* 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.
With sodium tetrahydroborate; cobalt(II) chloride hexahydrate In methanol at 60℃; for 51 h; Cooling with ice
B) tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate To a mixture of 1-tert-butyl 4-ethyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (2.5 g), cobalt(II) chloride hexahydrate (1.0 g) and methanol (50 mL) was added sodium borohydride (1.6 g) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and then at room temperature for 2 days, and then 60°C for 1 hr. 28percent Aqueous ammonia was added thereto, the precipitate was removed by filtration, and the filtrate was extract with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.1 g). 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.35 (2H, m), 1.40 (9H, s), 1.45-1.58 (2H, m), 1.90-1.98 (2H, m), 2.90 (2H, brs), 3.16 (2H, t, J = 7.2 Hz), 3.76-3.86 (2H, m), 7.56 (1H, brs).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6876 - 6881,6
9
[ 212782-43-9 ]
[ 268550-48-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6876 - 6881,6
10
[ 268550-47-6 ]
[ 268550-48-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6876 - 6881,6
11
[ 24424-99-5 ]
[ 268550-48-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6876 - 6881,6
12
[ 268550-48-7 ]
[ 832710-65-3 ]
Yield
Reaction Conditions
Operation in experiment
240 mg
With hydrogenchloride In ethanol; ethyl acetate at 60℃; for 2 h;
C) 2,8-diazaspiro[4.5]decan-1-one hydrochloride To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg), ethyl acetate (10 mL) and ethanol (2.0 mL) was added 4 M hydrogen chloride/ethyl acetate solution (5.0 mL) at room temperature, the mixture was stirred at 60°C for 2 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the obtained solid was collected by filtration to give the title compound (240 mg). 1H NMR (300 MHz, CDCl3) δ 1.47-1.64 (2H, m), 1.77-1.92 (2H, m), 1.93-2.03 (2H, m), 2.81-3.03 (2H, m), 3.11-3.34 (4H, m), 7.72 (1H, brs), 8.62-9.33 (2H, m).
With potassium carbonate; In tetrahydrofuran; water;pH ~ 10;
To a solution of 2, 8-diaza-spiro [4.5] decan-l-one hydrochloride (763 mg, 4 mmol, 1 equiv) in 10 mL of 1 : 1 THF and water was added (Boc) 20 (960 mg, 1.1 equiv). The pH of the solution was adjusted to-10 by addition of K2CO3. Upon completion, the mixture was extraction with EtOAc. Organic layer was dried over sodium sulfate, filtered, and evaporated to givel-oxo-2, 8-diaza-spiro [4,5] decane-8-carboxylic acid tert-butyl ester.
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃;
mixture of l-oxo-2, 8-diaza-spiro [4,5] decane-8-carboxylic acid tert-butyl ester (127 mg, 0.5 mmol, 1 equiv), 4-bromo-l-chloro-2-methoxy-benzene (221 mg, 2equiv), N, N- dimethylethylenediamine (14 mg, 0.3 equiv), Cul (29 mg, 0.3 equiv) and Cs2CO3 (325 mg, 2 equiv) in 1 mL of dioxane were heated at 110 C overnight and then cooled to room temperature, taken up in a 1 : 1 mixture of methanol and EtOAc, filtered through a thin pad of celite and concentrated. The crude product was purified by flash column to give 2- (4-Chloro- 3-methoxy-phenyl)-l-oxo-2, 8-diaza-spiro [4.5] decane-8-carboxylic acid tert-butyl ester.
Sodium hydride 600 mg (14. 7 mmol) (60% suspension in mineral oil) was added in a 500 mL round bottom flask under nitrogen followed by 20 mL of anhydrous DMF and 2. 5 g (9. 8 mmol) of 1-OXO-2, 8-diaza- spiro [4. 5] decane-8-carboxylic acid tert-butyl ester previously dissolved in 20 mL of anhydrous DMF. After agitating one hour at room temperature, 2. 5 g (9. 8 mmol) of 4-bromobenzylbromide diluted in 20 mL of anhydrous DMF were added and the reaction mixture was agitated an additional hour at room temperature. Then 100 mL of water were added and the solution was extracted with diethyl ether (2 x 150 mL). The combined organic layers were dried (NA2SO4), filtered and evaporated under reduced pressure to yield 4. 63 g 2- (4-BROMOBENZYL)-L-OXO-2, 8-diaza- spiro [4. 5] decane-8-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (400 MHz, DMSO-D6) [ppm] 7. 51 (d, 2H), 7. 12 (d, 2H), 4. 31 (s, 2H), 3. 8 (br d, 2H), 3. 14 (t, 2H), 2. 86 (br s, 2H), 1. 89 (t, 2H), 1. 54 (t x d, 2H), 1. 37 (S, 9H), 1. 32 (br d, 2H).
Introduce 600 mg (14.7 mmol) of sodium hydride (60% suspension in mineral oil) in a 500 mL round bottom flask under nitrogen before adding successively 20 mL of anhydrous DMF and 2.5 g (9.8 mmol) of 1-OXO-2, 8-diaza- spiro [4.5] decane-8-carboxylic acid tert-butyl ester previously dissolved in 20 mL of anhydrous DMF. After agitating one hour at room temperature, 2.5 g (9.8 mmol) of 4-bromobenzylbromide diluted in 20 mL of anhydrous DMF were added and the reaction mixture was agitated an additional hour at room temperature. Then 100 mL of water were added and the solution was extracted with diethyl ether (2 x 150 mL). The combined organic layers were dried (NA2SO4), filtered and evaporated under reduced pressure to yield 4.63 g of 2- (4-BROMOBENZYL)-L-OXO-2, 8- DIAZA-SPIRO [4.5] decane-8-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (400 MHz, DMSO-D6) : No. [PPM] 7.51 (d, 2H), 7. 12 (d, 2H), 4.31 (s, 2H)..,. 3. 8 (br d, 2H), 3.14 (t, 2H), 2.86 (br S, 2H), 1.89 (t, 2H), 1.54 (t x d, 2H), 1.37 (s, 9H), 1.32 (br d, 2H).
With hydrogenchloride; In ethanol; ethyl acetate; at 60℃; for 2h;
To a mixture of compound d (0.4 g, 1.6 mmol ), ethyl acetate (10 mL) and ethanol (2.0 mL) was added 4 M hydrogen chloride/ethyl acetate solution (5.0 mL) at room temperature, the mixture was stirred at 60C for 2 h, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the obtained solid was collected by filtration to obtain the desired product 1 (0.42 g) as a white powder, yield: 85.3%, mp: 280.5-281.6C. 1H NMR (600 MHz, DMSO) delta 7.73 (s, 1H, CONH), 3.25 (d, J = 12.7 Hz, 2H, diazaspiro-CH2), 3.17 (t, J = 6.8 Hz, 2H, diazaspiro-CH2), 2.93 (s, 2H, diazaspiro-CH2), 1.98 (t, J = 6.8 Hz, 2H, diazaspiro-CH2), 1.85 (ddd, J = 14.4, 10.8, 4.0 Hz, 2H, diazaspiro-CH2), 1.60 - 1.54 (m, 2H, diazaspiro-CH2). 13C NMR (151 MHz, DMSO) delta 179.40, 40.42, 40.28, 38.32, 31.96, 28.98. HRMS (ESI): calcd for C8H14N2O [M+H]+, 155.1179, found, 155.1180.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h;
To a solution of tert-butyl l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (I- 1 1) (5.0 g, 19.7 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (15.2 mL, 197 mmol) and the resulting solution was stirred at rt for lh. After evaporating the volatiles the residue was basified on ion exchange column washed with methanol followed by 1 N ammonia in methanol to give 2,8-diazaspiro[4.5]decan-l-one. LC/MS: (M+l)+: 155.1 1
With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h;
Step A: 2,8-diazaspiror4.51decan-l-one To a solution of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (5 g, 19.66 mmol) in methylene chloride(10 ml) was added trifluoroacetic acid (15.15 ml, 197 mmol). The resulting solution was stirred at rt for lh. Volatiles were removed, and the residue was basified to a free amine on Bond Elut SCX ion exchange column washed with methanol followed by 1 N ammonia in methanol to give 2,8-diazaspiro[4.5]decan-l-one. LCMS [M+l]+ = 155.11.
tert-butyl 2-(4-iodophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In acetonitrile; at 80℃; for 20h;Inert atmosphere;
General procedure: To a solution of 5 (500 mg, 1.966 mmol) in acetonitrile (15 mL) were added 1,4-diiodobenzene (3892 mg, 11.80 mmol), N1,N2-dimethylethane-1,2-diamine (52.0 mg, 0.590 mmol), copper(I) iodide (112mg, 0.590 mmol) and potassium carbonate (815 mg, 5.90 mmol) under nitrogen. The reaction mixture was stirred at 80 C for 20 hours. After cooling, the solution was filtered and the filtrate was concentrated and purified by flash chromatography on silica gel with petroleum/ethyl acetate (3/2) to give 230 mg 14 (26 %) as an off-white solid. LC/MS: tR = 3.74 min, m/z: 478.9 (M+Na)+.
tert-butyl 2-([1,1'-biphenyl]-4-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In acetonitrile; at 80℃; for 15h;
A mixture of <strong>[268550-48-7]tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate</strong> 5 (200 mg, 0.79 mmol) and 4-iodo-1,1?-biphenyl 6 (337 mg, 1.2 mmol) in acetonitrile (10 mL) at 40 C was degassed with stream of nitrogen for 20 min. Then K2CO3 (326 mg, 2.36 mmol), copper(I) iodide (37.4 mg, 0.20 mmol) and N1,N2-dimethylethane-1,2-diamine (20 mg, 0.23 mmol) were added sequentially. The reaction mixture was heated at 80 C for 15 h. After cooling, the solution was diluted with ethyl acetate and washed with 0.1M HCl aqueous solution. The organic layer was concentrated and purified by column chromatography to afford compound 7 (115 mg, 36%) as a white solid. MS (ES): C21H23N2O3 (M-tBu+H)+ calcd 351.2; found 351.1. LC/MS: tR= 3.95 min, >95%, m/z: 351.1 (M-tBu+H)+
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 65℃; for 16h;Inert atmosphere;
The mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.83 g, 7.20 mmol), commercially available 4-bromofuran-2(5H)-one (1.41 g, 8.63 mmol), xantphos (0.416 g, 0.720 mmol), water (0.389 mL, 21.6 mmol) , and potassium carbonate (1.989 g, 14.39 mmol) in toluene (50 mL) was degassed with nitrogen followed by addition of palladium acetate (0.081 g, 0.36 mmol). The resulting mixture was heated at 65 C for 16 h. After filtration through celite, the filtrate was concentrated and the residue was purified on silica gel column using EtOAc /hexane as eluting solvents to give the title compound. LC/MS: (M+l)+: 337.18.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 65℃; for 16h;Inert atmosphere;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.83 g, 7.20 mmol), commercially available 4-bromofuran-2(5H)-one (1.41 g, 8.63 mmol), Xantphos (0.416 g, 0.720 mmol), water (0.389 mL, 21.6 mmol), and potassium carbonate (1.989 g, 14.39 mmol) in toluene (50 mL) was degassed with nitrogen followed by addition of palladium acetate (0.081 g, 0.36 mmol). The resulting mixture was heated at 65 C for 16 h. After filtration through CELITE, the filtrate was concentrated and the residue was purified on silica gel column using EtOAc /hexane as eluting solvents to give the title compound. LC/MS: (M+l)+: 337.18.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 65℃; for 16h;Inert atmosphere;
Step A: tert-butyl l-oxo-2-(5-oxo-2,5-dihvdrofuran-3-yl)-2,8-diazaspiror4.51decane-8- carboxylate: A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1-55, 1.83 g, 7.20 mmol), commercially available 4-bromofuran-2(5H)-one (1.41 g, 8.63 mmol), Xantphos (0.416 g, 0.720 mmol), water (0.389 mL, 21.6 mmol), and potassium carbonate (1.99 g, 14.39 mmol) in toluene (50 mL) was added palladium acetate (0.081 g, 0.36 mmol) under N2. The mixture was heated at 65 C for 16 h, and filtered through CELITE. The filtrate was concentrated. The residue was purified on silica gel column using EtOAc /hexane as eluting solvents to give the title compound. LCMS [M+l]+ = 337.1.
With water; palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 60℃; for 16h;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-ethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (246 mg, 0.944 mmol), xantphos (45.5, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 60 C for 16 h. After filtration through celite, the filtrate was concentrated and the residue was purified on silica gel using ethyl acetate/hexane to give title compound. LC/MS: (M+l)+: 365.19.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 60℃; for 16h;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-ethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (246 mg, 0.944 mmol), Xantphos (45.5, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 60 C for 16 h. After filtration through CELITE, the filtrate was concentrated and the residue was purified on silica gel using ethyl acetate/hex ane to give the title compound. LC/MS: (M+l)+: 365.19.
With water; palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 66℃; for 16h;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (259 mg, 0.944 mmol), Xantphos (46 mg, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 66 C for 16h. After filtration through celite, the filtrate was concentrated and the residue was purified on silica gel column to give title compound. LC/MS: (M+l)+: 379.21.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 66℃; for 16h;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-l 1) (200 mg, 0.786 mmol), 4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (259 mg, 0.944 mmol), Xantphos (46 mg, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 66 C for 16h. After filtration through CELITE, the filtrate was concentrated and the residue was purified on a silica gel column to give the title compound. LC/MS: (M+l) : 379.21.
With water; palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 65℃; for 16h;Inert atmosphere;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (232 mg, 0.944 mmol), xantphos (45.5 mg, 0.079 mmol), palladium (II) acetate (8.83 mg, 0.039 mmol), water (0.043 mL, 2.359 mmol), and potassium carbonate (217 mg, 1.573 mmol) in toluene (20 mL) was degassed by nitrogen and heated at 65 C for 16 h. After filtration through celite the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+l)+: 351.15.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 65℃; for 16h;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.786 mmol), 2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (232 mg, 0.944 mmol), Xantphos (45.5 mg, 0.079 mmol), palladium (II) acetate (8.83 mg, 0.039 mmol), water (0.043 mL, 2.359 mmol), and potassium carbonate (217 mg, 1.573 mmol) in toluene (20 mL) was degassed by nitrogen and heated at 65 C for 16 h. After filtration through CELITE the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+l)+: 351.15.
With water; palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 65℃; for 16h;Inert atmosphere;
The mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane- 8-carboxylate (200 mg, 0.786 mmol), 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate, xantphos (45.5 mg, 0.079 mmol), water (0.043 mL, 2.4 mmol) and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was degassed by nitrogen for 20 min followed by addition of palladium acetate (8.8 mg, 0.039 mmol). The resulting mixture was heated at 65 C for 16 h. After filtration the filtrate was concentrated and the residue was purified on silica gel column eluting with EtOAc/hexane to give title compound. LC/MS: (M+l)+:365.20.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 65℃; for 16h;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (200 mg, 0.786 mmol), 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate, Xantphos (45.5 mg, 0.079 mmol), water (0.043 mL, 2.4 mmol) and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was degassed by nitrogen for 20 min followed by addition of palladium acetate (8.8 mg, 0.039 mmol). The resulting mixture was heated at 65 C for 16 h. After filtration the filtrate was concentrated and the residue was purified on silica gel column eluting with EtOAc/hexane to give the title compound. LC/MS: (M+l)+:365.20.
With water; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 65℃;Inert atmosphere;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol). The resulting mixture was heated at 65 C overnight. After filtration through celite, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+l)+: 355.15.
With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 65℃;Inert atmosphere;
A mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol). The resulting mixture was heated at 65 C overnight. After filtration through CELITE, the filtrate was concentrated and the residue was purified on silica gel column using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+l)+: 355.15.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 18h;Inert atmosphere;
fert-Butyl 2-(4-methyl-5-oxo-2.5-dihydrofuran-3-yl)-l-oxo-2.8-diazaspiro[4.5]decane-8- carboxylate: To a mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (INTERMEDIATE 11, 80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (INTERMEDIATE 9, 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), Cs2C03 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The resulting reaction mixture was heated to 90 C and stirred under N2 for 18 h. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by precipitation to give tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-l-oxo- 2,8-diazaspiro[4.5]decane-8-carboxylate. 1H-NMR (400 MHz, CDC13) delta 5.23 (s, 2H), 4.02-3.99 (m, 4H), 3.06-3.05 (m, 2H), 2.15-2.11 (m, 2H), 2.02 (s, 3H), 1.87-1.81 (m, 2H), 1.51-1.41 (m, 1H)
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 18h;Inert atmosphere;
To a mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I- 1 1 , 80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (1-9, 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), CS2CO3 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The resulting reaction mixture was heated to 90 C and stirred under N2 for 18 h. The mixture was filtered through a pad of CELITE and the filtrate was concentrated. The residue was purified by precipitation to give tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)- 1 -oxo-2,8-diazaspiro[4.5]decane-8- carboxylate. 1H NMR (400 MHz, CDCI3) delta 5.23 (s, 2H), 4.02-3.99 (m, 4H), 3.06-3.05 (m, 2H), 2.15-2.11 (m, 2H), 2.02 (s, 3H), 1.87-1.81 (m, 2H), 1.51-1.41 (m, 11H)
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 18h;Inert atmosphere;
Step A: tert-Butyl 2-(4-methyl-5-oxo-2,5-dihvdrofuran-3-yl)-l-oxo-2,8-diazaspiror4.51decane-8- carboxylate: To a mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1-55, 80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (1-53, 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), and Cs2C03 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The reaction mixture was heated at 90 C under N2 for 18 h, then filtered through a pad of CELITE. The filtrate was concentrated. The residue was purified via crystallization to give the title compound. 1H NMR (400 MHz, CDC13) delta 5.23 (s, 2 H), 4.02-3.99 (m, 4 H), 3.06-3.05 (m, 2 H), 2.15-2.11 (m, 2 H), 2.02 (s, 3 H), 1.87-1.81 (m, 2 H), 1.51-1.41 (m, 11 H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 18h;Inert atmosphere;
Step E: tert-Butyl 2-(4-methyl-5-oxo-2.5-dihydrofuran-3-yl)-1-oxo-2.8-diazaspiro[4.5ldecane-8- carboxylate:To a mixture of <strong>[268550-48-7]tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (80.0 g, 315 mmol) and 4-methyl-5 -oxo-2, 5 -dihydrofuran-3 -yl trifluoromethanesulfonate (Tnt. 1; 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), and Cs2CO3 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The reaction mixture was heated at 90 C under N2 for 18 h, filtered through a pad of CELITE. The filtrate was concentrated. The residue waspurified via crystallization to give the title compound. ?H NIVIR (400 IVIHz, CDC13) 5.23 (s, 2H), 4.02-3.99 (m, 4 H), 3.06-3.05 (m, 2 H), 2.15-2.11 (m, 2 H), 2.02 (s, 3 H), 1.87-1.81 (m, 2 H),1.51-1.41 (m, 11 H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 18h;Inert atmosphere;
To a mixture of tert-butyl l-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (80.0 g, 315 mmol) and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int. 1; 85.2 g, 346 mmol), Xantphos (13.6 g, 23.6 mmol), and Cs2C03 (153.7 g, 471.8 mmol) in toluene (1200 mL), was added Pd2(dba)3 (7.20 g, 7.86 mmol) under N2. The reaction mixture was heated at 90 C under N2 for 18 h, filtered through a pad of CELITE. The filtrate was concentrated. The residue was purified via crystallization to give the title compound. 1H NMR (400 MHz, CDC13) delta 5.23 (s, 2 H), 4.02-3.99 (m, 4 H), 3.06-3.05 (m, 2 H), 2.15-2.11 (m, 2 H), 2.02 (s, 3 H), 1.87-1.81 (m, 2 H), 1.51-1.41 (m, 11 H)
With ammonium hydroxide; hydrogen; In methanol; at 50℃; under 15001.5 Torr; for 18h;
A suspension of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and Eta320 (80 mL) was stirred at 2 MPa of hydrogen pressure at 50 C for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give the title compound. 1H-NMR (400 MHz, CDC13) delta 6.05 (s, 1H), 4.0 (s, 2H), 3.37- 3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.08-2.05 (m, 2H), 1.88-1.87 (m, 2H), 1.51-1.41(m, 11H)
With ammonium hydroxide; hydrogen; In methanol; at 50℃; under 15001.5 Torr; for 18h;
A suspension of 1 -tert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and NuEta320 (80 mL) was stirred at 2 MPa of hydrogen pressure at 50 C for 18 h. The reaction mixture was filtered through a pad of CELITE and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give the title compound. 1H-NMR (400 MHz, CDC13) delta 6.05 (s, 1H), 4.0 (s, 2H), 3.37- 3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.08-2.05 (m, 2H), 1.88-1.87 (m, 2H), 1.51-1.41(m, 11H)
With ammonium hydroxide; hydrogen; In methanol; at 50℃; under 15001.5 Torr; for 18h;
Step D: tert-Butyl l-oxo-2,8-diazaspiror4.51decane-8-carboxylate To a solution of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (350 g, 1.2 mol) in MeOH (6000 mL) were added NH3 H20 (400 mL) and Raney-Ni (300 g) at rt. The mixture was stirred under 2 MPa of hydrogen at 50 C for 18 h, and filtered. The filtrate was concentrated. The crude product was washed with EtOAc to give the title compound. 1H-NMR (400 MHz, CDCI3) delta 6.30 (s, 1 H), 4.08-3.92 (m, 2 H), 3.38-3.30 (m, 2 H), 3.01-2.91 (m, 2 H), 2.10-2.00 (m, 2 H), 1.88-1.78 (m, 2 H), 1.49-1.32 (m, 11 H).
With hydrogen; ammonium hydroxide; In methanol; at 50℃; under 15001.5 Torr; for 18h;
Step B: tert-butyl 1-oxo-2,8-diazaspiro[4.Sldecane-8-carboxylate: A suspension of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and NH3H2O (80 mL) was stirred at 2 MPa of hydrogen pressure at 50o . .C for 18 h. The reaction mixture was filtered through a pad of CELITE and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give the title compound. ?H-NMR (400 MHz, CDC13) oe 6.05 (s, 1H), 4.0 (s, 2H), 3.37- 3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.08-2.05 (m, 2H), 1.88-1.87 (m, 2H), 1.51-1.41(m, 11H).
With ammonium hydroxide; hydrogen; nickel; In methanol; at 50℃; under 15001.5 Torr; for 18h;
Step D: tert-Butyl 1 -oxo-2. 8-diazaspiro[4.5 ldecane-8-carboxylateTo a solution of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (350 g, 1.2 mol) in MeOH (6000 mL) were added NH3H20 (400 mL) and Raney-Ni (300 g) at rt. The mixture was stirred under 2 MPa of hydrogen at 50 C for 18 h, and filtered. The filtrate wasconcentrated. The crude product was washed with EtOAc to give the title compound. ?H-NIVIR (400 MFIz, CDC13) 6.30 (s, 1 H), 4.08-3.92 (m, 2 H), 3.38-3.30 (m, 2 H), 3.01-2.91 (m, 2 H), 2.10-2.00(m,2H), 1.88-1.78(m,2H), 1.49-1.32(m, 11 H).
With ammonium hydroxide; hydrogen; In methanol; at 50℃; under 15001.5 Torr; for 18h;
To a solution of 1-fert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (350 g, 1.2 mol) in MeOH (6000 mL) were added NuEta320 (400 mL) and Raney-Ni (300 g) at rt. The mixture was stirred under 2 MPa of hydrogen at 50 C for 18 h, and filtered. The filtrate was concentrated. The crude product was washed with EtOAc to give the title compound. 1H-NMR (400 MHz, CDCI3) delta 6.30 (s, 1 H), 4.08-3.92 (m, 2 H), 3.38-3.30 (m, 2 H), 3.01-2.91 (m, 2 H), 2.10-2.00 (m, 2 H), 1.88-1.78 (m, 2 H), 1.49-1.32 (m, 11 H).
With ammonium hydroxide; hydrogen; In methanol; at 50℃; under 15001.5 Torr; for 18h;
A suspension of 1-tert-butyl 4-methyl 4-(cyanomethyl) piperidine-1, 4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and NH3·H2O (80 mL) was stirred at 2 MPa of hydrogen at 50 for 18 h. The reaction mixture was filtered through a pad of and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give title compound. 1H-NMR (400 MHz, CDCl3) delta 6.05 (s, 1H) , 4.0 (s, 2H) , 3.37-3.34 (m, 2H) , 3.02-2.96 (m, 2H) , 2.08-2.05 (m, 2H) , 1.88-1.87 (m, 2H), 1.51-1.41 (m, 11H) .
With ammonium hydroxide; hydrogen; In methanol; at 50℃; under 15001.5 Torr; for 18h;
To a solution of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (350 g, 1.2 mol) in MeOH (6000 mL) were added H3 H20 (400 mL) and Raney-Ni (300 g) at rt. The mixture was stirred under 2 MPa of hydrogen at 50C for 18 h, and filtered. The filtrate was concentrated. The crude product was washed with EtOAc to give the title compound. 1H-NMR (400 MHz, CDC13) delta 6.30 (s, 1 H), 4.08-3.92 (m, 2 H), 3.38-3.30 (m, 2 H), 3.01-2.91 (m, 2 H), 2.10-2.00 (m, 2 H), 1.88- 1.78 (m, 2 H), 1.49-1.32 (m, 11 H).
With ammonium hydroxide; In methanol; at 50℃; under 15001.5 Torr; for 18h;
A suspension of 1-tert-butyl 4-methyl 4-(cyanomethyl)piperidine-l,4-dicarboxylate (70.0 g, 247.9 mmol) and Raney Ni (60 g) in MeOH (1500 mL) and NH3 H20 (80 mL) was stirred at 2 MPa of hydrogen at 50C for 18 h. The reaction mixture was filtered through a pad of CELITE and the filtrate was concentrated under vacuum to give a crude product, which was washed with ethyl acetate (200 mL) to give title compound. 1H-NMR (400 MHz, CDC13) delta 6.05 (s, 1H), 4.0 (s, 2H), 3.37-3.34 (m, 2H), 3.02-2.96 (m, 2H), 2.08-2.05 (m, 2H), 1.88-1.87 (m, 2H), 1.51-1.41(m, 11H).
With 1-methyl-pyrrolidin-2-one; triethylamine; at 220℃; for 2h;Microwave irradiation; Inert atmosphere;
4,5-Dichloro-3-fluoropyridin-2-amine (100 mg, 0.55 mmol) and <strong>[268550-48-7]tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (211 mg, 0.83 mmol) were introduced in a microwave vial and then NMP (1.4 mL) was added. The vial was sealed and placed under high vacuum until effervescence ceased. After three vacuum/argon cycles, triethylamine (230 muL, 1 .69 mmol) was added and the reaction mixture was heated in the microwave at 220 C for 2 h. The reaction mixture was concentrated and the crude was purified by chromatography on silica gel (DCM/EtOH) ]p give the title compound (105 mg, 64%) as a white solid. 1H NMR (500 MHz, DMSO-d6) ppm = 7.67 (s, H), 7.59 (s, 1 H), 6.17 (s, 2H), 3.34 - 3.27 (m, 2H), 3.19 (t, J=6.8, 2H), 3.12-3.05 (m, 2H), 2.01 (t, J=6.8, 2H), 1.83 - 1.76 (m, 2H), 1.44-1.38 (m, 2H). LC - MS (ESI, m/z) Rt = 1.73 min - 299 (M+H)+ (HPLC method B).
With 1-methyl-pyrrolidin-2-one; triethylamine; at 220℃; for 1h;Microwave irradiation; Inert atmosphere;
5-Bromo-3,4-dichloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (225 mg, 0.70 mmol) and 8- boc-2,8-diaza-spiro-[4.5]decan-1-one (197 mg, 0.77 mmol) were loaded in a microwave vial. The capped vial was evacuated using high vacuum and purged with nitrogen (each three times). Triethylamine (0.27 mL, 2.11 mmol) and NMP (2.3 mL) were added and the mixture was degassed by using the high vacuum and purged with nitrogen three times. The reaction mixture was heated in the microwave at 220 C for 1 h before it was cooled and dropped in vigorously stirred water (8 mL). The resulting precipitate was filtered off and the residue was purified by chromatography on silica gel (dichloromethane/ethanol) to give the title compound as a light brown solid (153 mg, 50%). 1H-NMR (500 MHz, CDCl3) ppm = 8.47 (s, 1H), 6.53 (bs, 1 H), 5.90 (s, 2H), 3.52 - 3.32 (m, 6H), 2.25 - 2.10 (m, 4H), 2.01 (s, 6H), 1.58 (d, J=13.0, 2H). HRMS m/z (ESI+) [M+H]+ C19H22BrClN4O, calc 437.0738, found 437.0733, Rt = 3.05 min (HPLC method B).
With 1-methyl-pyrrolidin-2-one; triethylamine; at 220℃; for 1h;Microwave irradiation;
(5-Bromo-3,4-dichloro-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine (1.60 g, 3.32 mmol), 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.52 g, 5.97 mmol) and triethylamine (0.755 g, 7.47 mmol) in NMP (10 mL) were heated in a microwave vial for 60 min at 220 C. The mixture was poured in water (600 mL), the formed precipitate was filtered and washed. The residue was purified using flash chromatography (petroleum ether/ethyl acetate). 1.08 g (1.80 mmol, 54%) of a colorless solid was obtained.
With triethylamine; at 220℃; for 2h;Microwave irradiation; Inert atmosphere;
A mixture of 5-bromo-4-chloro-3-(trifluoromethyl)pyridin-2-amine (87.0 mg, 0.316 mmol), <strong>[268550-48-7]tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate</strong> (241 mg, 0.948 mmol) and triethylamine (0.044 mL, 0.316 mmol) in 2-methoxy-2-isopropanol (1 mL) was reacted for 2 h at 220 C in the microwave under nitrogen atmosphere. The solvent was evaporated and the crude purified by flash chromatography (DCM/MeOH) to give the title compound (35.0 mg, 28%) as a pale yellow solid. 1H-NMR (500 MHz, CDCl3) ppm = 8.19 (s, 1 H), 5.75 (s, 1 H), 5.24 - 4.92 (m, 2H), 3.37 (t, J=6.7, 2H), 3.67 - 2.80 (m, 4H), 2.16 (t, J=6.7, 2H), 2.15 - 2.05 (m, 2H), 1.47 (d, J=13.8, 2H). HRMS m/z (ESI+) [M+H]+ C14H17BrN4O calc 393.0532, found 393.0535, Rt = 2.51 min (HPLC method B).
With 1-methyl-pyrrolidin-2-one; potassium fluoride; triethylamine; at 220℃; for 2h;Microwave irradiation; Inert atmosphere;
5-Bromo-3,4-dichloropyridin-2-amine (300 mg, 1.24 mmol), 8-boc-2,8-diaza-spiro-[4.5]decan-1-one (347 mg, 1.36 mmol) and potassium fluoride (144 mg, 2.48 mmol) were loaded in a microwave vial. The capped vial was evacuated using high vacuum and purged with nitrogen (each three times). Triethylamine (0.48 mL, 3.72 mmol) and NMP (3 mL) were added and the mixture was degassed using high vacuum and purged with nitrogen three times. The reaction mixture was heated in the microwave at 220 C for 2 2966 hr, cooled and then ethyl acetate and water were added and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgS04, filtered and the solvent was evaporated under reduced pressure. The resulting precipitate was purified by chromatography on silica gel (dichloromethane/ethanol) to give the title compound as a white solid containing 5% of NMP (260 mg, 60%). 1H-NMR (500 MHz, DMSO-d6) ppm = 7.92 (s, 1 H), 7.59 (s, 1 H), 6.34 (bs, 2H), 3.27 - 2.99 (m, 6H), 2.01 (t, J=6.8, 2H), 1.93 - .79 (m, 2H), 1.43 - 1.37 (m, 2H). HRMS m/z (ESI+) [M+H]+ C13H17BrClN4O, calc 359.0269, found 359.0268, Rt= 2.05 min (HPLC method B).
Step A: 2,8-diazaspiro[4.Sldecan-1-one hydrochloride: To a solution of tert-butyl 1-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (Inermediate 14, 92 g, 0.36 mol) in CH2C12 (1 L) was slowly added a 4 M HC1 solution (500 mL). The mixture was stirred for 8 h at RT. The mixture was concentrated under vacuum to afford the title compound. ?H NMR (400 MHz, DMSO-d6) oe 9.35 (s, 1H), 9.02 (s, 1H), 7.72 (s, 1H), 3.30-3.20 (m, 2H), 3.16 (m,J= 6.8Hz, 2H), 2.98-2.85(m, 2H), 1.96 (m,J= 6.8Hz, 2H), 1.90-1.80 (m, 2H), 1.55 (d,J 14Hz, 2H).
240 mg
With hydrogenchloride; In ethanol; ethyl acetate; at 60℃; for 2h;
C) 2,8-diazaspiro[4.5]decan-1-one hydrochloride To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg), ethyl acetate (10 mL) and ethanol (2.0 mL) was added 4 M hydrogen chloride/ethyl acetate solution (5.0 mL) at room temperature, the mixture was stirred at 60C for 2 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the obtained solid was collected by filtration to give the title compound (240 mg). 1H NMR (300 MHz, CDCl3) delta 1.47-1.64 (2H, m), 1.77-1.92 (2H, m), 1.93-2.03 (2H, m), 2.81-3.03 (2H, m), 3.11-3.34 (4H, m), 7.72 (1H, brs), 8.62-9.33 (2H, m).
With hydrogenchloride; In dichloromethane; ethyl acetate; at 20℃; for 8h;
To a solution of tert-butyl l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (INTERMEDIATE 14) (92 g, 0.36 mol) in CH2C12 (1 L) was slowly added a 4 M HC1 solution in EtOAc (500 mL). The mixture was stirred for 8 h at rt. The mixture was concentrated under vacuum to afford the title compound. 1H-NMR (400 MHz, DMSO-d6): delta 9.35 (s, 1H), 9.02 (s, 1H), 7.72 (s, 1H), 3.30-3.20 (m, 2H), 3.16 (m, J = 6.8Hz, 2H), 2.98-2.85 (m, 2H), 1.96 (m, J = 6.8Hz, 2H), 1.90-1.80 (m, 2H), 1.55 (d, J = 14 Hz, 2H).
tert-butyl 2-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90.0℃;Sealed tube;
To a reaction flask was charged tert-butyl 1-oxo-2, 8-diazaspiro [4.5] decane-8-carboxylate (2.00 g, 7.86 mmol) , 6-bromo-2-methylpyridazin-3 (2H) -one (1.64 mg, 8.65 mmol) , Pd2 (dba) 3 (180 mg, 0.197 mmol) , Xantphos (341 mg, 0.590 mmol) , and Cs2CO3 (5.12 g, 15.7 mmol) . The flask was sealed, degased, and filled with anhydrous dioxane (26 mL) . The reaction mixture was heated at 90 overnight, diluted with EtOAc and DCM, then filtered throughAfter solvent evaporation, the crude product was purified by silica gel column chromatography (0-10 MeOH/DCM as eluent) to afford the title compound.[0436]LC/MS: (M+1) +: 363.0. 1H NMR (500 MHz, CDCl3) , delta 8.50 (d, J 10.0 Hz, 1H) , 6.97 (d, J 10.0 Hz, 1H), 4.02 (br s, 2H) , 3.86 (t, J 7.0 Hz, 2H) , 3.74 (s, 3H) , 3.05-3.00 (m, 2H) , 2.06-2.02 (m, 2H) , 1.98-1.94 (m, 2H) , 1.58-1.50 (m, 2H) , 1.49 (s, 9H) .
tert-butyl 2-(4-bromo-3-methoxyphenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Sealed tube; Inert atmosphere;
in a sealable reaction tube was added i-brorno-4-iodo-2-rnethoxybenzene (2461 mg, 7.86 mrnol). tert-butyl I -oxo-2.8-diazaspiro[4.5] decane-8-carboxyiate (1000 mg, 3.93 mrnol), cesium carbonate (2562 mg, 7.86 rnrnol) and dioxane (7864 il). The reaction was purged with nitrogen. Then 9,9-dimethyi-4,5- bis(diphenyiphosphino)xanihene (341 rng, 0.590 mmol), Pd2(dba)3 (180 rng, 0.197 mrnoi)was added and nitrogen was bubbled through reaction for I mm. The reaction wassealed and stirred at 100 C overnight. The reaction was partitioned between EtOAc(50 ml) and water (30 ml). The organic layer was separated, washed with water (2 x 30m1) and brine (30 ml). dried over MgSO4, filtered and concentrated. The residue was purified using ISCO system (0-100% EtOAc/Hex gradient) to give tert-butyl 2-(4-bromo-3- rnethoxvphenyi)-i-oxo-2,8-diazaspiro[45]decane-8-carboxyiate (1.6 g, 364 mrnoi, 93 %yield) as a beige solid. ?H NMR (500MHz, DM50-do) d 7.67 (d, .J=2.2 Hz, 1H), 755(d, J=8.5 Hz, IH), 7.12 (dd, J=8.8, 2.5 Hz, 1H), 3.96 - 3.78 (m, 7H), 3.10 -2.84 (rn, 2H),2.10 (t. J=6.9 Hz, 21-1), 1.62 (dd, J=12.0, 4.0 Hz. 21-1), 1.51 (d, J=i3.5 Hz, 2F1), 1.42 (s,9H). MS (ESI) m/-: 43c.0, 441.0 (M+H).
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