* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60℃; for 1.25 h; Stage #2: With triethylamine In dichloromethane at -60 - 20℃;
A methylene chloride solution (6 ml) of dimethyl sulfoxide (2.0 ml, 28.2 mmol) was added dropwise to a methylene chloride solution (30 ml) of oxalyl chloride (1.7 ml, 19.5 mmol) at -60°C over a period of 10 minutes and stirred at -60°C for another 10 minutes. Then, a methylene chloride solution (140 ml) of tert-butyl 4-hydroxycyclohexylcarbamate (2.56 g, 11.9 mmol) was added dropwise thereto over a period of 35 minutes, and the resulting mixture was stirred at -60°C for 40 minutes. After triethylamine (8.4 ml, 60.3 mmol) was added thereto at -60°C, the resulting mixture was warmed up to room temperature spontaneously. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain tert-butyl 4-oxocyclohexylcarbamate (2.23 g, 87percent).1H-NMR (DMSO-d6): 1.06-1.20 (4H, m), 1.35 (9H, s), 1.69-1.76 (4H, m), 3.12-3.31 (2H, m), 4.48 (1H, s), 6.64 (1H, d, J=7.5Hz).
85.7%
With pyridinium chlorochromate In chloroform at 0 - 20℃; for 3 h;
Step-2, Synthesis of tert-butyl (4-oxocyclohexyl)carbamate: A solution of tert-butyl (4-oxocyclohexyl) carbamate (5g, 0.0232 mol) in chloroform (50ml_) was cooled to 0 °C and pyridiniumchlorochromate (12.49g, 0.058mol) was added portion wise. After addition completed the resulting mixture was allowed to RT and stirred for 3 h. The reaction mixture was diluted with chloroform (100ml_) and washed with brine, water, dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5percent MeOH-DCM) to afford tert-butyl (4-oxocyclohexyl)carbamate of 4.2g, 85.7percent yield.1HNMR (CDCI3, 300MHz): δ 4.5 (m, 1 H), 3.91 (m, 1 H), 2.4(m, 4H), 2.2 (m, 2H), 1.6 (m, 2H), 1 .45 (m, 9H).
82.1%
With Dess-Martin periodane In dichloromethane at 20℃; Cooling with ice
Dess-Martin oxidizer (29.0 g, 68.3 mmol) was added dropwise to a solution of N-4-Boc-aminocyclohexanol (9.8 g, 45.52 mmol) in dichloromethane (200 mL) with ice-bath stirring. Warm to room temperature and stir the reaction mixture overnight. The mixture was carefully quenched with a saturated aqueous solution of sodium thiosulfate in an ice bath and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on a silica gel column yielded 4-oxo. Tert-butyl cyclohexylcarbamate (7.96 g, yield 82.1percent).
7 g
With Dess-Martin periodane In dichloromethane at 20℃;
To a solution of tert- v y\ 4-hydroxy- cyclohexylcarbamate (10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at r.t. overnight and treated with aq. Na2S203 solution and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SC>4, and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / EtOAc (V:V, 10: 1) to afford desired product as a white solid (7.0 g, 70percent crude yield).
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 3 h; Inert atmosphere
The oxalyl chloride (11.8 mL, 0.14 mol) was dissolved in methylene chloride (100 mL) and then cooled to -78 ° C. Under nitrogen, To a solution of dimethylsulfoxide diluted in methylene chloride (100 mL) Im-1c-a (20 g, 0.093 mol) diluted in dichloromethane (19.8 mL, 0.28 mol) and methylene chloride (300 mL) were added dropwise. Methylene chloride (300 mL) was further added to the reaction mixture, and the mixture was stirred for 1 hour. Triethylamine (64.7 mL, 0.46 mol) was added dropwise and stirred for 1 hour. The reaction mixture was stirred for 2 hours while slowly raising the temperature to room temperature, and distilled water (100 mL) was added to terminate the reaction. The reaction mixture was extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and n-hexane was added to the residue to obtain a solid. The resulting solid was filtered and washed with n-hexane to give the title compound im-1c-b as a pale brown solid (20.5 g).
Reference：
[1] Heterocycles, 2002, vol. 58, p. 471 - 504
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 12, p. 3103 - 3107
[3] Patent: KR101798840, 2017, B1, . Location in patent: Paragraph 0270-0271; 0276-0277
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 12, p. 3103 - 3107
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 12, p. 3236 - 3240[3] Angew. Chem., 2014, vol. 126, # 12, p. 3300 - 3304,5
[4] Patent: KR101798840, 2017, B1,
11
[ 24424-99-5 ]
[ 179321-49-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 12, p. 3236 - 3240[2] Angew. Chem., 2014, vol. 126, # 12, p. 3300 - 3304,5
12
[ 24424-99-5 ]
[ 27489-62-9 ]
[ 179321-49-4 ]
Reference：
[1] Patent: EP1500643, 2005, A1,
13
[ 50910-54-8 ]
[ 179321-49-4 ]
Reference：
[1] Heterocycles, 2002, vol. 58, p. 471 - 504
14
[ 34619-03-9 ]
[ 179321-49-4 ]
Reference：
[1] Patent: EP1403255, 2004, A1,
15
[ 27489-62-9 ]
[ 179321-49-4 ]
Reference：
[1] Patent: EP1403255, 2004, A1,
16
[ 179321-49-4 ]
[ 675112-67-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
With diethylamino-sulfur trifluoride In dichloromethane for 15 h;
To a solution of 1, 1-dimethylethyl (4-oxocyclohexyl) carbamate (1 g, 4.69 MMOL, 1 equiv) in CH2CI2 (15 ml) was added DAST (1.05 MI, 7.98 mmol, 1.7 equiv) and the resulting mixture was stirred for 15 h. A saturated aqueous NAHC03 solution was added and the resulting biphasic mixture was stirred vigorously for 1 h. The two layers were separated and the aqueous phase extracted with CH2CI2. The combined organic phase were dried over MGS04 and concentrated in vacuo to give 1, 1-dimethylethyl (4, 4-difluorocyclohexyl) carbamate (D277) (1.03 g, 93percent) as a beige solid which was used in the next step without further purification.
56%
Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at -5 - 20℃; Inert atmosphere Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; Stage #3: at 0 - 20℃;
To a solution of tert-butyl 4-oxocyclo- hexylcarbamate (2.13 g, 10 mmol) in dry DCM (25 mL) was added DAST (2.58 g, 16 mmol) dropwise at -5 °C under nitrogen protection. After addition, the reaction mixture was stirred at r.t overnight. The reaction mixture was poured into ice water slowly and extracted by DCM ( 3 x 100 mL). The combined organic layers were washed with 2 N aq. NaHC03 and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography using petroleum ether / EtOAc (V: V, 5: 1) as eluent to afford a mixture of the title compound (-70percent) and the byproduct tert-butyl 4-fluorocyclohex-3-enylcarbamate (-30percent) as a light-yellow solid.
54.7%
Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at 20℃; Cooling with ice Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 5 - 20℃; Cooling with ice Stage #3: With sodium tetrahydroborate In methanol at 20℃; Cooling with ice
Step B: tert-butyl (4,4-difluorocyclohexyl)carbamateDiethylaminosulfur trifluoride (8.54 g, 52.981 mmol) was added dropwise to the methylene chloride containing tert-butyl 4-oxocyclohexylcarbamate (7.96 g, 37.323 mmol) while stirring in an ice salt bath. In a (200 mL) solution, slowly warm to room temperature and stir the reaction mixture overnight. The mixture was carefully quenched with saturated aqueous ammonium chloride under an ice bath and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.Separation of tert-butyl (4,4-difluorocyclohexyl)carbamate by column chromatography (about 70percent)With tert-butyl 4-fluorocyclohexyl-3-enylcarboxylate (about 30percent).Under ice-cooling, m-CPBA (6.9 g, 40.0 mmol) was slowly added dropwise to the methylene chloride solution of the above mixture while keeping the system temperature below 5°C. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred overnight. Quench with saturated aqueous sodium thiosulfate under an ice bath and stir at room temperature for half an hour, extract three times with methylene chloride, wash the combined organic phases with brine, dry over sodium sulfate, filter, and concentrate in vacuo, directly without purification. Used for the next step.The above concentrated residue was dissolved in methanol, and sodium borohydride (630 mg, 16.662 mmol) was added in small portions in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was concentrated in vacuo, methanol, and quenched with water under an ice bath. The mixture was quenched with stirring at room temperature for half an hour. Ethyl acetate was extracted three times. The combined organic phases were washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo gave tert-butyl (4,4-difluorocyclohexyl)carbamate (4.8 g, 54.7percent yield).
43%
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 16 h;
To a solution of 1, 1-dimethylethyl (4-oxocyclohexyl) carbamate (3.56 g, 16.7 MMOL, 1 equiv) in CH2CI2 (50 mi) was added DAST (4.6 MI, 35.1 mmol, 2.1 equiv) and the resulting mixture was stirred at room temperature for 16 h. A saturated aqueous NAHC03 solution (20 mi) was added and the biphasic mixture was vigorously stirred at room temperature for 1 h. The layers were separated and the aqueous phase extracted with CH2CI2. The combined organic layers were dried over MGS04 and concentrated in vacuo. Trituration of the residue with hexane gave 1, 1-dimethylethyl (4,4- difluorocyclohexyl) carbamate (D52) (1.7 g, 43percent) as a white solid which was used in the next step without further purification.
With diethylamino-sulfur trifluoride In dichloromethane at -5 - 20℃; Inert atmosphere
Step C: Tert-butyl 4,4-difluorocyclohexylcarbamate. To a solution of /3 and brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using petroleum ether / EtOAc (V:V, 5: 1) as eluent to afford a mixture of the title compound (-70percent) and the byproduct tert-butyl 4-fluorocyclohex-3-enylcarbamate (-30percent) as a light-yellow solid.
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; Cooling with ice
Step B: tert-butyl (4,4-difluorocyclohexyl)carbamateDiethylaminosulfur trifluoride (8.54 g, 52.981 mmol) was added dropwise to the methylene chloride containing tert-butyl 4-oxocyclohexylcarbamate (7.96 g, 37.323 mmol) while stirring in an ice salt bath. In a (200 mL) solution, slowly warm to room temperature and stir the reaction mixture overnight. The mixture was carefully quenched with saturated aqueous ammonium chloride under an ice bath and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.Separation of tert-butyl (4,4-difluorocyclohexyl)carbamate by column chromatography (about 70percent)With tert-butyl 4-fluorocyclohexyl-3-enylcarboxylate (about 30percent).Under ice-cooling, m-CPBA (6.9 g, 40.0 mmol) was slowly added dropwise to the methylene chloride solution of the above mixture while keeping the system temperature below 5°C. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred overnight. Quench with saturated aqueous sodium thiosulfate under an ice bath and stir at room temperature for half an hour, extract three times with methylene chloride, wash the combined organic phases with brine, dry over sodium sulfate, filter, and concentrate in vacuo, directly without purification. Used for the next step.The above concentrated residue was dissolved in methanol, and sodium borohydride (630 mg, 16.662 mmol) was added in small portions in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was concentrated in vacuo, methanol, and quenched with water under an ice bath. The mixture was quenched with stirring at room temperature for half an hour. Ethyl acetate was extracted three times. The combined organic phases were washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo gave tert-butyl (4,4-difluorocyclohexyl)carbamate (4.8 g, 54.7percent yield).
Reference：
[1] Patent: TW2017/36341, 2017, A, . Location in patent: Paragraph 0489; 0492; 0493
The oxalyl chloride (11.8 mL, 0.14 mol) was dissolved in methylene chloride (100 mL) and then cooled to -78 C. Under nitrogen, To a solution of dimethylsulfoxide diluted in methylene chloride (100 mL) Im-1c-a (20 g, 0.093 mol) diluted in dichloromethane (19.8 mL, 0.28 mol) and methylene chloride (300 mL) were added dropwise. Methylene chloride (300 mL) was further added to the reaction mixture, and the mixture was stirred for 1 hour. Triethylamine (64.7 mL, 0.46 mol) was added dropwise and stirred for 1 hour. The reaction mixture was stirred for 2 hours while slowly raising the temperature to room temperature, and distilled water (100 mL) was added to terminate the reaction. The reaction mixture was extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and n-hexane was added to the residue to obtain a solid. The resulting solid was filtered and washed with n-hexane to give the title compound im-1c-b as a pale brown solid (20.5 g).
Stage #1: diphenyl-3-tetrahydropyranyloxypropylphosphine oxide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h;
Stage #2: N-(tert-butoxycarbonyl)-4-aminocyclohexanone In tetrahydrofuran at -78 - 20℃; for 0.666667h;
Stage #3: With sodium hydride In tetrahydrofuran for 1.5h; Heating;
Step-1,Synthesis of tert-butyl (4-methylenecyclohexyl)carbamatePotassium tert-butoxide (5.2g, 0.046mol) was added to a solution of triphenyl phosphenomethylene bromide (16.8g, 0.046mol) in dry THF (100ml_) under nitorgen atmosphere at 0 C. The resulting mixture was stirred at for 30min. Solution of Tert-butyl (4-oxocyclohexyl)carbamate (5g, 0.0234 mmol) in dry THF (50ml_) added over a period of 20min. at 0 C under nitrogen atmosphere. The reaction mixture was stirred at 0 C for another 1 h. The reaction was monitored by TLC (30% EtOAc-Hexane). After completion of reaction, the reaction was quenched with ice cold water, extracted with ethyl acetate (3x15ml_). The combined organic layers were dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (30% EtOAc-Hexane) to afford tert-butyl methylenecyclohexyl)carbamate 5 g, 98% yield.1HNMR (CDCI3, 300MHz): δ 4.64 (s, 2H), 4.42 (m, 1 H), 3.59 (m, 1 H), 2.32-2.26 (m, 2H), 2.16-1 .97 (m, 4H), 1.45 (s, 9H), 1.30-1 .17 (m, 2H).
92.3%
Triphenylmethylphosphonium bromide (53.7g, 0.15mol) was dissolved in 500mL of tetrahydrofuran, potassium tert-butoxide (16.8g, 0.15mol) was added at -20C, reacted for 0.5h after the temperature was raised to 0C. Then, tert-butyl 4-oxo-cyclohexylcarbamate (Compound 7-1) (21.3g, 0.1mol) was dissolved in 100mL of THF and added dropwise into the flask under nitrogen. After 3 hours of reaction at room temperature, a small amount of water was added to dissolve the solids. The mixture was rotary evaporated to remove THF, extracted with anhydrous diethyl ether, and dried, concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 7-2 as a colorless liquid (19.5g, 92.3% yield).
92.3%
With potassium tert-butylate; In tetrahydrofuran; hexane; water;
1) tert-Butyl 4-methylenecyclohexylcarbamate (Compound 7-2) Triphenylmethylphosphonium bromide (53.7 g, 0.15 mol) was dissolved in 500 mL of tetrahydrofuran, potassium tert-butoxide (16.8 g, 0.15 mol) was added at -20 C., reacted for 0.5 h after the temperature was raised to 0 C. Then, tert-butyl 4-oxo-cyclohexylcarbamate (Compound 7-1) (21.3 g, 0.1 mol) was dissolved in 100 mL of THF and added dropwise into the flask under nitrogen. After 3 hours of reaction at room temperature, a small amount of water was added to dissolve the solids. The mixture was rotary evaporated to remove THF, extracted with anhydrous diethyl ether, and dried, concentrated, the concentrate was dissolved in n-hexane, and filtered by silica gel, then concentrated to give Compound 7-2 as a colorless liquid (19.5 g, 92.3% yield).
71%
Example 3 - Synthesis of AO-CHATo a slurry of PH3PCH3Br (4.2 lg) and THF (10ml) at 0C was added NaHMDS (11.8ml, 1M in THF) at <5C. The resulting yellow solution was stirred for lh before15 addition of a solution of N-Boc-4-aminocyclohexanone (2g) in THF (10ml) at 0-5C.After stirring for 4h at room temperature, TLC showed no starting material remained. Water (20ml) and brine (20ml) were added followed by EtOAc (40ml). The organic layer was separated, dried (MgS04), filtered and adsorbed onto silica (6g). Purification by column chromatography on silica (80g), eluting with 4:1 0 heptane.EtOAc gave 19 as a white solid (>95% by 1H NMR, 71 % yield).
71%
To a slurry of PH3PCH3Br (4.21 g) and THF (10 ml) at 0 C. was added NaHMDS (11.8 ml, 1M in THF) at <5 C. The resulting yellow solution was stirred for 1 h before addition of a solution of N-Boc-4-aminocyclohexanone (2 g) in THF (10 ml) at 0-5 C. After stirring for 4 h at room temperature, TLC showed no starting material remained. Water (20 ml) and brine (20 ml) were added followed by EtOAc (40 ml). The organic layer was separated, dried (MgSO4), filtered and adsorbed onto silica (6 g). Purification by column chromatography on silica (80 g), eluting with 4:1 heptane:EtOAc gave 19 as a white solid (>95% by 1H NMR, 71% yield).
Reference compound 9 is prepared by olefination of corresponding cyclohexanone. A solution of methyltriphenylphosphonium bromide (156 mg, 0.44 mmol) and KHMDS (880 μL of 0.5M solution in toluene, 0.44 mmol) in THF (10 mL) at 23 0C is allowed to stir for 1 hour. A THF solution of 4-N-Boc-amino- 1 -cyclohexanone (75 mg, 0.35 mmol) in 5 mL of THF is added and the reaction is stirred at 23 0C until complete as indicated by LC/MS. The reaction is quenched with water; THF is evaporated and redissolved in EtOAc and the layers are separated. The aqueous phase is washed with 2 x 10 mL EtOAc and the combined organic layers are washed with water, saturated NaCl, dried over MgSO4 and filtered. The solvent is removed in vacuo and the crude purified by silica gel chromatography (Hexanes/EtOAc gradient) to afford the desired product Reference compound 9 as a clear oil. LC/MS found 212.3 [M + H].
4 g
To a solution of methyltriphenylphosphonium bromide (16.75 g, 46.89 mmol, 2 eq) in THF (40 mL) was added potassium;2-methylpropan-2-olate (1 M, 47.0 mL, 2 eq) at -20C under N2. The mixture was stirred at -20C for 0.5 h, tert-butyl N-(4-oxocyclohexyl)carbamate (5 g, 23.44 mmol, 5.00 mL, 1 eq) was added into the mixture at 0C. The mixture was stirred at 20C for 14.5 h. LCMS showed complete consumption of the starting material and formation of a new peak. TLC showed all the starting material was consumed and the new major spot was the desired product. The reaction mixture was poured into water (500 mL), the aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether : Ethyl acetate=10:1 to 0:1) to produce tert-butyl (4-methylenecyclohexyl)carbamate (4 g, 18.93 mmol) as a white solid.
N-Boc-aniline (16.12 g, 83.4 mmol) (Al) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to -70 0C. To this solution was added dropwise, under nitrogen, a 1.7 M solution of tert-butyllithium in pentane (110 mL, 187 mmol) at -700C. After 30 min at -70 0C, the solution was warmed to -20 0C and maintained at that temperature for 2 hours. The solution was again cooled to -70 0C and treated dropwise with a solution of N-Boc-4-piperidone (15.98 g, 80.2 mmol) (A2) in anhydrous tetrahydrofuran (50 mL). The solution was slowly warmed to room temperature, treated with potassium tert-butoxide (25 mg) and stirred at room temperature overnight under nitrogen. The solution was diluted with diethyl ether (300 mL), cooled in an ice water bath and adjusted to pH 7 with 1.0 N HCl (aq). The layers were separated and the aqueous layer extracted once with diethyl ether (100 mL). The pooled organic layers were washed with water and saturated brine, then dried over Na2Stheta4 and filtered. The filtrate was concentrated under reduced pressure to afford a crude <n="44"/>product as a viscous pale yellow oil. The crude product was purified via silica gel flash chromatography (25-50% ethyl acetate in hexanes) to afford tert-butyl 2-oxo-l,2- dihydrospiro[benzo[d][l,3]oxazine-4,4'-piperidine]-r-catauboxylate (A3) as a pale yellow solid. LC/MS m/z 319.0 [M+H]+, retention time 2.72 min (RP-Cl 8, 10-99% CH3CN/0.05% TFA); 1 H-NMR (400 MHz, CDC13) delta 9.06 (br s, IH), 7.28 (m, IH), 7.12 (m, 2H), 6.91 (d, J = 8.5 Hz, IH), 4.12 (br d, J = 9.9 Hz, 2H), 3.36 (br t, J = 12.4 Hz, 2H), 2.13 (br d, J = 13.1 Hz, 2H), 1.98 (m, 2H), 1.51 (s, 9H).J001451 /er/-Butyl 2-oxo-l,2-dihydrospiro[benzo[d][l,3]oxazine-4,4'-piperidine]-r- carboxylate (6.71 g, 21.1 rrimol) (A3) was dissolved in dichloromethane (50 mL), treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice water bath, dissolved in ice-cold saturated brine (20 mL) and H2O (50 mL) and basified with ice-cold 35% NaOH (aq). A small amount of product (obtained from extraction with 50 mL ethyl acetate) was added to the aqueous layer to initiate crystallization. The suspension obtained was cooled in an ice-H2O bath, filtered, rinsed with ice-cold H2O and dried to afford spiro[benzo[d][ l,3]oxazine-4,4'-piperidin]-2(lH)-one (A4) free base as a white crystalline solid. Additional free base was obtained via extraction of the mother liquor with ethyl acetate (10 x 50 mL) and subsequent trituration of the crude free base with acetonitrile (overall yield = 84%). LC/MS m/z 219.2 [M+H]+, retention time 0.58 min (RP-C18, 10-99% CH3CN/O.O5% TFA); 1H-NMR (400 MHz, DMSO-cfe) delta 10.17 (br s, IH), 7.23 (m, 2H), 7.02 (m, IH), 6.87 (dd, J= 8.2, 1.2 Hz, IH), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).
A methylene chloride solution (6 ml) of dimethyl sulfoxide (2.0 ml, 28.2 mmol) was added dropwise to a methylene chloride solution (30 ml) of oxalyl chloride (1.7 ml, 19.5 mmol) at -60C over a period of 10 minutes and stirred at -60C for another 10 minutes. Then, a methylene chloride solution (140 ml) of tert-butyl 4-hydroxycyclohexylcarbamate (2.56 g, 11.9 mmol) was added dropwise thereto over a period of 35 minutes, and the resulting mixture was stirred at -60C for 40 minutes. After triethylamine (8.4 ml, 60.3 mmol) was added thereto at -60C, the resulting mixture was warmed up to room temperature spontaneously. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain tert-butyl 4-oxocyclohexylcarbamate (2.23 g, 87%).1H-NMR (DMSO-d6): 1.06-1.20 (4H, m), 1.35 (9H, s), 1.69-1.76 (4H, m), 3.12-3.31 (2H, m), 4.48 (1H, s), 6.64 (1H, d, J=7.5Hz).
85.7%
With pyridinium chlorochromate; In chloroform; at 0 - 20℃; for 3h;
Step-2, Synthesis of tert-butyl (4-oxocyclohexyl)carbamate:A solution of tert-butyl (4-oxocyclohexyl) carbamate (5g, 0.0232 mol) in chloroform (50ml_) was cooled to 0 C and pyridiniumchlorochromate (12.49g, 0.058mol) was added portion wise. After addition completed the resulting mixture was allowed to RT and stirred for 3 h. The reaction mixture was diluted with chloroform (100ml_) and washed with brine, water, dried over sodium sulphate and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5% MeOH-DCM) to afford tert-butyl (4-oxocyclohexyl)carbamate of 4.2g, 85.7% yield.1HNMR (CDCI3, 300MHz): delta 4.5 (m, 1 H), 3.91 (m, 1 H), 2.4(m, 4H), 2.2 (m, 2H), 1.6 (m, 2H), 1 .45 (m, 9H).
82.1%
With Dess-Martin periodane; In dichloromethane; at 20℃;Cooling with ice;
Dess-Martin oxidizer (29.0 g, 68.3 mmol) was added dropwise to a solution of N-4-Boc-aminocyclohexanol (9.8 g, 45.52 mmol) in dichloromethane (200 mL) with ice-bath stirring. Warm to room temperature and stir the reaction mixture overnight. The mixture was carefully quenched with a saturated aqueous solution of sodium thiosulfate in an ice bath and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on a silica gel column yielded 4-oxo. Tert-butyl cyclohexylcarbamate (7.96 g, yield 82.1%).
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 2h;
To a solution of the compound obtained from step a above (5 g, 23.4 mmol) in dichloromethane (100 mL), was added pyridinium chlorochromate (7.6 g, 35. 0 mmol) and celite (5. 0G). The reaction mixture was stirred at room temperature for 2 hours. Dichloromethane was evaporated under reduced pressure and the residue was diluted with ethylacetate. The reaction mixture filtered through celite pad and concentrated under reduced pressure. The crude compound thus obtained was purified by column chromatography to furnish the title compound. Yield: 3.5 g
With Dess-Martin periodane; In dichloromethane; at 20℃;
Step B: Tert-butyl 4-oxocyclohexylcarbamate. To a solution of /<?r/-butyl 4-hydroxycyclohexylcarbamate (10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at room temperature overnight, quenched with aq. Na2S203 solution and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / EtOAc (V:V, 10: 1) to afford desired product as a white solid.
7 g
With Dess-Martin periodane; In dichloromethane; at 20℃;
To a solution of tert- v y 4-hydroxy- cyclohexylcarbamate (10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at r.t. overnight and treated with aq. Na2S203 solution and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SC>4, and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / EtOAc (V:V, 10: 1) to afford desired product as a white solid (7.0 g, 70% crude yield).
With Dess-Martin periodane; In dichloromethane; at 20℃;
To a solution of tert-butyl 4-hydroxycyclohexyl-carbamate (10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at room temperature overnight, quenched with aq. Na2S2O3solution and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether/EtOAc (V:V, 10:1) to afford desired product as a white solid.
With Dess-Martin periodane; In dichloromethane; at 20℃;
Step B: Tert-butyl 4-oxocyclohexylcarbamate. To a solution of tert-buty 4-hydroxycyclohexylcarbamate ( 1 0.0 g, 46.5 mmol) in DCM ( 100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at room temperature overnight, quenched with aq. Na2S203 solution and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous aiSC , and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / EtOAc (V:V, 10: 1 ) to afford desired product as a white solid.
With triethylamine; In dichloromethane; dimethyl sulfoxide;
Step 2: To a stirred solution of oxalyl chloride (0.83 g) in dry dichloromethane (15 mL) at -60 C. was added dimethylsulfoxide (1.0 mL) in dichloromethane (3 mL) dropwise. The reaction mixture was stirred at -60 C. for 10 min, then N-tert-butyloxycarbonyl-trans-4-aminocyclohexanol (1.28 g) in dichloromethane (70 mL) was added over 15 min. The resulting mixture was stirred at -60 C. for a further 15 min, then triethylamine (4.2 mL) was added and the solution was allowed to warm to room temperature. The mixture was washed with water (20 mL) and this aqueous layer was extracted once with dichloromethane (20 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Drying under vacuum gave N-tert-butyloxycarbonyl-4-aminocyclohexanone (1.25 g) as a colorless solid.
methyl N-{cis-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-4-chloro-D-phenylalaninate[ No CAS ]
methyl N-{trans-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-4-chloro-D-phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 18 N-[cis-4-({(1R)-1-(4-chloro-benzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-yl-methyl)piperidin-1-yl]-2-oxoethyl}amino)cyclohexyl]-glycinamide hydrochloride (compound No. 116) 18.1: methyl N-{cis-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-4-chloro-D-phenylalaninate 10 g of methyl 4-chloro-L-phenylalaninate hydrochloride in the presence of 8.5 g of tert-butyl (4-oxocyclohexyl)carbamate are placed in 200 ml of dichloromethane. 11.0 g of sodium triacetoxyborohydride are added. Stirring is maintained at ambient temperature for 18 h. The solution is hydrolyzed with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane until the aqueous phase is completely depleted. After drying over MgSO4 and concentration to dryness, the crude obtained is chromatographed on silica gel, elution being carried out with a mixture of dichloromethane/ethyl acetate/methanol/aqueous ammonia ranging from 95/5/1/0.1 to 85/15/3/0.3. 6.1 g of methyl N-{cis-4-[(tert-butoxy-carbonyl)amino]cyclohexyl}-4-chloro-D-phenylalaninate and 7.4 g of methyl N-{trans-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-4-chloro-D-phenylalaninate are obtained. 18.2: 1N-{cis-4-[(tert-butoxycarbonyl)-amino]cyclohexyl}-4-chloro-D-phenylalanine
In tetrahydrofuran; sodium hydroxide; dichloromethane
52 Preparation of 4-[N-(tert-butyloxycarbonyl)]amino-cyclohexanone:
Preparation of 4-[N-(tert-butyloxycarbonyl)]amino-cyclohexanone: A solution of trans-4-aminocyclohexanol hydrochloride (2.67 g, 1.14 mol) in 1 N NaOH (40 mL) was washed with CHCl3 (40 mL), CH2Cl2 (2*30 mL) and EtOAc (4*30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the desired free base (0.43 g) as a white solid. To a suspension of trans-4-aminocyclohexanol (0.43 g, 4.09 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate (0.89 g, 4.09 mmol) and the mixture stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the resultant crude product was used without further purification in the next reaction. To a suspension of the alcohol from above (~3.7 mmol) and powdered 3 A molecular sieves (0.90 g) in CH2Cl2 (10 mL) was added 4-methylmorpholine N-oxide (0.696 g, 5.95 mmol) and tetrapropylammonium perruthenate (0.089 g, 0.25 mmol) and the mixture stirred overnight. The reaction was concentrated under reduced pressure and purified by column chromatography through a plug of silica gel (ethyl acetate/hexanes, 1:1) to afford the title compound (0.670 g, 84% over 2 steps) as a white solid. 1H NMR (CDCl3) δ 1.45 (br s, 9H), 1.64-1.73 (m, 2H), 2.21-2.27 (m, 2H), 2.37-2.44 (m, 4H), 3.89-3.95 (m, 1H), 4.50 (br s, 1H, NH).
molecular sieves; In dichloromethane; ethyl acetate;
To a solution of <strong>[224309-64-2](4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester</strong> (5.80 g, 26.9 mmol) in dry methylene chloride (67 mL) was added in order activated 3 A molecular sieves (6.54 g), 4-methylmorpholine N-oxide (5.04 g, 43.0 mmol) and tetrapropylammonium perruthenate (380 mg, 1.08 mmol). The mixture was stirred at 25 C. for 18 h under nitrogen then the mixture was concentrated. Purification by column chromatography on silica gel with hexane/ethyl acetate (1:1) afforded (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester as a white solid (5.52 g, 96%). 1H NMR (CDCl3) delta 1.46 (s, 9H), 1.64-1.74 (m, 2H), 2.21-2.27 (m, 2H), 2.39-2.45 (m, 4H), 3.97 (bs, 1H), 4.40 (bs, 1H).
cis-[4-(indan-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester[ No CAS ]
trans-[4-(indan-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%; 19%
With ethanol; sodium cyanoborohydride; for 16h;
Sodium cyanoborohydride (590 mg, 9.39 mmol) was added to a solution of Boc-4- aminocyclohexanone (1.00 g, 4.69 mmol) and <strong>[2338-18-3]2-aminoindane hydrochloride</strong> (955 mg, 5.63 mmol) in ethanol (25 mL). After stirring for 16 h, the reaction mixture was poured into aqueous l.OM sodium hydroxide solution (75 mL) and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. Filtration followed by removal of volatiles under reduced pressure afforded a gummy solid. Flash chromatography (0-5% methanol in ethyl acetate) provided (in order of elution): cis-[4-(indan-2-ylamino)-cyclohexyl]-carbamic acid tert- butyl ester (700 mg; 45%) and £r°Hs-[4-(indan-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (300 mg; 19%) as gummy solids.
Triphenylmethylphosphonium iodide (17.2 g, 42.5 mmol) and potassium tert-butoxide (4.13 g, 36. 8 mmol) were taken together under nitrogen atmosphere and dry tetrahydrofuran (150 mL) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature. To the resulting reaction mixture was added a solution of the compound obtained form step b above in dry tetrahydrofuran under nitrogen atmosphere and cooled to 0 C followed by stirring for 10 hours at room temperature. The reaction mixture was quenched with water (5.0 mL) and concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane, washed with water, brine and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure and the residue thus obtained was purified by column chromatography to furnish the title compound. Yield = 2.1 g Mass (m/z): 211 (M++1).
To a suspension of magnesium strip (283.6 mg, 11.67 mmol) in diethyl ether (4 mL) was added a piece of iodine followed by 0.3 mL of <strong>[71916-91-1]2-(bromomethyl)-4-chloro-1-fluorobenzene</strong> under nitrogen atmosphere. A high intensity heat gun was applied to initiate the reaction, then 2- (bromomethyl)-4-chloro-1-fluorobenzene (2.61 g, 11.67 mmol) in diethyl ether (4.5 mL) was added slowly at such a speed that a gentle reflux was maintained. After the addition was completed, the reaction mixture was refluxed for 3 hours, cooled to room temperature and a solution of tert-butyl (4-oxocyclohexyl) carbamate (2.49 g, 11.67 mmol) in diethyl ether (9 mL) and THF (9 mL) was added slowly with vigorous stirring. After the addition was completed, the reaction mixture was left at room temperature for 3 hours. Aqueous NH4CI (20 mL) was added and the mixture was stirred at room temperature overnight, extracted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0- 30% ethyl acetate in petroleum benzene) to give the subtitled compound (1.4 g).
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; Inert atmosphere;
1
[00484] 4,4-Difluoro-cyclohexylamine (25) and 4-Fluoro-cyclohex-3- enylamine (26): In a 100 mL Teflon round bottom flask, a solution of N-Boc-4- aminocyclohexanone 24 (5.0 g, 23.4 mmol) in dichloromethane (25 mL) was combined with diethylaminosulfur trifluoride (DAST) (5.5 mL, 39.9 mmol) under an inert nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature followed by quenching with saturated sodium bicarbonate. The product was extracted into dichloromethane then precipitated from solution by the addition of HCl in ethyl ether. The product consisted of the two compounds 25 and 26 shown as compound mixture.
Stage #1: phenylmethyl 1-piperazinecarboxylate; N-(tert-butoxycarbonyl)-4-aminocyclohexanone With acetic acid In methanol for 0.5h;
Stage #2: With 2-picoline borane complex In methanol for 12h;
1
To a solution of tert-butyl N-(4-oxocyclohexyl)carbamate (10 g, 46.89 mmol, 1 eq) in methanol (150 mL) was added acetic acid (15 mL) and benzyl piperazine-1-carboxylate (10.33 g, 46.89 mmol, 1 eq). The mixture was stirred at 30° C. for 0.5 hour. Then 2-methylpyridine borane complex (10.03 g, 93.78 mmol, 2 eq) was added and the mixture was stirred at 30° C. for 12 hours. LCMS analysis of an aliquot indicated completion of the reaction. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with a saturated aqueous solution of sodium bicarbonate (200 mL) and saturated brine (300 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether:ethyl acetate (V/V=5:1, 150 mL) to give benzyl 4-[4-(tert-butoxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (13 g, 31.1 mmol, 66.4% yield) obtained as a white solid. MS (ESI) m/z: 418.2[M+H]+.
With methanol; sodium tris(acetoxy)borohydride at 20℃;
9.v
Example 9:; Synthesis of 4-{4-[(1 H-Benzotriazole-δ-carbonylJ-aminoJ-cyclohexy^-piperazine-i carboxylic acid; 3-chloro-5-trifluoromethyl-benzyl esterv. Compound 36 (1.20 g, 5.63 mmol) and compound 37 (1.50 g, 6.81 mmol) were dissolved in methanol (100 ml.) and sodium triacetoxyborohydride (1.50 g, 7.07 mmol) was added at RT slowly. The mixture was stirred for 18 h at RT. The solvent was evaporated and the residue redissolved in dichloromethane. The organic phase was washed with saturated sodium hydrogencarbonate solution. This aqueous solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated to dryness. The crude solid compound 38 (1.90 g, 4.55 mmol, 81%) was used without further purification.In analogy to the general procedures d, c, b. and e compound 39 was synthesized.
With sodium tris(acetoxy)borohydride; In dichloromethane; at 25℃; for 6h;
To a solution of tert-butyl 4-oxocyclohexylcarbamate (350 mg, 1.641 mmol) in methylene chloride (8 mL) was added <strong>[147688-58-2]2,2-<strong>[147688-58-2]dimethylmorpholine</strong></strong> (189 mg, 1.641 mmol) followed by sodium triacetoxyborohydride (1.739 g, 8.21 mmol). Reaction mixture was stirred at 25 C for 6 hr. Reaction mixture was diluted with EtOAc and washed with water. Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by column chromatography [Si02; 12 g] to provide the title compound as a yellow oil. LCMS (m/z): 313.1 [M+H]+; Retention time = 0.60 min.
With sodium tris(acetoxy)borohydride; In dichloromethane; at 25℃; for 6h;
To a solution of tert-butyl 4-oxocyclohexylcarbamate (350 mg, 1.641 mmol) in methylene chloride (8 mL) was added <strong>[147688-58-2]2,2-<strong>[147688-58-2]dimethylmorpholine</strong></strong> (189 mg, 1.641 mmol) followed by sodium triacetoxyborohydride (1.739 g, 8.21 mmol). Reaction mixture was stirred at 25 C for 6 hr. Reaction mixture was diluted with EtOAc and washed with water. Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by column chromatography [Si02; 12 g] to provide the title compound as a yellow oil. LCMS (m/z): 313.1 [M+H]+; Retention time = 0.60 min
With sodium tris(acetoxy)borohydride; In dichloromethane; at 25℃; for 6h;
To a solution of tert-butyl 4-oxocyclohexylcarbamate (350 mg, 1.641 mmol) in methylene chloride (8 mL) was added <strong>[147688-58-2]2,2-<strong>[147688-58-2]dimethylmorpholine</strong></strong> (189 mg, 1.641 mmol) followed by sodium triacetoxyborohydride (1.739 g, 8.21 mmol). Reaction mixture was stirred at 25 C for 6 hr. Reaction mixture was diluted with EtOAc and washed with water.Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by column chromatography [Si02; 12 g] to provide the title compound as a yellow oil. LCMS (m/z): 313.1 [M+H]+; Retention time = 0.60 min
With sodium tris(acetoxy)borohydride; In dichloromethane; at 25℃; for 6h;
Synthesis of cis- and frans-4-(2,2-dimethylmorpholino)cyclohexanamineStepl : Preparation of tert-butyl cis/trans-4-(2,2-dimethylmorpholino)cyclohexylcarbamateTo a solution of tert-butyl 4-oxocyclohexylcarbamate (350 mg, 1.641 mmol) in methylene chloride (8 mL) was added <strong>[147688-58-2]2,2-<strong>[147688-58-2]dimethylmorpholine</strong></strong> (189 mg, 1.641 mmol) followed by sodium triacetoxyborohydride (1.739 g, 8.21 mmol). Reaction mixture was stirred at 25 C for 6 hr. Reaction mixture was diluted with EtOAc and washed with water.Organics were isolated, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by column chromatography [Si02; 12 g] to provide the title compound as a yellow oil. LCMS (m/z): 313.1 [M+H]+; Retention time = 0.60 min.
[01783] Step 1 : Synthesis of methyl 3-(((l r,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate[01 784] To a stirred solution of methyl 3-amino-5-chloro-2-methyl benzoate (5.0 g, 25 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (6.95 g, 32.6 mmol) in 25 ml of dichloroethane, was added acetic acid (9.0 mL, 450.75 mmol) at room temperature. The reaction mixture was cooled and sodium triacetoxyborohydride (22.8 g, 108 mmol) was added and the mixture stirred at room temperature overnight. The mixture was neutralized with sat. NaHC03 and extracted with DCM. The combined organic phases were dried over a2S04, concentrated under reduced pressure and the product isomers separated by silica gel (100-200) column chromatography to give the less polar as m-isomer, methyl 3-((( l s,4s)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (5.2 g, 52%) and the more polar title compound /rara-isomer, methyl 3-(((l r,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (3.5 g, 35%).
32.5%; 29.1%
To a stirred solution of <strong>[294190-18-4]methyl 3-amino-5-chloro-2-methylbenzoate</strong> (500 mg, 2.505 mmol) and 4-N-Boc-aminocyclohexanone (2.0 g, 9.38 mmol) in methanol (20 mL) was added zinc chloride (1.0 g, 7.34 mmol). The reaction was stirred for 2 h at room temperature, then sodium cyanoborohydride (700 mg, 1 1.14 mmol) was added portionwise over 2 h. The reaction was then heated to 40 C and stirred for 24 h. LCMS showed that the reaction was mostly complete (1 1% starting amine remained with two product peaks 40%) and 49%> corresponding to the trans and cis products). The reaction was evaporated to dryness, taken up in EtOAc, washed with aq. NH4C1, 1 N Na2C03, brine, dried (Na2S04), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF25-80g, 10 to 30% EtOAc in hexanes). The cis- diastereomer was contaminated with 27% of the methyl 3-amino-5-chloro-2- methylbenzoate starting material. Trituration and filtration from a small volume of 10% EtOAc in hexanes gave the pure cz's-diastereomer methyl 3-(((cis)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2 -methylbenzoate (305 mg, 0.730 mmol, 29.1 % yield) as a white solid. 1H NMR (400MHz ,DMSO-d6) delta = 6.85 (d, J= 2.3 Hz, 1 H), 6.74 (d, J = 2.0 Hz, 1 H), 6.62 (d, J= 7.1 Hz, 1 H), 4.66 (d, J = 6.8 Hz, 1 H), 3.81 (s, 3 H), 3.47 (br. s., 2 H), 2.19 (s, 3 H), 1.75 - 1.51 (m, 8 H), 1.39 (s, 9 H). MS(ES) [M+H]+ 397.2. The more polar trans-diastereomer was isolated pure after trituration and filtration from 10% EtOAc in hexanes to obtain methyl 3-(((trans)-4-((tert- butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (340 mg, 0.814 mmol, 32.5 % yield) as a white solid. 1H NMR (400MHz ,DMSO-d6) delta = 6.83 (br. s., 0 H), 6.82 (d, J= 2.0 Hz, 1 H), 6.73 (d, J = 2.0 Hz, 1 H), 4.94 (d, J = 8.3 Hz, 1 H), 3.80 (s, 3 H), 3.23 (br. s., 2 H), 2.13 (s, 3 H), 1.99 - 1.86 (m, 2 H), 1.81 (br. s., 2 H), 1.39 (s, 9 H), 1.36 - 1.23 (m, 4 H). MS(ES) [M+H]+ 397.2.
Step B: Tert-butyl 4-oxocyclohexylcarbamate To a solution of tert-butyl 4-hydroxycyclohexylcarbamate (10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at r.t. overnight and treated with aq. Na2S2O3 solution and extracted with DCM (3*100 mL). The combined organic layers were washed with water (2*100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether/EtOAc (V:V, 10:1) to afford desired product as a white solid (7.0 g, 70% crude yield).
In ethyl acetate; Petroleum ether;
Step B: Tert-butyl 4-oxocyclohexylcarbamate To a solution of tert-butyl 4-hydroxycyclohexyl-carbamate (10.0 g, 46.5 mmol) in DCM (100 mL) was added Dess-Martin periodinane (39.4 g, 92.9 mmol) portionwise. The resulting solution was stirred at room temperature overnight, quenched with aq. Na2S2O3 solution and extracted with DCM (3*100 mL). The combined organic layers were washed with water (2*100 mL) and brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether/EtOAc (V:V, 10:1) to afford desired product as a white solid.
Step 1 : Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl) amino) cyclohexyl) amino)-5-chloro-2-methylbenzoate: [0910] To a stirred solution of <strong>[294190-18-4]methyl 3-amino-5-chloro-2-methylbenzoate</strong> (100 g, 502 mmol) and tert-butyl (4-oxocyclohexyl) carbamate (160.5 g, 753 mmol) in dichloroethane (1 L), acetic acid (180.9 g, 3015 mmol) was added and the reaction was stirred at rt for 30 min. Then sodium triacetoxyborohydride (319.5 g, 1507 mmol) was added at 0 C and the reaction was stirred at rt for 16 h. The progress of the reaction was monitored by TLC. Upon completion; the reaction was quenched with aqueous sodium bicarbonate, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (100-200 mesh size) eluting with 2, 4, 6 & 8% ethyl acetate in hexane to remove maximum cis isomer. This afforded 120 g of mixture of cis and trans isomers (40:60 by HPLC). The trans isomer was purified by repetitive recrystazlisation with ethyl acetate: hexane (1 :2) to afford 65 g of pure trans isomer (65 g, 33%).
Step 1: A solution of NaCN (2.75 g, 56.02 mmol, 2.39 eq) in H20 (10 mL) was added to the mixture of compound 19_1 (5.00 g, 23.44 mmol, 1.00 eq) and (NH4)2C03 (4.96 g, 51.57 mmol, 2.20 eq) in EtOH (25 mL) and H2O (25 mL). The reaction mixture was stirred at 10 C for 16 hours and then at 70 C for another 24 hours. TLC (PE:EA=3:1) showed that reactant was consumed (Rf=0.55) and a major spot fromed (Rf=0.25). The reaction mixture was allowed to cool down and filtered. The filter cake was washed with H20 (100 mL) and dried. Compound 19_2 (4.00 g, 14.12 mmol, 60.2% yield) was obtained as a white solid. NMR (DMSO-d6, 400 MHz) delta 10.51 (s, 1H), 8.48 (s, 1H), 6.70-6.72 (d, / = 8.0 Hz, 1H), 3.16 (s, 1H), 1.79-1.76 (m, 2H), 1.65-1.64 (d, / = 4.0 Hz, 2H), 1.62-1.52 (m, 2H), 1.60-1.59 (m, 1H), 1.37 (s, 11H).
tert-butyl(4-(isoquinolin-5-ylamino)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.3%
With sodium cyanoborohydride; acetic acid; sodium sulfate at 20℃; Cooling with ice;
3
According to the above synthetic line PT109,Compound 5 (442.31 mg, 2.07 mmol),5-aminoisoquinoline (230.00 mg, 1.60 mmol) and anhydrous Na2SO4 (1.13 g, 7.98 mmol) were dissolved in glacial acetic acid (10 mL)Sodium cyanoborohydride (200.50 mg, 3.19 mmol) was added under ice-cooling,The ice bath was removed and the reaction was stirred overnight at room temperature.After completion of the reaction, glacial acetic acid was removed by a rotary evaporator, and the saturated NaHCO3 solution was added to the residue,The aqueous phase was extracted with DCM.The combined organic phases were washed with saturated brine (10 mL x 1), dried over anhydrous Na2SO4, and the solvent was removed by rotary distillation. The residue was passed through a silica gel columnChromatography to give compound 6 as a yellow solid (372 mg, yield 68.3%).
68.3%
With sodium cyanoborohydride; acetic acid; sodium sulfate In methanol at 0 - 20℃;
Synthesis of tert-butyl (4-(isoquinolin-5-ylamino)cyclohexyl)carbamate (14):
To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (442.31mg, 2.07mmol), isoquinolin-5-amine (230.00mg, 1.60mmol) and anhydrous Na2SO4 (1.13g, 7.98mmol) in AcOH (10ml), NaBH3CN (200.50mg, 3.19mmol) was added dropwise at 0°C. The reaction mixture was stirred at rt overnight and evaporated to remove AcOH. The resulting mixture was basified with saturated NaHCO3 aq (10ml). The aqueous layer was extracted with DCM (20ml×3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (MeOH/DCM 1/100-1/50) to give the compound 14 as a dense yellow oil (372mg, 1.09mmol, 68.3% yield). 1H NMR (400MHz, CDCl3) δ 9.15 (s, 1H), 8.46 (s, 1H), 7.53 (s, 1H), 7.49-7.39 (m, 1H), 7.30 (s, 1H), 6.77 (s, 1H), 4.71-4.12 (m, 2H), 3.55 (m, 3H), 2.27 (d, J=12.0Hz, 1H), 2.14 (d, J=12.6Hz, 1H), 2.06-1.88 (m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.34 (m, 3H).
tert-butyl N-[4-(5-bromoindolin-1-yl)cyclohexyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: 5-bromoindoline; N-(tert-butoxycarbonyl)-4-aminocyclohexanone With titanium(IV) isopropylate In methanol at 20℃; for 12h; Inert atmosphere;
Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 12h; Inert atmosphere;
44.1 tert-butyl N-[4-(5-bromoindolin-1-yl)cyclohexyl]carbamate (07-10-1)
To a stirred solution of 5-bromoindoline (5.00 g, 25.2 mmol, 1.0 eq) and tert-butyl N- (4-oxocyclohexyl)carbamate (8.10 g, 37.9 mmol, 8.10 mL, 1.50 eq) in MeOH (100 mL) was added Ti(i-PrO)4 (10.80 g, 38.0 mmol, 11.25 mL, 1.51 eq) at 20 °C. After 12 h, NaBH3CN (3.50 g, 55.7 mmol, 2.2 eq) was added to the mixture in portions. The resulting mixture was stirred at 20 °C for another 12 h, poured into water (300 mL), and filtered through a pad of Celite. The filter cake was washed with DCM (50 mL×10) and the organic layer was separated, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2) to give compound 07-10-1 (5.00 g, 12.6 mmol, 50% yield).1H NMR (CDCl3, 400 MHz): δ 7.07-6.99 (m, 2H), 6.20-6.11 (m, 1H), 3.47-2.98 (m, 4H), 2.90-2.77 (m, 2H), 2.03 (br d, J = 12.3 Hz, 1H), 1.85 (br d, J = 13.8 Hz, 1H), 1.81-1.72 (m, 1H), 1.62 (br d, J = 12.7 Hz, 1H), 1.57-1.50 (m, 1H), 1.49-1.40 (m, 2H), 1.38 (d, J = 5.6 Hz, 9H), 1.22-1.07 (m, 1H).
Stage #1: diazomethyl-trimethyl-silane With n-butyllithium In diethyl ether at -78℃; for 0.5h; Inert atmosphere;
Stage #2: N-(tert-butoxycarbonyl)-4-aminocyclohexanone In diethyl ether at -78℃; for 0.5h;
1 Step 1: tert-Butyl (4-oxocycloheptyl)carbamate
The title compound was prepared from tert-butyl (4-oxocyclohexyl)carbamate according to the procedure described in Liu, H.; et al, Chem. Eur. J 2012, 18, 11889: To a solution of n-BuLi (2 M in hexane, 9.76 mL, 24.4 mmol, 1.3 eq) in Et2O (50 mL) at -78° C. under a N2 atmosphere was added TMSCH2N2 (12 mL, 24.4 mmol, 1.3 eq) dropwise and the mixture was allowed to stir at -78° C. for 30 min. A solution of tert-butyl (4-oxocyclohexyl)carbamate (4.0 g, 18.8 mmol, 1.0 eq) in Et2O (50 mL) was then added dropwise and the solution was stirred at -78° C. for a further 30 min. The reaction was quenched with MeOH (1.6 mL) and allowed to warm to RT, diluted with water (50 mL) and extracted with Et2O (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:EtOAc, 8:1 to 6:1, v/v) to afford the title compound as a 2:1 mixture of isomers (1.8 g, 42%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.59-2.46 (m, 1H), 2.33-2.12 (m, 4H), 2.01-1.68 (m, 4H), 1.43 (s, 9H), 1.25-1.06 (m, 2H).
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