P7C3-A20 synthesis

10synthesis methods

Product Name:P7C3-A20
CAS Number:1235481-90-9
Molecular formula:C22H19Br2FN2O
Molecular Weight:506.21

Benzenesulfonamide, N-[3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl]-N-(3-methoxyphenyl)-4-nitro-

1260172-05-1

1235481-90-9

To a vial containing N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide (21.0 mg, 0.030 mmol) were added lithium hydroxide (3.2 mg, 0.134 mmol), N,N-dimethylformamide (0.5 mL, 0.06 M), and mercaptoacetic acid ( 4.2 μL, 0.060 mmol). The reaction mixture was stirred for 1 h at room temperature, then diluted with ethyl acetate and washed sequentially with water, saturated sodium bicarbonate solution, water (3 times) and brine. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: 30% ethyl acetate/hexane containing 0.2% triethylamine) to give 13.6 mg of the target compound in 88% yield. Another synthetic method: DAST (diethylamino sulfur trifluoride, 0.12 mL, 0.916 mmol) was added dropwise to a solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (0.102 g, 0.203 mmol) in anhydrous dichloromethane (6.0 mL), and the reaction was carried out at -78 °C. The reaction mixture was stirred at -78 °C for 1 h, then slowly warmed to 0 °C and kept for 5 h. The reaction was carried out at -78 °C. The reaction was quenched by addition of phosphate buffer (pH=8) and extracted with dichloromethane. The aqueous phase was extracted twice with dichloromethane (10 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel fast column chromatography (eluent: 20% ethyl acetate/hexane containing 0.2% triethylamine) and the fraction containing the desired fluorinated product was further purified with 40% ethyl acetate/hexane containing 0.1% triethylamine to give 5.7 mg of the target compound. Analytical data for 3,6-dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine: 1H NMR (CDCl3, 500 MHz) δ 8.16 (2H, J = 2.0 Hz), 7.56 (dd, 2H, J = 1.9, 8.7 Hz), 7.31 (d, 2H, J = 8.6 Hz), 7.11 (t, 1H, J = 8.1 Hz), 6.36 (dd, 1H, J = 2.2, 8.1 Hz), 6.23 (dd , 1H, J = 2.0, 8.0 Hz), 6.15 (t, 1H, J = 2.3 Hz), 5.11 (ddd, 1H, J = 4.6, 5.8, 10.4, 47.7 Hz), 4.60 (m, 2H), 4.39 (dm, 2H), 3.95 (t, 1H, J = 6.3 Hz), 3.75 (s, 3H). MS (ESI), m/z: 504.9 (M + 1)+. ([M + 1]+ for C22H19Br2FN2O calculated: 505.0).

Ethanamine, N-[(3,5-dichlorophenyl)methylene]-2,2-diethoxy-

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Yield: 88%

Reaction Conditions:

with mercaptoacetic acid;lithium hydroxide in N,N-dimethyl-formamide at 20; for 1 h;

Steps:

6a.5 N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline

To a vial containing N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-4-nitrobenzenesulfonamide (21.0 mg, 0.030 mmol; see representative procedure 4) was added lithium hydroxide (3.2 mg, 0.134 mmol), dimethylformamide (0.5 ml, 0.06 M) and mercaptoacetic acid (4.2 ul 0.060 mmol).
After stirring at rt for 1 h the reaction mixture was diluted with EtOAc and washed sequentially with water, saturated sodium bicarbonate solution, water (3*) and brine.
The organic layer was dried over Na₂SO₄, filtered and condensed.
The crude reaction mixture was purified in 30% EtOAc/hexanes (+0.2% TEA), with 13.6 mg isolated. Yield=88% Additional Representative Procedure (1370) DAST [(Et₂NSF₃) 0.12 ml, 0.916 mmol] was added dropwise to a solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (0.102 g, 0.203 mmol) in 6.0 ml of anhydrous DCM at -78° C. The reaction was stirred at -78° C. for one hour before being slowly warmed to 0° C. over 5 hours. The reaction was quenched by addition of phosphate buffer (pH=8) and extracted with DCM. The aqueous phase was extracted twice with 10 ml DCM. The combined organics were dried over Na₂SO₄, filtered and concentrated. The crude reaction material was purified by flash chromatography on Si02 (20% EtOAc/hexanes/0.2% TEA). Fractions containing the desired fluorinated product were further purified with 40% EtOAc/hexanes (+0.1% TEA). Isolated 5.7 mg desired product. Analytical Data for the Title Compound of Example 6a (1371) ¹H NMR (CDCl₃, 500 MHz) ζ 8.16 (2H, J=2.0 Hz), 7.56 (dd, 2H, J=1.9, 8.7 Hz), 7.31 (d, 2H, J=8.6 Hz), 7.11 (t, 1H, J=8.1 Hz), 6.36 (dd, 1H, J=2.2, 8.1 Hz), 6.23 (dd, 1H, J=2.0, 8.0 Hz), 6.15 (t, 1H, J=2.3 Hz), 5.11 (dddd, 1H, J=4.6, 5.8, 10.4, 47.7 Hz), 4.60 (m, 2H), 4.39 (dm, 2H), 3.95 (t, 1H, J=6.3 Hz), 3.75 (s, 3H) (1372) MS (ESI), m/z: 504.9 (M+1)⁺. ([M+1]+ for C₂₂H₁₉Br₂FN₂O calculated 505.0)

References:

Board of Regents of The University of Texas System;McKnight, Steven L.;Pieper, Andrew A.;Ready, Joseph M.;De Brabander, Jef K. US9095571, 2015, B2 Location in patent:Page/Page column 97; 98