| 91% |
With potassium carbonate In methanol at 5 - 20℃; Cooling with ice; |
5.1 tert-butyl 4-ethynylpiperidine-1-carboxylate
Dissolve 4-formylpiperidine-1-carboxylic acid tert-butyl ester (10g, 46.95mmol) in a 500mL single-neck round bottom flask with 200mL methanol, and cool down to 5-10 in an ice water bath.Add (1-diazo-2-oxopropyl) dimethyl phosphonate (12.46g, 56.34mmol) and potassium carbonate (25.92,187.8mmol) in sequence, warm to room temperature and stir for 3-4 hours, monitored by TLC The reaction is over. Dilute with 200mL ethyl acetate, filter with a sand core funnel, wash the filter cake with 100mL ethyl acetate, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain tert-butyl 4-ethynylpiperidine-1-carboxylate. Ester (5a), colorless oil (8.92g, yield: 91%). |
| 88% |
With potassium carbonate In methanol at 20℃; |
23.3
At 0 C, to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 rng, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1:5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M - M3u + 2H). (J. Am. Chem. Soc. 2003, 125, 3714.) |
| 88% |
With potassium carbonate In methanol at 20℃; |
18.3
At 0 C, to a stirred mixture of 4-formyl-piperidine-1-carboxylic acid fert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)- phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1 :5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M - f-Bu + 2H). (J. Am. Chem. Soc. 2003, 725, 3714.) |
| 81% |
With potassium carbonate In methanol at 20℃; |
|
| 81% |
With potassium carbonate In methanol at 20℃; for 18h; |
General procedure for the synthesis of compound 9
A solution of compound 7 (0.1 g, 0.41 mmol) in methanolwas stirred at room temperature for 10 min. Then compound8 (95 mg, 0.49 mmol) and K2CO3 (113 mg, 0.82 mmol) were added and stirred at room temperature for 18 h. Thereaction mixture was filtered through a celite pad to removeK2CO3. The solvent was evaporated under vacuum. Thenwater was added and the product was extracted by ethylacetate (3 × 30 ml). The crude material was purified bycolumn chromatography to obtain product. Compound 9 Yield 81%, white solid powder; MS: [M+H]+ 210.09; 1H-NMR (400MHz, CDCl3-D) δ 3.72 (m, 2H),3.20 (m, 2H), 2.06 (s, 1H), 2.12 (d, J = 2.4 Hz, 1H), 1.81(m, 2H), 1.60 (m, 2H), 1.47 (s, 9H). 13C-NMR (100MHz,CDCl3-D) δ 154.8, 86.4, 79.5, 69.5, 31.2, 28.4, 26.7. |
| 55% |
With potassium carbonate In methanol for 20h; |
124.A
Example 124; Preparation of tert-butyl 4-(2-(7-(4-(1-(carbamoyl)cyclopropanecarboxamido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)ethynyl)piperidine-1-carboxylate; Step A: Preparation of tert-butyl 4-ethynylpiperidine-1-carboxylate; To a stirred suspension of tert-butyl 4-formylpiperidine-1-carboxylate (0.427 g, 2.00 mmol), K2CO3 (0.553 g, 4.00 mmol), and MeOH (25 mL) was added all at once the Bestman-Ohira reagent, dimethyl 2-oxo-1-diazo-propylphosphonate (0.461 g, 2.40 mmol, see Synthesis 2004, 1, 59-62). Stirring was continued for 20 hours under nitrogen. The reaction was diluted with Et2O (50 mL), washed with a 2:1 mixture of water and aqueous saturated NaHCO3 (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Yield: 253 mg (55%). 1H NMR (400 MHz, CDCl3) δ 3.72 (m, 2H), 3.19 (m, 2H), 2.58 (m, 1H), 2.10 (d, J=2 Hz, 1H), 1.77 (m, 2H), 1.61 (m, 2H), 1.46 (s, 9H). |
|
With potassium carbonate In methanol for 3h; |
|
|
Stage #1: 4-formyl-piperidine-1-carboxylic acid tert-butyl ester With potassium carbonate In methanol for 0.5h;
Stage #2: dimethyl 1-(1-diazo-2-oxopropyl)phosphonate In methanol for 12h; |
1.1D Example 1D tert-butyl 4-ethynylpiperidine-1-carboxylate
Example 1D tert-butyl 4-ethynylpiperidine-1-carboxylate To a solution of Example 1C (1 g, 4.69 mmol) in methanol (20 mL) was added potassium carbonate (3.89 g, 28.1 mmol) and the mixture was stirred for 30 minutes. Dimethyl 1-diazo-2-oxopropylphosphonate (3.60 g, 18.76 mmol) was added and the mixture was stirred for 12 hours. The mixture was filtered through diatomaceous earth with methanol, concentrated and purified by column chromatography on silica gel (Isco, Redi-Sep column), eluting with 15% ethyl acetate in hexane to afford the title compound. LCMS: 110 (M+H-Boc)+. |
|
With potassium carbonate In methanol at 20℃; |
21B tert-butyl 4-ethynylpiperidine-1-carboxylate
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2.2 g, 10.4 mmol) and potassium carbonate (2.9 g, 20.8 mmol) in methanol (100 mL) was added Example 21A (2.0 g, 10.4 mmol) in methanol (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate (twice). The combined organic layers were washed with brine and concentrated. Purification by flash chromatography on silica gel (Teledyne CombiFlash Rf, 1:5 ethyl acetate/hexane) gave the title compound. MS (DCI/NH3) m/z 210 (M+H)+. |
|
With potassium carbonate In methanol at 0℃; for 5h; |
|
|
With potassium carbonate In methanol |
|
|
With potassium carbonate In methanol at 0 - 25℃; for 12h; Inert atmosphere; |
45.1 Step 1:
tert-Butyl 4-ethynylpiperidine-1-carboxylate
To a mixture of tert-butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol, 1 eq), K2CO3 (1.30 g, 9.38 mmol, 2 eq) in MeOH (15 mL) was added a solution of 1-diazo-1-dimethoxyphosphoryl-propan-2-one (901.00 mg, 4.69 mmol, 1 eq) in MeOH (5 mL) at 0° C. Then the mixture was stirred at 25° C. for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc (30 mL) and H2O (20 mL) and extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ether gradient 30 mL/min) to yield tert-butyl 4-ethynylpiperidine-1-carboxylate (1 g, 4.41 mmol, 93.9% yield, 92.2% purity) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (d, J=6.8 Hz, 2H), 3.28-3.14 (m, 2H), 2.69-2.51 (m, 1H), 2.14 (d, J=2.2 Hz, 1H), 1.91-1.75 (m, 2H), 1.64 (d, J=4.0 Hz, 1H), 1.61-1.56 (m, 1H), 1.49 (s, 9H); ES-LCMS m/z 154.1 [M-t-Bu+H]+. |
|
With potassium carbonate In methanol for 3h; |
FIGURE 86 shows the synthesis of IL-2 binding bifunctional molecule IL2-GN3. |
|
With potassium carbonate In methanol at 0 - 20℃; for 4h; |
3 Synthesis of tert-butyl 4-ethynylpiperidine-1-carboxylate (Intermediate 5)
K2CO3 (260 g) was added to a solution of N-Boc-piperidine-4-aldehyde (100 g) in MeOH (500 mL) at 0° C. Then dimethyl 1-diazoacetonylphosphonate (108 g) was slowly added at 0° C. After stirring at room temperature for 4 h, the mixture was quenched with water, then most of the MeOH was removed by rotary evaporation. The residue was extracted with ethyl acetate, and the organic layer washed with brine, dried with Na2SO4, and concentrated to give Intermediate 5 which was used in next step without further purification. |
|
With potassium carbonate In methanol for 3h; |
|
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
