* 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 triethylamine In dichloromethane at 20℃; for 15 h;
The compound 48-d (0.33 g, 2.36 mmol) was dissolved in methylene chloride (15 mL), di-tert-butyl dicarbonate (0.76 g, 3.49 mmol) and triethylamine (0.6 mL, And the mixture was stirred at room temperature for 15 hours. 2N HCl aqueous solution (2 mL) was added to the reaction mixture, stirred for 10 minutes, and further distilled water (20 mL) was added thereto, followed by extraction with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give the title compound 49-a (0.15 g, 27percent) as a colorless liquid.
With palladium diacetate; triethylamine; triphenylphosphine In N,N-dimethyl-formamide at 20℃; for 12 h;
To a mixture of tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-3 ,6-dihydropyridine-1(2H)-carboxylate (5.6 g, 16.8 mmol), Et3N (4.7 ml, 33.0 mmol) in DMF (69 ml) andMeOH (52 ml) was added PPh3 (0.2 g, 1.0 mmol) and Pd(OAc)2 (0.1 g, 0.5 mmol) at RT under nitrogen followed by stirring under CO atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography to give 2.0 g of the title compound as a greenish liquid. 1H-NMR (400MHz; DMSO-d6): ö 6.85 (d, 1H), 4.00 (t, 2H), 3.67 (s, 3H), 3.42 (d, 2H), 2.25 (t, 2H),1.41 (s, 9H).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4544 - 4567
[2] Heterocycles, 1996, vol. 43, # 10, p. 2131 - 2138
[3] Patent: WO2018/115591, 2018, A1, . Location in patent: Page/Page column 84; 85
3
[ 138647-49-1 ]
[ 184368-74-9 ]
Yield
Reaction Conditions
Operation in experiment
65%
With triethylamine; triphenylphosphine In methanol; hexane; N,N-dimethyl-formamide
B. Methyl 1-boc-1,2,3,6-Tetrahydro-4-pyridinecarboxylate To a stirred solution of 1-Boc-1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine (74.84 g, 226 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine (4.2 mL, 30.2 mmol), palladium acetate (0.100 g, 0.45 mmol), triphenylphosphine (0. 235 g, 0.9 mmol), and methanol (24.5 mL) and the solution was placed under an atmosphere of carbon monoxide. After stirring for 48 h, the solvent was removed in vacuo. The residue was chromatographed over silica gel, eluding with 5-10percent ethyl acetate in hexane. The product containing fractions were combined and concentrated in vacuo to give 2.35 g (65percent) of the title compound as a clear oil. 1H-NMR; FD-MS, m/e 240.2 (m); Analysis for C12H19NO4: Calcd: C, 59.74; H, 7.94; N, 5.81; Found: C, 59.60; H, 8.07; N, 5.85.
With palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 20.0℃; for 12.0h;
To a mixture of tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-3 ,6-dihydropyridine-1(2H)-carboxylate (5.6 g, 16.8 mmol), Et3N (4.7 ml, 33.0 mmol) in DMF (69 ml) andMeOH (52 ml) was added PPh3 (0.2 g, 1.0 mmol) and Pd(OAc)2 (0.1 g, 0.5 mmol) at RT under nitrogen followed by stirring under CO atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography to give 2.0 g of the title compound as a greenish liquid. 1H-NMR (400MHz; DMSO-d6): oe 6.85 (d, 1H), 4.00 (t, 2H), 3.67 (s, 3H), 3.42 (d, 2H), 2.25 (t, 2H),1.41 (s, 9H).
(2R,4S)-N-Butyl-4-hydroxy-2-methyl-4-((E)-(4aS,7S,10R,17aR)-7-methyl-5,8-dioxo-1,3,4,4a,5,6,7,8,9,10,11,13,16,17a-tetradecahydro-2H-12,17-dithia-2,6,9-triaza-benzocyclopentadecen-10-yl)-butyramide[ No CAS ]
With sodium chloride; ammonium chloride; In tetrahydrofuran; methanol;
1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-methanol 17.6 g of <strong>[184368-74-9]methyl 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylate</strong> was dissolved in 300 ml of tetrahydrofuran. After adding 4.77 g of lithium tetrahydroborate and then 20 ml of methanol, the resulting mixture was stirred at room temperature for 20 minutes. Saturated ammonium chloride was added to the reaction mixture under ice-cooling and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 10.7 g of the title compound as a colorless oily substance. 1H-NMR(CDCl3) delta ppm: 1.47(s, 9H), 1.64(br.s, 1H), 2.08-2.16(m, 2H), 3.47-3.58(m, 2H), 3.91(br.s, 2H), 4.06(br.s, 2H), 5.64(br.s, 1H)
With sodium chloride; triethylamine; In methanol; dichloromethane;
Methyl 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylate 4.62 g of <strong>[80845-58-5]methyl 1-benzyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate</strong> was dissolved in 30 ml of dichloromethane. Under ice-cooling, 4.29 g of 1-chloroethyl chloroformate was added thereto and the resulting mixture was heated under reflux for 2 hours. After adding 50 ml of methanol, the mixture was stirred at 70 C. for 1 hour and 20 minutes. Then triethylamine was added to the reaction mixture under ice-cooling until the pH value of the mixture exceeded 7. After further adding 4.37 g of tert-butyl dicarbonate, the resulting mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.46 g of the title compound as a yellow oily substance. 1H-NMR(CDCl3) delta ppm: 1.47(s, 9H), 2.40(br.s, 2H), 3.51(t, J=5.6 Hz, 2H), 3.76(s, 3H), 4.07(d, J=2.4 Hz, 2H), 6.88(br.s, 1H)
With triethylamine; triphenylphosphine;palladium diacetate; In methanol; hexane; N,N-dimethyl-formamide;
B. Methyl 1-boc-1,2,3,6-Tetrahydro-4-pyridinecarboxylate To a stirred solution of 1-Boc-1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine (74.84 g, 226 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine (4.2 mL, 30.2 mmol), palladium acetate (0.100 g, 0.45 mmol), triphenylphosphine (0. 235 g, 0.9 mmol), and methanol (24.5 mL) and the solution was placed under an atmosphere of carbon monoxide. After stirring for 48 h, the solvent was removed in vacuo. The residue was chromatographed over silica gel, eluding with 5-10% ethyl acetate in hexane. The product containing fractions were combined and concentrated in vacuo to give 2.35 g (65%) of the title compound as a clear oil. 1H-NMR; FD-MS, m/e 240.2 (m); Analysis for C12H19NO4: Calcd: C, 59.74; H, 7.94; N, 5.81; Found: C, 59.60; H, 8.07; N, 5.85.
With lithium hydroxide; In tetrahydrofuran; at 20.0℃; for 2.0h;
Compound 49-a (0.15 g, 0.63 mmol) was dissolved in tetrahydrofuran (3 mL), 1N aqueous lithium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a 2N aqueous solution of hydrogen chloride was added to the solution so that the pH became 2 or less and the solution was extracted with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 49-b (0.13 g, 92%) as a white solid.
1.62 g (78%)
With sodium hydroxide; In methanol;
C. 1-boc-1,2,3,6-Tetrahydro-4-pyridinecarboxylic Acid To a stirred solution of <strong>[184368-74-9]methyl 1-Boc-1,2,3,6-tetrahydro-4-pyridinecarboxylate</strong> (2.22 g, 9.2 mmol) in methanol (10 mL) was added 1.0 N aqueous sodium hydroxide (25 mL). After stirring for 2 h, the solvent was removed in vacuo. The residue was partitioned between diethyl ether and water, and the layers were separated. The aqueous phase was acidified to pH 2.5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 1.62 g (78%) of the title compound as a white solid. 1H-NMR; IS-MS, m/e 226.1 (m-1)-; Analysis for C11H17NO4: Calcd: C, 58.14; H, 7.54; N, 6.16; Found: C, 57.41; H, 7.48; N, 6.19.
methyl 1,2,3,6-tetrahydro-4-pyridinecarboxylate[ No CAS ]
[ 184368-74-9 ]
Yield
Reaction Conditions
Operation in experiment
27%
With triethylamine; In dichloromethane; at 20.0℃; for 15.0h;
The compound 48-d (0.33 g, 2.36 mmol) was dissolved in methylene chloride (15 mL), di-tert-butyl dicarbonate (0.76 g, 3.49 mmol) and triethylamine (0.6 mL, And the mixture was stirred at room temperature for 15 hours. 2N HCl aqueous solution (2 mL) was added to the reaction mixture, stirred for 10 minutes, and further distilled water (20 mL) was added thereto, followed by extraction with methylene chloride. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give the title compound 49-a (0.15 g, 27%) as a colorless liquid.
With diisobutylaluminium hydride; In dichloromethane; toluene; at -78.0℃;
To a solution of 1 -(tert-butyl)4-methyl-3 ,6-dihydropyridine- 1 ,4(2H)-dicarboxy-late (1.7 g, 7.3 mmol) in DCM (20 ml) at -78 C was added DIBAL-H (1.0 M in toluene,10.5 ml, 10.5 mmol) followed by stirring at RT for 16 h. The reaction was cooled to 0C and quenched with water and extracted with DCM. The organic layer was dried,filtered and concentrated under reduced pressure to give 1.5 g of the title compound asgreenish viscous liquid. LC-MS: mlz 214 (M+H) +.
methyl 7,7-difluoro-3-azabicyclo[4.1.0]heptane-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrabutyl ammonium fluoride; In toluene; at 110.0℃; for 16.0h;Inert atmosphere; Sealed tube;
To a solution of 1-tert-butyl 4-methyl 3,6-dihydro-2H-pyridine-l,4-dicarboxylate (500 mg, 2.07 mmol) in toluene (2.5 mL) was added tetrabutylammoniumbromide (33 mg, 0.10 mmol) under N2, then [bromo(difluoro)methyl]-trimethyl-silane (842 mg, 4.14 mmol) was added drop-wise under N2. The reaction mixture was heated at 110 C and stirred for 16 h in a sealed tube. The residue was filtered and concentrated under reduced pressure to provide the title compound (700 mg) as a brown oil, which was used in the next step without further purification. LC-MS: m/z = 192.1 [M+H]+.
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