| 90% |
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -60 - 20℃; |
|
| 89% |
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃; |
|
| 85% |
With pyridinium chlorochromate In dichloromethane at 20℃; for 6h; |
|
| 85% |
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; Sodium hydrogenocarbonate; sodium chloride; potassium bromide In dichloromethane; water monomer at 0℃; for 1.16667h; |
|
| 85% |
With sodium chlorine monoxide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; Sodium hydrogenocarbonate; sodium chloride; potassium bromide In dichloromethane; water monomer at 0℃; for 1.16667h; |
|
| 81% |
With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 10 - 20℃; for 1.5h; |
|
| 80% |
With sulphur trioxide pyridine complex; dimethyl sulfoxide; triethylamine |
|
| 71% |
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.25h;
Stage #2: With triethylamine In dichloromethane at -78 - 0℃; for 0.5h; |
|
| 66% |
With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 2h; |
18-1 tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate
To a solution of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (6.87 g, 30 mmol) in DCM (100 mL) was added PCC (9.72 g, 45 mmol) at 0. The reaction mixture was allowed to stir at rt for 2h and then concentrated under reduced pressure to give crude product which was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc 20/1 to 5/1) to afford tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (4.5 g, 66) . LRMS m/z (M-100) 128.1 found, 128.1 required. |
| 60% |
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 5h; |
Step 2: tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (LXXII)
To a stirred solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (LXXI, 1.5 g, 6.55 mmol) in dry dichloromethane (40 mL) was added Dess-Martin periodinane (3.3 g, 7.86 mmol) at 0 °Cand the resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with 10 % sodium thiosulphate solution (20 mL) and saturated sodium bicarbonate solution (20 mL) and then extracted with dichloromethane (2 x 50 mL).The organic portion was washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulphate and concentrated under reduced pressure to afford the product as yellow semi-solid (LXXII, 0.9 g, 60 %). |
| 40% |
With Dess-Martin periodane In dichloromethane at 20℃; for 2h; |
|
|
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, -78 deg C, 20 min, 2.) CH2Cl2, from -78 deg C to RT, 1.5 h; Multistep reaction; |
|
|
With oxalyl dichloride; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane |
|
|
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane for 3h; |
tert-Butyl 4-(formylmethyl)piperidine-1-carboxylate: To a flask containing tert-butyl 4-(2 hydroxyethyl)piperidine-1-carboxylate (4.4 g, 19.2 mmol) in CH2Cl2 (20 mL) was added TEMPO (300 mg, 1.92 mmol) followed by iodobenzene diacetate (6.8 g, 21.1 mmol). The reaction was stirred 3 hours and then diluted with CH2Cl2 (100 mL). Saturated aqueous solution of Na2S2O3 (100 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organics were washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40-70% Et2O/pentanes) to provide the title compound, which was identical to the reported literature compound (see Sato et al. (2001) Heterocycle 54: 747). 13C NMR (75 MHz, CDCl3) 201.5, 154.7, 79.4, 50.3, 43.7, 31.9, 30.6, 28.4. |
|
With pyridinium chlorochromate In dichloromethane; ethyl acetate |
268.B B.
B. 1-(tert-Butoxycarbonyl)piperidine-4-acetaldehyde A solution of 1-(tert-butoxycarbonyl)piperidine-4-ethanol (5.0 g, 22 mmol) in methylene chloride (100 mL) was treated with pyridinium chlorochromate (5.2 g, 24 mmol), and diatomaceous earth (5 g). After 3 days, the mixture was filtered through diatomaceous earth, concentrated, and the residue purified by column chromatography (SiO2: 20 to 30% EtOAc:hexanes) affording 4.0 g (81%) of the title compound. 1NMR; IS-MS, m/e 228 (m+1). |
|
With pyridine-SO3 complex; triethylamine In dichloromethane; dimethyl sulfoxide for 2h; |
8.A
Example 8 fert-Butyl 4-[2-hydroxy-2-(4-oxo-2-phenyl-455-dihydro-2i-7-pyrazolo[354-c]quinolin-l- yl)ethyl]piperidine- 1 -carboxylatePart A To a mixture of tert-hvXy 4-(2-hydroxyethyl)ρiperidine-l -carboxylate (3.4 g, 15 mmol) and dichloromethane (18 mL) at 0 °C was added triethyl amine (10 mL), dimethyl sulfoxide (18 mL), and sulfur trioxide pyridine (5.9 g, 37 mmol). The reaction was stirred 2 hours before diluting with ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to 3.3 g of tert-hvXy 4-(2-oxoethyl)piperidine-l -carboxylate as a colorless oil. |
|
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 1h;
Stage #2: With anhydrous sodium carbonate In dichloromethane; water monomer |
b; 20.C
Trichloroisocyanuric acid (2.66 g, 11.46 mmol) is added to a solution of the alcohol (2.39 g, 10.42 mmol) in DCM, and the solution is stirred and maintained at 0° C., followed by addition of a catalytic amount of TEMPO. After the addition, the mixture is warmed to room temperature and stirred for an hour and then filtered on Celite. The organic phase is washed with saturated aqueous Na2CO3, followed by 1N HCl and brine. The organic layer is dried (MgSO4), and the solvent is evaporated to yield 20-C. 1H-NMR (CDCl3, 400 MHz) δ 9.72 (1H, s), 4.07-4.01 (2H, m), 2.70-2.57 (2H, m), 2.35-2.31 (2H, m), 2.05-1.94 (1H, m), 1.64-1.46 (2H, m), 1.39 (9H, s), 1.30-1.02 (2H, m). |
|
With trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 1h; |
1.b
1-C: Trichloroisocyanuric acid (2.66 g, 11.46 mmol) is added to a solution of the alcohol 1-B (2.39 g, 10.42 mmol) in DCM, and the solution is stirred and maintained at 0 C., followed by addition of a catalytic amount of TEMPO. After the addition, the mixture is warmed to room temperature and stirred for an hour and then filtered on Celite. The organic phase is washed with saturated aqueous Na2CO3, followed by 1N HCl and brine. The organic layer is dried (MgSO4) and the solvent is evaporated to give 1-C. 1H NMR (CDCl3, 400 MHz) ? 9.72 (1H, s), 4.07-4.01 (2H, m), 2.70-2.57 (2H, m), 2.35-2.31 (2H, m), 2.05-1.94 (1H, m), 1.64-1.46 (2H, m), 1.39 (9H, s), 1.30-1.02 (2H, m). |
|
With oxalyl dichloride; triethylamine In dichloromethane; dimethyl sulfoxide at -78 - 20℃; for 5h; |
|
|
With trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 1h; |
b
Trichloroisocyanuric acid (2.66 g, 11.46 mmol) is added to a solution of the alcohol (2.39 g, 10.42 mmol) in DCM, and the solution is stirred and maintained at 0 0C, followed by addition of a catalytic amount of TEMPO. After the addition, the mixture is warmed to room temperature and stirred for an hour and then filtered on Celite. The organic phase is washed with saturated aqueous Na2Cθ3, followed by IN HCL and brine. The organic layer is dried (MgSO4) and the solvent is evaporated to give 4-C. 1H NMR (CDCI3, 400 MHz) δ 9.72 (IH, s), 4.07-4.01 (2H, m), 2.70-2.57 (2H, m), 2.35-2.31 (2H, m), 2.05- 1.94 (IH, m), 1.64-1.46 (2H, m), 1.39 (9H, s), 1.30-1.02 (2H, m). |
|
With trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 1h; |
b
Trichloroisocyanuric acid (2.66g, 11.46 mmol) is added to a solution of the alcohol (2.39g, 10.42 mmol) in CH2Cl2, and the solution is stirred and maintained at 0 0C, followed by addition of a catalytic amount of TEMPO. After the addition, the mixture is warmed to room temperature and stirred for an hour and then filtered on Celite. The organic phase is washed with saturated aqueous Na2CO3, followed by IN HCl and brine. The organic layer is dried (MgSO4) and the solvent is evaporated to give compound 8-C. 1H NMR (CDCl3, 400 MHz) δ 9.72 (IH, s), 4.07-4.01 (2H, m), 2.70-2.57 (2H, m), 2.35-2.31 (2H, m), 2.05-1.94 (IH, m), 1.64-1.46 (2H, m), 1.39 (9H, s), 1.30-1.02 (2H, m). |
|
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.666667h;
Stage #2: With triethylamine In dichloromethane at -78 - 30℃; for 5h; |
1.1
Dimethyl sulfoxide (7.43 mL, 0.105 mol) was added to oxalyl chloride (5.53 mL, 0.0654 mol) in methylene chloride (244.2 mL) at -78 0C. After 10 min, tert-butyl 4-(2-hydroxyethyl)piperidine- 1 - carboxylate (10.0 g, 0.0436 mol) in methylene chloride (488.4 mL) was added and the resultant mixture was stirred at -78 0C for 30 min. Triethylamine (30.4 mL, 0.218 mol) was then added and the mixture was stirred for 5 h with the temperature allowed to gradually warm up to room temperature. After being quenched with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over MgSO/t, evaporated to dryness and used directly in next step. LCMS (M+Na) 250.0. |
|
With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 2h; |
|
|
With sulphur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 20℃; for 0.5h; |
21
Reference Example 21 8.60 ml of di-tert-butyl dicarbonate was added to a solution of 5.00 g of 2-piperidin-4-ylethanol in 50 ml of tetrahydrofuran, followed by stirring at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 8.80 g of an oil. The oil was dissolved in 60 ml of dimethylsulfoxide, and the resulting solution was added 20.5 ml of triethylamine and 12.2 g of sulfur trioxide-pyridine complex, followed by stirring at ambient temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 6.40 g of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate. _ |
|
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 2h; |
5.1
70.9 g (167 mmol) of 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin reagent) are added portionwise to a solution, cooled to 0° C., of 30.4 g (132 mmol) of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate in 150 ml of dichloromethane. The mixture is stirred at ambient temperature for 2 hours, then 150 ml of a 10% aqueous sodium thiosulphate (Na2S2O3) solution are added and stifling is continued for an additional 30 minutes. The organic phase is separated by settling, washed with a saturated aqueous sodium carbonate solution, dried over sodium sulphate and evaporated to dryness to produce 30.1 g (132 mmol) of product in the form of a colourless oil used as is in the following stage. |
|
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1.5h;
Stage #2: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester In dichloromethane at -78℃; for 1.33333h;
Stage #3: With triethylamine more than 3 stages; |
14 Example 14; [1- [1-OXO-3- (5,] 6,7, [8-TETRAHYDRO-1,] 8-naphthyridin-2-yl) [PROPYL]-D-PHENYL-4-] piperidinebutanoic acid (Cpd 13)
Di-tert-butyl dicarbonate (41.25g, 189 mmol) was added in one portion to a solution of 4- (2-hydroxyethyl) piperidine Compound 14a (24.42g, 189 mmol) in DMF (200 mL) at [0 °C.] After 1 hour, the cooling bath was removed and the reaction mixture was allowed to stir for 20 h at RT. The reaction mixture was treated with Et2O (200 [ML)] and [H20] (500 mL). The organic layer was separated, washed with sat NH4C1 (200 mL) and brine (200 mL) and dried [MGS04).] After filtration and evaporation, Compound 14b was obtained as a transparent oil and used as such without further purification. A solution of DMSO (14g, 179 mmol) in DCM (80 mL) was added dropwise over a period of 1.5 h to a 2M solution of oxalyl chloride (62.8mL, 125.6 mmol) in dry DCM (200 mL) [AT-78 °C,] such that the temperature did not [EXCEED-60 °C.] A solution of Compound 14a in DCM (30 mL) was added dropwise at-78°C over a 50 min period. After stirring 30 min [AT-78 °C,] the cooling bath was removed and the temperature of the reaction mixture was allowed to rise to-30 °C over a 30 min period. TEA (25.41 g, 251 mmol) was added and the reaction mixture was allowed to stir for lh at rt. The solid precipitate that had formed was removed by filtration and the filtrate was washed with 0.3N [HC1] (2 x [100] mL) and brine (200 mL). The organic phase was dried [(NA2SO4),] evaporated and the residue was purified via flash column chromatography (eluent gradient : hexane/EtOAc 100/0 to 70/30) to yield Compound 14c. A 1M solution [OF LIHMDS] (73 mL, 73 mmol) was added via syringe to a solution of trimethyl phosphonoacetate (13.29g, 73 mmol) in THF (200 mL) at-78°C under argon. The reaction mixture was then stirred for 20 min at-78°C and a solution of Compound 14c (8.3g, 36.5 mmol) in THF (50 mL) was added over a 30 min period. After stirring for 15 min [AT-78 °C,] the cooling bath was removed and the reaction mixture was heated to reflux for 2. The reaction mixture was allowed to cool to room temperature and a saturated [NH4CL] solution (40 mL) was added. [ET20] (200 mL) was added, the organic layer was separated and washed with brine (140 mL) and dried [(NA2S04).] After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient : hexane/EtOAc: 100/0 to 85/15), yielding a mixture of [E-AND] Z- isomers of Compound 14d. Compound 14d, phenyl boronic acid [(1.] [55G,] 12.32 mmol), [RhCl (Cod) ] 2 [(0.] [LU ; 0.] 227 mmol) and Cod (0.557g, 5.15 mmol) were combined in [H20] [(15ML)] and heated to 100 [°C] for 3 h under a nitrogen atmosphere. Phenylboronic acid [(L.] [OG,] 8. 2 mmol) was added again and the reaction mixture was heated to [100 °C] for another 6 h. The reaction mixture was allowed to cool to rt, Et20 (100 mL) was added and the organic layer was separated. The aqueous layer was washed with [ET20] (2 x 100 mL) and the combined organic layers were dried [(NA2SO4),] filtered and evaporated. The residue was purified via flash column chromatography, yielding Compound 14e. TFA (6 mL) was added to a solution of Compound 14e (1.48 g, 4.09 mmol) in DCM (14 mL). The mixture was stirred at rt for 20 min, concentrated under vacuum and purified via RP-HPLC to yield Compound 14f as a trifluoroacetate salt. HOBt (0.333 g, 2.46 mmol), EDC (0.47 g, 2.46 mmol) and NMM (0.68 g, 5.28 mmol) were added to a solution of Compound 8a [(0. 64] g, 2.64 mmol) in DMF (30 mL) under argon. The mixture was stirred at rt for 1 h, then a solution of Compound 14f (0.66 g, 1.76 mmol) and NMM (0. [68] g, 5.28 mmol) in DMF (10 mL) was added. The resulting mixture was stirred overnight at rt. Water (2 mL) was added, followed by DCM (20 mL). The organic layer was separated, dried [(NA2SO4)] and concentrated. The resulting crude Compound 14g was used as such in the next reaction. To a solution of Compound 14g in dioxane (2 mL) and [H20] [(1] mL) was added [NAOH] (0.78g, 19. 5 mmol). The mixture was stirred at rt for 5 h and neutralized with 2N HCI. After the solvent was evaporated, the residue was purified by RP-HPLC to give Compound 13 after lyophilization |
|
With Dess-Martin periodane In dichloromethane at 20℃; for 1.5h; |
22.1
To a solution of ter£-butyl 4-(2-hydroxyethyl)piperidine-l-carboxylate (0.6 g, 2.6 mmol) in dichloromethane (30 mL) was added Dess-Martin-periodinane (1.2 g, 2.8 mmol), and the mixture was stirred at room temperature for 90 min. A 10% aqueous solution of sodium thiosulfate (15 mL) was added followed by saturated sodium bicarbonate (15 mL), and the biphasic mixture was stirred at room temperature for 1 h. The layers were separated, the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate,fltered and concentrated to afford tert-butyl 4-(oxoethyl)piperidine-l-carboxylate that was used directly without further purification |
|
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With Dess-Martin periodane In dichloromethane at 20℃; for 1.5h;
Stage #2: With sodium thiosulfate; Sodium hydrogenocarbonate In dichloromethane; water monomer at 20℃; for 1h; |
22.1
To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-l-carboxylate (0.6 g, 2.6 mmol) in dichloromethane (30 mL) was added Dess-Martin-periodinane (1.2 g, 2.8 mmol), and the mixture was stirred at room temperature for 90 min. A 10% aqueous solution of sodium thiosulfate (15 mL) was added followed by saturated sodium bicarbonate (15 mL), and the biphasic mixture was stirred at room temperature for 1 h. The layers were separated, the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate,fltered and concentrated to afford tert-butyl 4-(oxoethyl)piperidine-l-carboxylate that was used directly without further purification. |
|
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5h;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 5h; |
5.1
Dimethyl sulfoxide (7.43 mL, 0.105 mol) was added to oxalyl chloride (5.53 mL, 0.0654 mol) in DCM (244.2 mL) at -78 °C. After 10 min, tert-butyl 4-(2- hydroxyethyl)piperidine-l-carboxylate (from Aldrich, 10.0 g, 0.0436 mol) in DCM (488.4 mL) was added and the resultant mixture was stirred at -78 °C for 30 min. Triethylamine (30.4 mL, 0.218 mol) was then added and the mixture was stirred for 5 h and the temperature allowed to gradually warm up to RT. After being quenched with water, the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried, and evaporated to dryness. LCMS calculated for Ci2H2iN03Na(M+Na)+: m/z = 250.2; Found: 250.0. |
|
With Dess-Martin periodane In dichloromethane at 20℃; for 1.5h; |
22.1
To a solution of tert-butyl 4-(2-hydroxyethy Opiperidine- 1 -carboxylate (0.6 g, 2.6 mmol) in dichloromethane (30 mL) was added Dess-Martin-periodinane (1.2 g, 2.8 mmol), and the mixture was stirred at room temperature for 90 min. A 10% aqueous solution of sodium thiosulfate (15 mL) was added followed by saturated sodium bicarbonate (15 mL), and the biphasic mixture was stirred at room temperature for 1 h. The layers were separated, the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate.filtered and concentrated to afford tert-butyl 4-(oxoethy piperidine- 1 -carboxylate that was used directly without further purification. |
|
With Dess-Martin periodane In dichloromethane at 20℃; Inert atmosphere; |
|
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Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.833333h; Inert atmosphere;
Stage #2: With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; |
|
|
Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 1.33333h;
Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide at -78 - 20℃; for 2h; |
|
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With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 3h; |
|
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With pyridinium chlorochromate In dichloromethane at 20℃; for 3h; |
|
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Stage #1: 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -70℃; for 1h; Inert atmosphere; Schlenk technique;
Stage #2: With triethylamine In dichloromethane at -78 - 0℃; for 3.5h; Inert atmosphere; Schlenk technique; |
|
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With Dess-Martin periodane In dichloromethane at 20℃; for 2h; |
B Step B: synthesis of 2-(1-tert-butoxycarbonyl-4-piperidyl)acetaldehyde
2-(1-Tert-butoxycarbonyl-4-piperidyl)ethanol (4.89 g, 21.32 mmol) was dissolved in 50 mL dichloromethane, Dess-Martin oxidant (9.95 g, 23.46 mmol) was added in one portion. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured into a mixture of 250 mL 10% sodium thiosulfate aquesou solution and 150 mL saturated sodium bicarbonate aqueous solution and the mixture was stirred for 45 min. After that, the reaction mixture was extracted with dichloromethane (100 mL×3). The combined organic layer was washed with 150 mL saturated sodium bicarbonate aqueous solution and 150 mL saturated sodium chloride aqueous solution sequentially, dried over anhydrous sodium sulfate, filtered and the filtrate was concnetrated under vacuum to afford 2-(1-tert-butoxycarbonyl-4-piperidyl)acetaldehyde (4.85 g, crude), which was used in next step directly. |
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With phthalic acid dimethyl ester In dichloromethane at 25℃; for 1h; |
9.B Step B: tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate
To a solution of tert-butyl 4-(2- hydroxyethyl)piperidine-1-carboxylate (500 mg, 2.18 mmol) in DCM (10 mL) was addedDMP (1.39 g, 3.27 mmol). The reaction mixture was stirred at 25 °C for lh, then the reaction was quenched with NaOH (20 mL, 1M). The resulting mixture was stirred at 25 °C until thesolid dissolved, then extracted with DCM (20 mL x 3). The combined organic layers werewashed with brine (20 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give title compound, which was used for next step without further purification. MS(ESI) m/z: 213.1 [M-56+MeCN+Hj ‘H NMR (400 MHz, CDC13): & 9.78 (s, 1H), 4.16 - 4.00 (m, 1H), 2.83 -2.68 (m, 1H), 2.39 (d, J= 6.7 Hz, 2H), 2.13 - 1.99 (m, 1H), 1.70 (d, J=12.5 Hz, 1H), 1.46 (s, 9H), 1.25 - 1.12 (m, 1H) |
|
With Dess-Martin periodane In dichloromethane |
Synthesis of tert-butyl 4-(formylmethyl)-1-piperidinecarboxylate
Synthesis of tert-butyl 4-(formylmethyl)-1-piperidinecarboxylate To a solution of tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (1 eq.) in DCM is added DMP (2 eq.). The mixture is stirred at room temperature overnight. After aqueous work-up, the residue is purified by flash chromatography to yield the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3), δ (ppm): 9.78 (br s, 1H), 4.08 (br d, 2H), 2.74 (br t, 2H), 2.39 (d, 2H), 2.12-1.89 (m, 1H), 1.79-1.64 (m, 2H), 1.45 (s, 9H), 1.26-1.10 (m, 2H) |
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With oxalyl dichloride; dimethyl sulfoxide; triethylamine |
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