Reacción #1053651

Ecuación de reacción

PPh3

3-Azido-1,3,4,5-tetrahydro-benzo[b]azepin-2-one

CH3CN

NaN3

→

3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Rendimiento 76.0%

Disolventes

H2O

EtOAc

H2O

DMF

Condiciones de reacción

Tratamiento posterior

1. 1
   Lavadothe organic layer was washed with H2O (2×), brine (2×)
2. 2
   Secadodried over MgSO4
3. 3
   Concentraciónconcentrated (ca. 1.8 g, yield: 100%)
4. 4
   workup.STIRRINGThe mixture was stirred for 30 min
5. 5
   workup.STIRRINGThe mixture was stirred at 50° C. for 3 h
6. 6
   Otrocompletion of the reaction
7. 7
   ConcentraciónThe mixture was concentrated
8. 8
   ExtracciónIt was extracted with Et2O (2×)
9. 9
   Extracciónextracted with CH2Cl2 (2×)
10. 10
    Lavadowashed with brine
11. 11
    Secadodried over MgSO4
12. 12
    Concentraciónconcentrated to dryness

Procedimiento

Part A. 2-Bromo-3,4-dihydro-2H-naphthalen-1-one oxime: α-Tetralone: (31.25 g, 0.214 mol) was stirred in MeOH (300 mL). Br2 (11.02 mL, 1.0 eq) was added dropwise during a 1.5 h-period. LC-MS showed completion of the reaction after the addition. NH2OH.HCl (38.10 g, 2.6 eq) was added to the above stirred solution, followed by the addition of H2O (35 mL). The resulting mixture was stirred at RT O/N. LC-MS showed completion of the reaction. H2O (155 mL) was added. The mixture was stirred at RT for 5 h. The light tan oil at the lower level was precipitated out while cooling in an ice bath for 30 min. The precipitate was filtered, and rinsed with H2O. It was azeotroped with toluene (2×50), vacuum dried, and used directly in the next step. LC-MS (ESI+) 240.2, 242.4 (M+H). Part B. 3-Bromo-1,3,4,5-tetrahydro-benzo[b]azepin-2-one: The product from Ex. 78, Part A (9.0 g, 37.66 mmol) was added portionwise to PPA (48 g) with stirring at 80° C. under N2. The resulting mixture was stirred at 80° C. for 36 h. The hot mixture was poured into ice H2O, extracted with EtOAc (2×), washed with H2O (2×), brine (2×), and dried over MgSO4. The residue was purified by flash column chromatography (silica gel, hexanes: CH2Cl2=1:1 to 0:1, then CH2Cl2: EtOAc=4:1) to produce light tan crystals of the product (3.53 g, 39%). 1H NMR (CDCl3) δ 9.03 (br, s, 1H), 7.29-7.07 (m, 4H), 4.53 (m, 1H), 3.05-2.93 (m, 1H), 2.82-2.60 (m, 3H). 13C NMR (CDCl3) δ 169.6, 136.8, 133.0, 129.7, 128.0, 126.4, 122.5, 47.1, 40.3, 30.3 (10 out of 10 expected peaks obtained). LC-MS (ESI+) 240.2, 242.4 (M+H). Part C. 3-Azido-1,3,4,5-tetrahydro-benzo[b]azepin-2-one: The product from Ex. 78, Part B (1.9 g, 7.95 mmol) and NaN3 (1.0 g, 15.38 mmol, 2.0 eq) were stirred in DMF at RT under N2 O/N. LC-MS showed completion of the reaction (tR=2.81 min, 10-90% CH3CN in H2O in a 4-min run). EtOAc was added; the organic layer was washed with H2O (2×), brine (2×), dried over MgSO4, and concentrated (ca. 1.8 g, yield: 100%). The crude product was used directly in the next step. 1H NMR (CDCl3) δ 8.85 (br, s, 1H), 7.26-7.19 (m, 2H), 7.14 (dd, J=7.7, 1.4 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 3.86 (dd, J=11.3, 8.0 Hz, 1H), 2.96 (m, 1H), 2.70 (m, 1H), 2.49 (m, 1H), 2.27 (m, 1H). 13C NMR (CDCl3) δ 171.4, 136.3, 133.3, 129.6, 128.0, 126.3, 122.4, 59.1, 34.9, 28.3. LC-MS (ESI+) 203.4 (M+H), 405.6 (2M+H). Part D. 3-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one: The product from Ex. 78, Part C (1.8 g, 8.91 mmol) was stirred in THF (20 mL) at RT. PPh3 (2.8 g, 1.2 eq) was added. The mixture was stirred for 30 min. H2O (6 mL) was added. The mixture was stirred at 50° C. for 3 h. LC-MS showed completion of the reaction. The mixture was concentrated, and acidified with 1N HCl. It was extracted with Et2O (2×). The aqueous layer was basified with 50% NaOH, extracted with CH2Cl2 (2×), washed with brine, dried over MgSO4, and concentrated to dryness to produce 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.06 g, 76%). 1H NMR (CDCl3) δ 8.69 (br, s, 1H), 7.25 (m, 2H), 7.12 (dd, J=7.5, 1.2 Hz, 1H), 6.99 (dd, J=7.5, 1.2 Hz, 1H), 3.42 (dd, J=11.3, 7.7 Hz, 1H), 2.90 (m, 1H), 2.56 (m, 1H), 2.45 (m, 1H), 1.92 (m, 1H). 13C NMR (CDCl3) δ 177.4, 136.8, 134.4, 129.6, 127.5, 125.9, 122.0, 51.5, 39.2, 29.0. LC-MS (ESI+) 353.6 (2M+H). Part E. 3-Amino-1-(4-bromophenyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one: The product from Ex. 78, Part D (1.02 g, 5.80 mmol) was stirring in dry CH2Cl2 (15 mL) under N2 at RT. PhCHO (0.58 mL, 1.0 eq) was added, followed by the addition of Et3N (1.63 mL) and MgSO4 (1.65 g). The resulting mixture was stirred at RT for 1 day. The mixture was filtered, rinsed with CH2Cl2, washed with H2O, brine, dried over MgSO4, and concentrated to dryness. The residue (1.3 g, 4.92 mmol) and 4-bromo-1-iodobenzene (1.66 g, 1.2 eq) were stirred in 1,4-dioxane (5 mL) at RT under N2. K2CO3 (1.36 g, 2.0 eq) was added, followed by the addition of CuI (0.19 g, 10% mol) and trans-1,2-cyclohexyldiamine (0.1 ml, 10% mol). The resulting mixture was stirred at 110° C. for 2 h. LC-MS showed 80% of conversion with 20% starting material remaining. The mixture was cooled to RT, and sat'd NH4Cl was added. The mixture was extracted with EtOAc, washed with H2O, brine, and concentrated. The resulting residue was dissolved in Et2O (10 ml). 1N HCl (30 mL) was added. The mixture was stirred at RT for 3 h. LC-MS showed completion of the reaction. The Et2O layer was separated. The aqueous layer was washed with Et2O (2×), basified with 50% aqueous NaOH. It was extracted with CH2Cl2 (2×), washed with brine, and dried over MgSO4. The crude product of 3-amino-1-(4-bromophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was used directly in the next step after vacuum drying. LC-MS (ESI+) 331.4 (M+H), tR=7.72 min (5-98% CH3CN in H2O in a 10-min run). Part F. [1-(4-Bromophenyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]carbamic acid tert-butyl ester: The product from Ex. 78, Part E (0.87 g, 2.64 mmol) was stirred in CH2Cl2 (18 mL). (Boc)2O (0.69 g, 1.2 eq) was added as one single portion, followed by the addition of 1N NaOH (3 mL). The resulting mixture was stirred at RT under N2 for 1 h. LC-MS showed completion of the reaction (tR=9.01 min, 5-98% CH3CN in H2O in a 10-min run) with M+H=333.2. NH4Cl was added, extracted with EtOAc (2×), washed with brine, dried over MgSO4, filtered, and concentrated to give tert-butyl 1-(4-iodophenyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate (1.13 g, 100%). It was used directly in the next step without further purification. Part G. tert-butyl 1-[2′-(methylthio)-1,1′-biphenyl-4-yl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-ylcarbamate: The product from Ex. 78, Part F (0.48 g, 1.11 mmol), o-thiomethylphenylboronic acid (0.28 g, 1.5 eq), Na2CO3 (0.24 g, 2.0 eq), and Pd(PPh3)4 (0.13 g, 10% mol) were degassed twice. Toluene (5 mL) and H2O (0.6 mL) were added. The mixture was stirred at 85° C. under N2O/N. LC-MS showed completion of the reaction. NH4Cl was added, extracted with EtOAc (2×), washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, CH2Cl2:hexanes=0:1 to 1:0, them 10-20% EtOAc in CH2Cl2) produced the product (0.28 g, 53%). 1H NMR (CDCl3) δ 7.44 (m, 2H), 7.40-7.21 (m, 9H), 6.96 (m, 1H), 7.36-7.10 (m, 7H), 6.92 (d, J=8.8 Hz, 2H), 5.56 (m, 1H), 4.45 (m, 1H), 3.12 (m, 1H), 2.75 (m, 2H), 2.37 (s, 3H), 2.03 (m, 1H), 1.43 (s, 9H). 13C NMR (CDCl3) δ 171.3, 154.9, 141.3, 140.7, 140.0, 138.9, 137.1, 135.4, 130.1, 129.9, 129.3, 128.1, 127.2, 126.7, 126.0, 125.3, 124.8, 79.6, 60.4, 51.1, 37.1, 28.4, 15.9. LC-MS (ESI+) 475.4 (M+H), 375.4 (M+H-Boc). Part H. 5-Chloro-thiophene-2-sulfonic acid [1-(2′-methanesulfonyl-biphenyl-4-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]-amide: The product from Ex. 78, Part G (0.252 g, 0.53 mmol) was stirred in CH2Cl2 (5 mL) at RT under N2. MCPBA (0.61 g, 4.0 eq) was added as one single portion. LC-MS showed completion of the reaction after 30 min. Sat'd NaHCO3 was added. The mixture was extracted with EtOAc, washed with H2O, brine, dried over MgSO4, and concentrated. The residue was dissolved in CH2CO2 (10 mL). TFA (5 mL) was added. The mixture was stirred at RT for 20 min. LC-MS showed completion of the reaction (tR=0.65 min, 407.6 (M+H)). The solvents were evaporated. EtOAc was added, washed with sat'd NaHCO3, brine, dried over MgSO4, and concentrated. The above residue (0.13 g, 0.32 mmol) and 5-chloro-2-thiophenesulfonic acid (0.10 g, 0.46 mmol) were stirred in CH2Cl2 (2 mL). Aqueous Na2CO3 (10% w/w, 0.6 mL) was added. The mixture was stirred at RT under N2 for 1 h. NH4Cl was added. It was extracted with EtOAc, washed with brine, and concentrated. The residue was purified by prep LC-MS (tR=6.20 min, 5-98% CH3CN in H2O in a 10-min run) to give the target compound as a pure white floatable solid after lyophilization (25 mg, 14%). 1H NMR (CDCl3) δ 8.04 (dd, J=7.9, 1.3 Hz, 1H), 7.89 (m, 1H), 7.64 (td, J=7.7, 1.5 Hz, 1H), 7.55 (td, J=7.7, 1.5 Hz, 1H), 7.36-7.10 (m, 7H), 6.92 (d, J=8.8 Hz, 2H), 6.86 (m, 1H), 3.96 (m, 1H), 2.96 (m, 1H), 2.90 (m, 2H), 2.61 (s, 3H), 2.35 (m, 1H), 2.14 (m, 1H). LC-MS (ESI+) 587.2 (M+H). Examples 79-81 were prepared from Ex. 35 by alkylation with the indicated alkylhalide in the presence of potassium carbonate in DMF as solvent using the procedure described for the synthesis of the compound of Ex. 33, Part A.

Fuente