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Structure of 1440-60-4 * Storage: {[proInfo.prStorage]}
* 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 0 - 20℃; for 6 h;
General procedure: To a solution of morpholine (14a; 4.50 mL, 51.45 mmol) and triethylamine (7.90 mL, 56.68 mmol) in CH2Cl2 (80 mL) was slowly added 2-chloroacetyl chloride (6a; 3.70 mL, 46.45 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h, and then diluted with CH2Cl2, washed with saturated NaHCO3 and brine, dried over MgSO4 and filtered. The residue was concentrated under reduced pressure to afford -chloroamide 15aa (7.55 g, 99percent) as a light yellow liquid
90%
at 0 - 23℃; for 1 h; Inert atmosphere
To a solution of piperidine (51.9 ml, 525 mmol, 2.1 equiv) in THF (1000 mL) was added chloroacetic chloride (19.9 ml, 250 mmol, 1.0 equiv) slowly at 0 °C under nitrogen atmosphere. The reaction was allowed to warm to 23 °C, and stirred for 1 hour. The reaction mixture was extracted with EA (2 x 500 ml) from sat. NH4C1 solution, the combined organic layer was washed by brine (300 mL), dried over anhydrous Na2S04. After filtration and evaporation under reduced pressure, the crude product (36.4g, 90percent) obtained was used directly for the next step without further purification. NMR (CDC13, 400 MHz, 25 °C) δ 4.06 (s, 2H), 3.54 (t, 7= 5.5 Hz, 2H), 3.43 (t, J= 5.2 Hz, 2H), 1.70-1.60 (m, 4H), 1.60-1.51 (m, 2H) ppm. 13C NMR (CDCb, 100 MHz, 25 °C) 164.9, 47.5, 43.4, 41.3, 26.4, 25.5, 24.4 ppm.
82%
With pyridine In dichloromethane for 1 h;
General procedure: To a stirred solution of the amine (2 g) in dichloromethane was added pyridine (1.2 eq.) followed by dropwise addition of the acid chloride(1.2 eq.). After 1 hr, further dichloromethane (10 ml) was added, the solution then washed successively with saturated aqueous sodium hydrogen carbonate, hydrochloric acid (2 M), water, then dried and the solvent removed under reduced pressure to give the amide.
70%
With sodium hydrogencarbonate In dichloromethane at 0℃; for 1 h;
General procedure: Propionyl chloride (6.0mmol) in dry CH2Cl2 (10mL) was added dropwise to a mixture of 4-methoxybenzenamine (5.0mmol), sodium bicarbonate (12.5mmol) and dry CH2Cl2 (15mL). The mixture was stirred in ice water bath for 1h and poured into water and then extracted with CH2Cl2 (3×30mL). The combined organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was evaporated to dryness to afford the compound 4a. Others amide derivatives 4b–4s were synthesized similarly. Physical constants and spectral data of compounds 4a–4s are summarized below.
507 mg
at 0 - 20℃; for 15 h;
Piperidine (452.4 mg, 5.313 mmol) was dissolved in THF 2.5 ml. After a 2chloroacetylchloride (300 mg, 2.656 mmol) wasdissolved in 2.5 ml THF was added dropwise at 0 ° C for 5 minutes and stirred at room temperature for 15 hours. It was thendiluted with EA and washed three times with water. The organic layer was dehydrated with Na2SO4, and concentrated underreduced pressure to afford 507 mg of a yellow liquid. Obtained 2chloro1(piperidin1yl)ethanone154 mg (0.954 mmol),Preparation Example 2.3. The compound (250 mg, 0.795 mmol) and K2CO3 (439.7 mg, 3.181 mmol) obtained from wasdissolved in DMF 2.7 ml. 60 To stirred for 2 hours at 65 ° C. To cool to room temperature then diluted with EA and washed three times with water. The organic layer was dehydrated with Na2SO4, and concentrated under reduced pressure and thenseparated by column chromatography to give 297 mg of the title compound as a white solid.
12.7 g
at 20℃; for 1 h;
Piperidine 17 g, 60 ml of toluene were mixed under stirring to 18 g of chloroacetyl chloride and 120 ml of toluenedropwise addition, the reaction one hour at room temperature, the solid was filtered off, the filtrate was concentrated to dryness to give a pale yellow oil of 2-chloro -N - piperidyl acetamide 12.7 g.
507 mg
at 0 - 20℃; for 15.0833 h;
To a solution of piperidine(452.4 mg, 5.313 mmol)in THF(2.5 ml) was added dropwise a solution of 2-chloroacetyl chloride(300 mg, 2.656 mmol) in THF(2.5 ml) over 5 mm at 0. After stirring for 15 h at rt, the mixture was diluted with EtOAc and washed with water for three times. The organic layer was dried over Na2SO4 and concerntrated under reduced pressure to afford the desired product(507 mg) as a yellow liquid. A mixure of the yellow liquid, 2-chloro- 1 -(piperidin- 1 -yl)ethanone(432 mg, 2.67 mmol), tert-butyl 4-(2,6-difluoro-4-hydroxyphenyl)piperazine- 1 -carboxylate(700 mg, 2.227 mmol) and K2C03(769 mg, 5.567 mmol)in DMF(7.4 ml) was heated to 60 to 65 for 2 h. The mixture was allowed to cool down to ii, diluted with EtOAc and washed with water for three times. The organic layer was dried over Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product(823 mg) as a white solid.LC-MS (ESI, mlz) = 440.2(M+H÷).
240 mg
With triethylamine In dichloromethane
In Step 1, 1 gram of Compound 35 was dissolved in DCM and then subjected to BBr3 to afford 930 milligrams of Compound 52. The H-NMR was clean. In Step 2, Compound 52 was reacted with sodium hydride and benzyl bromide to afford Compound 53. In Step 3, 200 milligrams of Compound 33 was dissolved in DCM and triethylamine and reacted with 2-chloroacetyl chloride to afford 240 milligrams of Compound 54 after work-up and purification. In Step 4 Compound 54 was then dissolved in DMF and reacted with sodium hydride and 4-(benzyloxy)phenol to afford 300 milligrams of Compound 55 after work-up and purification. In Step 5, 300 milligrams of Compound 55 was reduced by lithium aluminum hydride to afford 260 milligrams of Compound 56 as an oil after work-up and purification. The H-NMR was clean. In Step 6, 260 milligrams of Compound 56 was hydrogenated to afford 200 milligrams of Compound 57. The H-NMR was clean. In Step 8, 100 milligrams of Compound 57 was mixed with Compound 53 in DMF in the presence of cesium carbonate to afford 160 milligrams of Compound 58. In Step 10, 30 milligrams of Compound 58 was hydrogenated with palladium on carbon in the presence of hydrogen gas to afford 20 milligrams of Compound 106 after work-up and purification.
Reference：
[1] Canadian Journal of Chemistry, 2004, vol. 82, # 5, p. 622 - 630
[2] Molecules, 2015, vol. 20, # 11, p. 19984 - 20013
[3] Synthetic Communications, 1998, vol. 28, # 22, p. 4257 - 4272
[4] Patent: WO2012/52843, 2012, A1, . Location in patent: Page/Page column 73-74
[5] Chemistry - A European Journal, 2012, vol. 18, # 29, p. 8978 - 8986
[6] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 8, p. 1115 - 1121
[7] Organic Letters, 2005, vol. 7, # 8, p. 1653 - 1656
[8] Tetrahedron, 2007, vol. 63, # 30, p. 7187 - 7212
[9] Chemical Biology and Drug Design, 2012, vol. 80, # 6, p. 918 - 928,11
[10] Chemical Biology and Drug Design, 2012, vol. 80, # 6, p. 918 - 928
[11] Chemical Biology and Drug Design, 2013, vol. 82, # 2, p. 156 - 166
[12] Heterocycles, 1991, vol. 32, # 5, p. 965 - 973
[13] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 13, p. 3405 - 3413
[14] Russian Journal of General Chemistry, 2014, vol. 84, # 8, p. 1539 - 1542[15] Zhurnal Obshchei Khimii, 2014, vol. 84, # 8, p. 1316 - 1319,4
[16] Journal of the American Chemical Society, 1919, vol. 41, p. 460
[17] Journal of Biological Chemistry, 1915, vol. 21, p. 150
[18] Gazzetta Chimica Italiana, 1951, vol. 81, p. 98,102
[19] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 1, p. 119 - 123
[20] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 2, p. 297 - 303
[21] Arzneimittel-Forschung/Drug Research, 2002, vol. 52, # 11, p. 817 - 821
[22] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 14, p. 3836 - 3840
[23] Patent: WO2011/160084, 2011, A1, . Location in patent: Page/Page column 40
[24] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 338 - 347
[25] Tetrahedron Letters, 2015, vol. 56, # 8, p. 1011 - 1014
[26] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4098 - 4101
[27] Journal of the Serbian Chemical Society, 2015, vol. 80, # 11, p. 1367 - 1374
[28] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 34 - 46
[29] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 608 - 621
[30] Patent: KR2016/7347, 2016, A, . Location in patent: Paragraph 0311; 0312; 0318; 0319; 0320
[31] Patent: CN101921247, 2016, B, . Location in patent: Paragraph 0024-0026
[32] Patent: CN106146410, 2016, A, . Location in patent: Paragraph 0126; 0127
[33] Patent: WO2017/99424, 2017, A1, . Location in patent: Paragraph 183; 184
[34] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 234 - 245
[35] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 968 - 977
[36] Patent: US2018/230123, 2018, A1, . Location in patent: Paragraph 0629-0630
[37] Patent: US2654754, 1950, ,
3-[2-oxo-2-(1-piperidinyl)ethyl]-6-nitro-4(3H)-quinazolinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
0.48 g (2.5 mmol) of 6-nitro-4 (3H) -quinazolinone was dissolved in 30 mL of DMF and 0.69 g (5 mmol) of K2CO3 was added and stirred in an oil bath at 110 C for 30 min. After cooling, 2-chloro-1- (1-piperidinyl) ethanone (5 mmol) was added and the reaction was continued for 7 h. Cooled to room temperature, 200 mL of cold water was added,Washed with a small amount of water and dried, yielding 0.6 g of product in 75% yield
4-(3,4-dimethoxybenzyl)-3-(3-methoxy-4-(2-oxo-2-(piperidin-1-yl)ethoxy)benzyl)dihydrofuran-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 12h;
General procedure: To a stirred solution of <strong>[26687-82-1]arctigenin</strong> (0.1 mmol), appropriate amidecompounds (0.13 mmol) and K2CO3 (0.2 mmol) in DMF (10 ml). Thereaction mixturewas stirred at 60 C for 12 h monitored by TLC andthen concentrated under reduced pressure. The residue was addedwater (10.0 mL) and extracted with ethyl acetate. The combinedorganic phases were washed with brine, dried over anhydrous sodiumsulfate and evaporated to dryness. Then it can be purified bychromatography on silica eluting to obtain the compound (E1-E6)as a white solid (yield: 32%58%).
2-(5-(benzyloxy)-1H-indol-1-yl)-1-(piperidin-1-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 5-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h;
Stage #2: 1-chloroacetyl-piperidine In N,N-dimethyl-formamide; mineral oil at 20℃; for 24h;
General Procedure 6 (GP6) - N-alkylation of 1H-indole:
General procedure: To an ice-bath cooled solution of corresponding 5-substituted 1H-indole (1.0eq.) in DMF (10mL), NaH (60% dispersion on mineral oil, 1.5eq.) was added. After stirring the reaction mixture on an ice bath for 20min, corresponding alkyl chloride (1.5eq.) was added and stirring continued at room temperature for 24h. The volatile components were removed in vacuo and residue was dissolved in EtOAc (50mL), washed with H2O (30mL), saturated brine (30mL), dried over Na2SO4, filtered, and volatile components were evaporatedin vacuo. The product was purified by column chromatography or by crystallization.
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