic acid in ethyl acetate (108.05 g, net 19.82 g, 110 mmol) was added dropwise at a temperature in the range of 50 C.-55 C. over 3.9 hr. After stirring at the above-mentioned temperature for 4.5 hr, a solution of mono-perphthalic acid in ethyl acetate (10.36 g, net 1.90 g, 10.4 mmol) was further added dropwise over 10 min. Then the mixture was stirred for 1 hr and left standing overnight at room temperature. The mixture was adjusted to pH=8 (universal test paper) with 20% aqueous KOH solution and partitioned. The organic layer was washed with deionized water (20 ml) in which Na2S2O5 (5.0 g) had been dissolved, dried over MgSO4, decolorized with activated carbon (carborafine 0.5 g), and concentrated under reduced pressure. Toluene (60 ml) was added to the residue and the mixture was heated to 80 C. After cooling to 25 C., the mixture was filtrated to give 4-cyano-N-(2,3-epoxy-2-methylpropionyl)-3-trifluoromethylaniline (11.37 g, yield 77.3%). Purity 98.7%. Analytical data: 1H-NMR (400 MHz, CDCl3): delta=8.40 (s, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.90 (dd, J=8.5, 2.1 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 3.00 (s, 1H), 1.68 (s, 3H). |
| 75% |
With maleic anhydride; urea hydrogen peroxide adduct; In ethyl acetate; at 20℃; for 72h; |
N- (4-CYANO-3-TRIFLUOROMETHYLPHENYL)-2-METHYLPROPENAMIDE (10.2 g, 40 mmol) and maleic anhydride (7.8 g, 80 mmol) were dissolved in ethyl acetate (100 mL). The UHP complex (15.1 g, 160 mmol) was added to this solution, and the mixture was stirred at room temperature for 72 hours. Subsequently, the reaction mixture was neutralized with a solution of NAOH (6.4 g, 160 mmol) in water (25 mL). After the phases separated, the organic phase was washed first with a solution of Na2SO3 (LG) in water, followed by washing with water. The solvent was evaporated, affording the crude product (10.3 g), which was crystallized from isopropanol to give pure N- (4-CYANO-3- TRIFLUOROMETHYLPHENYL) -2,3-EPOXY-2-METHYLPROPANAMIDE ; YIELD: 8.1 g (75%). |
| 73% |
With phthalic anhydride; urea hydrogen peroxide adduct; In ethyl acetate; at 20℃; for 72h; |
N- (4-CYANO-3-TRIFLUOROMETHYLPHENYL)-2-METHYLPROPENAMIDE (10.2 g, 40.1 mmol) and phthalic anhydride (10.2 g, 80.3 mmol) were dissolved in ethyl acetate (100 mL). The UHP complex (15.0 g, 159 mmol) was added to this solution, and the mixture was stirred at room temperature for 72 hours. Subsequently, a solution of NAOH (6.4 g, 160 mmol) in water (25 mL) was added to the reaction mixture. After the phases separated, the organic phase was washed first with a solution of Na2SO3 (1G) in water (25 mL), and then with water. The solvent was evaporated, resulting in the crude product (10.2 g), which was crystallized from isopropanol to give pure N- (4-CYANO-3-TRIFLUOROMETHYLPHENYL) -2,3-EPOXY-2- methylpropanamide (7.9 g; 73%); m. p. 90-92C ; IR (KBr): 3348, 3081,2933, 2228,1707, 1618,1592, 1531,1327, 1148,906, 849,748, 560 cm-1. |
| 70% |
With dihydrogen peroxide; trifluoroacetic anhydride; In dichloromethane; water; at 20℃; for 2h; |
General procedure: To a solution of N-arylmethacrylamides (13a or 13b, 1.7 mmol) in CH2Cl2 (25 mL) was added 0.31 mL of hydrogen peroxide (30%, w/w) followed by 1.25 mL of trifluoroacetic anhydride. After stirring at rt for 2 h, the reaction was quenched by addition of sodium bisulfide and extracted with CH2Cl2. The organic layer was washed with satd NaHCO3 then brine, and dried over MgSO4. After removal of the solvent by evaporation, the crude was purified through a CombiFlash chromatograph system to afford the desired products as racemic epoxides. |
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Example 3; N-methacryloyl-4-cyano-3-trifluoromethylaniline (57.3 g, 0.225 mol), ethyl acetate (340 ml) and phthalic anhydride (116.9g, 0.789 mol) were charged and the mixture was heated to 50 to 55C. To the mixture was added dropwise 35% aqueous hydrogen peroxide solution (43.8 g, 0.451 mol) over 8 hours and the mixture was matured for 20 hours. After adding ethyl acetate (114 ml), the mixture was cooled to 15C and then aqueous solution (145 ml) of sodium sulfite (25.6 g) was added dropwise thereto. After confirming absence of the per-oxy acid, 15% aqueous potassium hydroxide solution was added dropwise to the mixture, for adjusting pH to 7.3. Phases were separated and a layer was washed with a solution prepared from water (230 ml), sodium chloride (40.5 g) and 35% aqueous hydrochloric acid (0.23 g). After concentrating the organic layer under reduced pressure, toluene (400 ml) was added and the layer was further concentrated. The concentrate obtained was combined with THF (344 ml) and cooled down to 5C. Then triethylamine (11.4 g, 0.113 mol) and subsequently methanesulfonyl chloride (6.5 g, 0.056 mol) were added dropwise and the mixture was matured at the same temperature for 30 minutes. Then, a mixed solution of 4-fluorothiophenol (34.7 g, 0.27 mol) with toluene (28 ml), and subsequently triethylamine (11.4 g, 0.113 mol) were added dropwise, and the mixture was matured at the same temperature for 30 minutes. After heating to 50C, the mixture was matured at the same temperature for 5 hours. After cooling to 15C, the mixture was washed with 135 g of 15% aqueous sodium chloride, then with a solution prepared from 143 ml of water, 19.5 g of sodium chloride and 7.8 g of sodium carbonate. At this point, the content of Deoxy-Sulfide Compound was 0.064% (LC area percentage). After phase separation, the organic layer was concentrated, combined with 400 ml of toluene and concentrated further under reduced pressure. After heating to 75C, 69 ml of toluene, 2.9 g of alumina and 3.4 g of activated carbon were added and the mixture was stirred at the same temperature for 30 minutes. After filtering while hot, the filter was washed with 57 ml of toluene and the obtained organic layer was cooled down to 55C. After crystallization by seeding with seed crystals (0.017% by weight), the mixture was matured at 56 to 50C for an hour. Then, the mixture was cooled (13.3C/hour) down to 10C over 3 hours. After cooling, the mixture was matured at 10+/-2C for 2 hours. Upon filtration and washing, 80.0 g of a wet cake of 4'-cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3'-trifluoromethylpropionanilide was obtained. After drying, 76.0 g (yield: 84.6%) of a dry cake was obtained. The content of Deoxy-Sulfide Compound in the dry cake was not detected (n.d.). To the purified and Deoxy-Sulfide Compound non-detected crystals of 4'-cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3'-trifluoromethylpropionanilide was added Deoxy-Sulfide Compound, separately prepared, at ratios (LC area percentage (%)) shown in Table 1. Using the obtained crystals of 4'-cyano-3-(4-fluorophenylthio)-2-hydroxy-2-methyl-3'-trifluoromethylpropionanilide, the experiments were conducted in the same manner as in Example 2 to give crystals of 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-trifluoromethylpropionanili de. The results are shown in Table 1.; Example 4; N-methacryloyl-4-cyano-3-trifluoromethylaniline (1 part by weight), ethyl acetate (5.4 parts by weight) and phthalic anhydride (2 parts by weight) were charged and the mixture was heated to 50 to 55C. To the mixture was added dropwise 35% aqueous hydrogen peroxide solution (0.57 part by weight) over 9.7 hours and the mixture was matured for 22.3 hours. After adding ethyl acetate (1.8 parts by weight), the mixture was cooled to 15C and then aqueous solution (1 part by weight) of sodium sulfite (0.17 part by weight) was added dropwise thereto. After confirming absence of the per-oxy acid, 15% aqueous potassium hydroxide solution was added dropwise to the mixture, for adjusting pH to 7.0. Phases were separated and a layer was washed with a solution prepared from water (4 parts by weight), sodium chloride (0.7 part by weight) and 35% aqueous hydrochloric acid (0.004 part by weight). After concentrating the organic layer under reduced pressure, toluene (6 parts by weight) was added and the layer was further concentrated. The concentrate was combined with THF (5.3 parts by weight) and cooled down to 5C. Then triethylamine (0.08 parts by weight) and subsequently methanesulfonyl chloride (0.045 parts by weight) were added dropwise and the mixture was matured at the same temperature for 30 minutes. Then, a mixed solution of 4-fluorothiophenol (0.6 part by weight) with toluene (0.43 part by weight), and subsequently triethylamine (0.2 part by weight) were added dropwise, and the mixture was matured at the same temperature for 30 minutes. After heating to 50C, the mixture was matured at the same temperat... |
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With 3-chloro-benzenecarboperoxoic acid; sodium sulfite; In dichloromethane; |
EXAMPLE 2 N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-2-oxiranecarboxamide (5A) 460 mg of the amide (7) from the Example 1 was dissolved in 30 ml of dichloromethane. 560 mg of m-chloroperbenzoic acid (purity 70-75%) was added. The reaction mixture was stirred overnight at reflux. The reaction was monitored with HPLC. The reaction mixture was washed successively with 2*20 ml of a sodium sulfite solution, 2*20 ml of saturated aqueous NaHCO3 and 20 ml of brine. The organic layer was dried (Na2SO4), filtrated and evaporated under reduced pressure yielding the epoxide (5A) as yellow solid material. Isolated yield: 400 mg (82%). 1H- and 13C-NMR confirmed the expected structure. HPLC: 96% purity. |
| 2.44 g (76.5%) |
With dihydrogen peroxide; acetic anhydride; |
EXAMPLE 3 N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-2-oxiranecarbox-amide (5A) 10 ml of 30% aqueous hydrogen peroxide is heated to 35-40 C. 20 ml of acetic anhydride is added dropwise under cooling, so that the temperature does not exceed 40-50 C. 0.02 g of wolframic acid is added and the reaction mixture is stirred for 0.5 hours at 50-55 C. 3 grams of the amide (7) is added to the mixture portionwise and the reaction mixture is stirred for 6 hours at 50-55 C. The suspension is then cooled to 20-25 C. and poured, under stirring, into 100 ml of cold (0-5 C.) water. The suspension is stirred for 30 minutes and the solid is filtered off, washed by water and dried at 40-50 C. Yield: 2.44 g (76.5%). |
|
With dihydrogen peroxide; trifluoroacetic acid; In dichloromethane; water; at 0℃; |
Example 110; 2-Methyl-oxirane-2-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)- amide; 2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (1.35 g, 5.0 mmol) in CH2CI2 (15 ml) was treated by TFA (3.0 ml) at 00C. To the reaction mixture was then added H2O2 (30%, 1.0 ml, 10.0 mmol) dropwise. The reaction mixture was stirred overnight and quenched by NaHCO3, then extracted by ethyl acetate. The organic layers were combined and dried over EPO <DP n="146"/>Na2SO4, concentrated and purified by silica gel column using hexanes:ethyl acetate 4:1 as eluent to yield the title compound as a white solid.1H NMR (CDCI3) 58.40 (br. 1 H), 8.10-7.80 (m, 3H), 5.85 (s, 1 H), 5.60 (s, 1 H), 2.00 (s, 3H).MS (m/z): MNa+ (293). |
|
With dihydrogen peroxide; trifluoroacetic anhydride; In dichloromethane; at 20℃; for 24h;Inert atmosphere; |
General procedure: To a stirred solution of the different intermediate 12-17 (3 mmol) in DCM (7 mL) was added30% hydrogen peroxide (3.6 mL, 32.03 mmol). The reaction mixture was put in awater bath at r.t. and trifluoroacetic anhydride (3.7 mL, 26.7 mmol) was addedslowly to the mixture, which was then stirred for 24 h. The reaction mixturewas transferred to a separating funnel using DCM (30 mL). The organic layer waswashed with distilled water (20 mL), sat. aq. Na2S2O3(4x20 mL), sat. aq. NaHCO3 (3x20 mL) and brine (20 mL), dried overNa2SO4 and concentrated at reduced pressure. |
|
With Peroxyformic acid; dihydrogen peroxide; |
As shown in FIG. 4B, the synthesis of iodinated bicalutamide will be performed by techniques known in the art to incorporate a radiolabel. Briefly, 4-amino-2-(trifluoromethyl)-benzonitrile (9) will be condensed with methacroyl chloride to produce compound 10, which will be treated with performic acid to afford epoxide 11. Opening of the epoxide ring in 11 with either 4-bromothiophenol (R1?H, R2?Br) or 3-bromo-4-fluorothiphenol (R1?Br, R2?F) will give the bromo-thiobicalutamide 12 or 13, respectively, which will be converted to the alkyl tin reagent 14 or 15 using hexabutyl ditin in the presence of tetrakis(triphenylphosphine)palladium(0) catalyst. Labeling of compound 14 or 15 with 1-124 or 1-131 will be achieved by treatment of these tin adducts with either [124]NaI or [131]NaI in the presence of peracetic acid as described above to produced labeled versions of compound 7 or 8. In embodiments, an alternative strategy of synthesizing iodine-131-labeled anti-androgens will be adopted. Although the binding affinity of non-steroid anti-androgens will appear be lower than that of DHT analogs, they are relatively stable in vivo and have been successfully used as therapeutic agents in prostate cancer patients. Use of iodine-131-labeled anti-androgens would not only competitively inhibit AR binding to endogenous androgens but also induce DNA damage to cause prostate cancer cell death by directly binding to the AR, providing a two-fold therapeutic effect. This will provide another approach for us to develop radiolabeled compounds for TRT in at least some methods of the disclosure. |
| 26.2 kg |
With phthalic anhydride; dihydrogen peroxide; at 60 - 70℃;Large scale; |
Add 85kg of ethyl acetate and 12kg of triethylamine to a 500L enamel reactor.20 kg of 4-cyano-3-(trifluoromethyl)aniline, and the ice-cold brine was placed in the jacket of the enamel reactor.Cooling the reaction system to below 0 C,Then, a solution of 11.5 kg of methacryloyl chloride and 15 kg of ethyl acetate was added dropwise, and after the addition was completed,Change to normal warm water, slowly warm to room temperature, stir for 2h, TLC tracking the progress of the reaction,After the reaction is completed, add water to the jacket of the enamel reaction kettle to the temperature below 20 C.After thoroughly stirring, the layers were separated, and the organic layer was washed three times with saturated brineFiltration, the solid is discarded, the filtrate is transferred to the enamel reactor, 16 kg of phthalic anhydride is added, carefully heated to 60-70 C with steam, and 13 kg of 30% hydrogen peroxide is added dropwise.Heated to reflux, TLC followed the progress of the reaction, after the reaction was completed, cooled to room temperature, and separated.The organic layer was washed once with a sodium thiosulfate solution and then washed twice with saturated brine.Ethyl acetate was recovered by rotary distillation under reduced pressure, and ethyl acetate was evaporated under reduced pressure.When the amount of ethyl acetate recovered reaches 70 kg, it is stopped, and 40 kg of petroleum ether is added.Stirring and cooling, stirring, filtering, drying,The white solid was 26.2 kg, and the yield was 90.3%. |
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