2,2-difluoropropane-1,3-diamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-difluoropropane-1,3-diamine (1.1 g, 10 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room temperature overnight, the resulting mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10-25% methanol in dichloromethane) to afford 41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287. extracted with dichloromethane (50 mL×2) The combined organic layers were washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by flash column chromatography (eluting with 10-25% methanol in dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-difluoropropane-1,3-diamine (1.1 g, 10 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room temperature overnight, the resulting mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10-25% methanol in dichloromethane) to afford 41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287. extracted with dichloromethane (50 mL×2) The combined organic layers were washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by flash column chromatography (eluting with 10-25% methanol in dichloromethane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 448, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.04 (dd, J=1.2, 7.6 Hz, 1 H), 7.99 (s, 1 H), 7.84-7.82 (d, J=7.6 Hz, 1 H), 7.72-7.67 (m, 2 H), 7.63-7.58 (m, 1 H), 7.56-7.54 (dd, J=1.2, 8 Hz, 1 H), 5.35 (s, 2 H), 4.54 (s, 2 H), 4.44-4.37 (t, J=14 Hz, 2 H), 3.72-3.64 (m, 4 H), 2.46 (s, 3 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 448, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.04 (dd, J=1.2, 7.6 Hz, 1 H), 7.99 (s, 1 H), 7.84-7.82 (d, J=7.6 Hz, 1 H), 7.72-7.67 (m, 2 H), 7.63-7.58 (m, 1 H), 7.56-7.54 (dd, J=1.2, 8 Hz, 1 H), 5.35 (s, 2 H), 4.54 (s, 2 H), 4.44-4.37 (t, J=14 Hz, 2 H), 3.72-3.64 (m, 4 H), 2.46 (s, 3 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (s, 1 H), 7.82-7.80 (d, 1 H), 7.74-7.69 (m, 2 H), 7.63-7.53 (m, 3 H), 5.40 (d, 1 H), 5.10 (m, 1 H), 4.75 (m, 1 H), 4.60-4.33 (m, 3 H), 3.63 (m, 4 H), 2.45 (s, 3 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 432, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (s, 1 H), 7.82-7.80 (d, 1 H), 7.74-7.69 (m, 2 H), 7.63-7.53 (m, 3 H), 5.40 (d, 1 H), 5.10 (m, 1 H), 4.75 (m, 1 H), 4.60-4.33 (m, 3 H), 3.63 (m, 4 H), 2.45 (s, 3 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1 H), 7.80-7.68 (m, 1 H), 7.60-7.58 (m, 2 H), 7.51-7.49 (m, 1 H), 7.30-7.27 (t, 1 H), 7.24-7.20 (t, 1 H), 5.15 (s, 2 H), 4.37-4.31 (m, 4 H), 3.51-3.49 (m, 4 H), 3.14 (s, 2 H), 2.45 (s, 3 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2,2-difluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI+) [(M+H)+] 416, 1H NMR (400 MHz, CD3OD) δ ppm 7.96 (s, 1 H), 7.80-7.68 (m, 1 H), 7.60-7.58 (m, 2 H), 7.51-7.49 (m, 1 H), 7.30-7.27 (t, 1 H), 7.24-7.20 (t, 1 H), 5.15 (s, 2 H), 4.37-4.31 (m, 4 H), 3.51-3.49 (m, 4 H), 3.14 (s, 2 H), 2.45 (s, 3 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.21 (s, 1 H), 7.86-7.81 (m, 2 H), 7.77-7.74 (m, 2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.21 (s, 1 H), 7.86-7.81 (m, 2 H), 7.77-7.74 (m, 2 H), 7.58 (m, 2 H), 6.32 (s, 1 H), 5.45 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.48 (m, 1 H), 4.20 (m, 2 H), 3.68 (t, 2 H), 3.50 (m, 2 H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 7.93 (s, 1 H), 7.81-7.79 (m, 1 H), 7.76-7.74 (d, 2 H), 7.62-7.52 (m, 3 H), 6.25 (s, 1 H), 5.45-5.41 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.45 (m, 1 H), 4.23-4.16 (m, 2 H), 3.72-3.64 (t, 2 H), 3.50 (m, 2 H), 2.47 (s, 3 H).