1-(1,1-Dimethylethyl) 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate

1-tert-butyl 4-ethyl 2, 3, 6, 7-tetrahydro-1H-azepine-1, 4-dicarboxylate A solution of example 42C (0.77 g, 2.1 mmol) in 30 mL of benzene was treated with DBU (0.9 ml ) at 60° C. for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by flash column chromatography (30percent EtOAc in hexane) to give the title product (540 mg, 95percent yield). MS (DCI/NHA solution of 1-(tert-butyl) 4-ethyl 5-((methylsulfonyl)oxy)azepane-1, 4-dicarboxylate (5.0 g, 13.7 mmol)and DBU (10 mL) in toluene (50 mL) was heated to 60° C.and stirred overnight. Upon completion of the reaction, thereaction mixture was quenched with water (70 mL) andextracted with EtOAc (100 mLx3). The combined organicphase was dried over Na2S04 and concentrated underreduced pressure. The residue was purified by silica-gelcolunm chromatography to afford 3.31 g of 1-(tert-butyl)4-ethyl 2, 3, 6, 7 -tetrahydro-1H-azepine-1 , 4-dicarboxylate asa yellow oil. LC-MS (ESI+ ): m/z 292 [M+Nat.To a solution of 1-tert-butyl 4-ethyl 5-oxoazepane-1, 4-dicarboxylate (13) (94.5 g, 0.331 mol) in MeOH (1.3 L), NaBH4 (3.74 g, 0, 099 mol) was added portionwise at 0 °C and the mixture was stirred at the same temperature for additional 1 h. The resulting solution was concentrated under vacuum. The residue was diluted with H2O (700 mL) and extracted with EtOAc (3300 mL). The combined organic extracts were washed with H2O (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 80.1 g of crude product, that was used in the next step without further purification. To a solution of the crude 1-tert-butyl 4-ethyl 5-hydroxyazepane-1, 4-dicarboxylate (80.1 g) in CH2Cl2 (1.1 L), NEt3 (117 mL, 0.834 mol) was added at 0 °C. Methanesulfonyl chloride (36.5 mL, 0.474 mol) was added dropwise while the temperature was maintained below 5 °C and the solution was stirred at rt for 4 h. The resulting mixture was treated with 10percent aq NaHCO3 (500 mL), organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3300 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 95.3 g of crude product, which was used in the next step without further purification. S4 To a solution of obtained crude 1-tert-butyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1, 4-dicarboxylate (95.3 g) in THF (2.1 L), DBU (54.6 mL, 0.365 mol) was added in one portion and the reaction mixture was stirred overnight. The resulting solution was diluted with EtOAc (500 mL), washed with brine (4500 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the title product. Yield: 56.8 g (64 percent); colorless oil. The compound existed as ca. 1:1 mixture of rotamers.Example 18C EXAMPLE 42D; 1-tert-butyl 4-ethyl 2, 3, 6, 7-tetrahydro-1H-azepine-1, 4-dicarboxylate A solution of example 42C (0.77 g, 2.1 mmol) in 30 mL of benzene was treated with DBU (0.9 ml ) at 60° C. for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by flash column chromatography (30percent EtOAc in hexane) to give the title product (540 mg, 95percent yield). MS (DCI/NHA solution of 1-(tert-butyl) 4-ethyl 5-((methylsulfonyl)oxy)azepane-1, 4-dicarboxylate (5.0 g, 13.7 mmol)and DBU (10 mL) in toluene (50 mL) was heated to 60° C.and stirred overnight. Upon completion of the reaction, thereaction mixture was quenched with water (70 mL) andextracted with EtOAc (100 mLx3). The combined organicphase was dried over Na2S04 and concentrated underreduced pressure. The residue was purified by silica-gelcolunm chromatography to afford 3.31 g of 1-(tert-butyl)4-ethyl 2, 3, 6, 7 -tetrahydro-1H-azepine-1 , 4-dicarboxylate asa yellow oil. LC-MS (ESI+ ): m/z 292 [M+Nat.To a solution of 1-tert-butyl 4-ethyl 5-oxoazepane-1, 4-dicarboxylate (13) (94.5 g, 0.331 mol) in MeOH (1.3 L), NaBH4 (3.74 g, 0, 099 mol) was added portionwise at 0 °C and the mixture was stirred at the same temperature for additional 1 h. The resulting solution was concentrated under vacuum. The residue was diluted with H2O (700 mL) and extracted with EtOAc (3300 mL). The combined organic extracts were washed with H2O (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 80.1 g of crude product, that was used in the next step without further purification. To a solution of the crude 1-tert-butyl 4-ethyl 5-hydroxyazepane-1, 4-dicarboxylate (80.1 g) in CH2Cl2 (1.1 L), NEt3 (117 mL, 0.834 mol) was added at 0 °C. Methanesulfonyl chloride (36.5 mL, 0.474 mol) was added dropwise while the temperature was maintained below 5 °C and the solution was stirred at rt for 4 h. The resulting mixture was treated with 10percent aq NaHCO3 (500 mL), organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3300 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 95.3 g of crude product, which was used in the next step without further purification. S4 To a solution of obtained crude 1-tert-butyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1, 4-dicarboxylate (95.3 g) in THF (2.1 L), DBU (54.6 mL, 0.365 mol) was added in one portion and the reaction mixture was stirred overnight. The resulting solution was diluted with EtOAc (500 mL), washed with brine (4500 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the title product. Yield: 56.8 g (64 percent); colorless oil. The compound existed as ca. 1:1 mixture of rotamers.Example 18C To a suspension of NaH (21.2 g, 0.318 mol, 60% dispersion in mineral oil) in DMSO (650 mL), S, S, S-trimethylsulfoxonium iodide (72.9 g, 0.331 mol) was added in small portions and stirred at rt for 1 h until gas evolution ceased. A solution of Example 18C EXAMPLE 42E; 1-tert-butyl 4-ethyl azepane-1, 4-dicarboxylate A solution of example 42D (0.54 g, 2.0 mmol) in 20 ml of MeOH was treated with 10% Pd/C (50 mg) under hydrogen overnight. Solid material was filtered off and the filtrate was concentrated. The residue was purified by flash column chromatography (20% EtOAc in hexane) to give the title product (310 mg, 55% yield). MS (DCI/NH3) m/z 272 (M+H)+.EXAMPLE 42D; A solution of 1-(tert-butyl) 4-ethyl 5-((methylsulfonyl)oxy)azepane-1, 4-dicarboxylate (5.0 g, 13.7 mmol)and DBU (10 mL) in toluene (50 mL) was heated to 60 C.and stirred overnight. Upon completion of the reaction, thereaction mixture was quenched with water (70 mL) andextracted with EtOAc (100 mLx3). The combined organicphase was dried over Na2S04 and concentrated underreduced pressure. The residue was purified by silica-gelcolunm chromatography to afford 3.31 g of 1-(tert-butyl)4-ethyl 2, 3, 6, 7 -tetrahydro-1H-azepine-1 , 4-dicarboxylate asa yellow oil. LC-MS (ESI+ ): m/z 292 [M+Nat.To a solution of 1-tert-butyl 4-ethyl 5-oxoazepane-1, 4-dicarboxylate (13) (94.5 g, 0.331 mol) in MeOH (1.3 L), NaBH4 (3.74 g, 0, 099 mol) was added portionwise at 0 C and the mixture was stirred at the same temperature for additional 1 h. The resulting solution was concentrated under vacuum. The residue was diluted with H2O (700 mL) and extracted with EtOAc (3300 mL). The combined organic extracts were washed with H2O (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 80.1 g of crude product, that was used in the next step without further purification. To a solution of the crude 1-tert-butyl 4-ethyl 5-hydroxyazepane-1, 4-dicarboxylate (80.1 g) in CH2Cl2 (1.1 L), NEt3 (117 mL, 0.834 mol) was added at 0 C. Methanesulfonyl chloride (36.5 mL, 0.474 mol) was added dropwise while the temperature was maintained below 5 C and the solution was stirred at rt for 4 h. The resulting mixture was treated with 10% aq NaHCO3 (500 mL), organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3300 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 95.3 g of crude product, which was used in the next step without further purification. S4 To a solution of obtained crude 1-tert-butyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1, 4-dicarboxylate (95.3 g) in THF (2.1 L), DBU (54.6 mL, 0.365 mol) was added in one portion and the reaction mixture was stirred overnight. The resulting solution was diluted with EtOAc (500 mL), washed with brine (4500 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the title product. Yield: 56.8 g (64 %); colorless oil. The compound existed as ca. 1:1 mixture of rotamers.

Molecular Weight:269.34
XLogP3:2.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:269.16270821
Monoisotopic Mass:269.16270821
Topological Polar Surface Area:55.8
Heavy Atom Count:19
Complexity:368
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes