There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 1440-61-5 * 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 potassium carbonate In toluene at 60℃; for 2 h;
Step 1 A toluene (30 mL) solution of morpholine (1.00 mL, 11.5 mmol) was added with potassium carbonate (3.17 g, 22.9 mmol) and chloroacetyl chloride (0.91 mL, 11.4 mmol), followed by stirring at 60°C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain N-chloroacetylmorpholine (1.87 g, quantitative yield). 1H-NMR (270 MHz, CDCl3) δ 3.51-3.54 (m, 2H), 3.62-3.65 (m, 2H), 3.68-3.74 (m, 4H), 4.07 (s, 2H).
100%
Stage #1: With triethylamine In dichloromethane at 0 - 27℃; for 2 h; Stage #2: With hydrogenchloride In dichloromethane; water
Chloroacetyl chloride (840 mg, 6.89 mmol) was added to a solution of morpholine (500 mg, 5.74 mmol) in anhydrous CH2CI2 (25 ml_) containing Et3N (1 .74 g, 17.22 mmol) at 0 °C. The mixture was stirred and warmed to 27 °C for 2 h. The mixture was washed with 1 M HCI(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give 2-chloro-1 -morpholinoethanone (1 .13 g, 100percent yield). C6HnCINO2; brown oil; 1H NMR (400 MHz, CDCI3) δ 4.05 (2 H, s), 3.69 (4 H, m), 3.62 (2 H, m), 3.52 (4 H, m); 13C NMR (100 MHz, CDCI3) δ 164.4, 66.5, 66.4, 46.8, 42.5, 40.8; ESI-HRMS calcd for C6Hi2CIN02: 164.0478, found: m/z164.0478 [M + H]+.
99%
With triethylamine In dichloromethane at 0 - 20℃; for 6 h;
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: 1H-NMR(CDCl3) δ 3.54 (t, J = 4.5 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H), 3.70–3.74 (m, 4H), 4.07 (s, 2H); 13C-NMR(CDCl3) δ 40.7, 42.5, 46.8, 66.6, 66.7, 165.3; LC-MS (ESI) m/z 164 ([M + 1]+).
96%
With triethylamine In dichloromethane at 25℃; for 1 h;
To a solution of 2-chloroacetyl chloride (1.0 g, 8.8 mmol) and morpholine (771 mg, 8.85 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.34 g, 13.3 mmol). The reaction was stirred at25 00 for 1 h then concentrated and purified by column chromatography (silica gel, 30percent ethyl acetate/petroleum ether) to give 2-chloro-1-morpholinoethanone (1.1 g, 96percent) asyellow oil. 1H NMR (400 MHz, ODd3) O [ppm] 4.07 (5, 2H), 3.72 (td, J = 4.9,10.0 Hz, 4H), 3.67 - 3.60 (m, 2H), 3.59 - 3.48 (m, 2H).
87%
for 2 h; Inert atmosphere; Cooling with ice
The precursor, 2-chloro-1-morpholinoethanone was prepared by modified literature report [19] (see Scheme 1 ). 12.35 g (0.143 mol) of morpholine, diluted with 60 mL of diethyl ether was taken into two necked round bottomed flask. To that 8 g (0.072 mol) of chloroacetyl chloride diluted with 20 mL of diethyl ether was added drop wise at ice cooled condition under nitrogen atmosphere. The reaction mixture was stirred for 2 h. The reaction mixture was filtered to remove the white precipitate of morpholine hydrochloride salt and then diluted with 100 mL of ice cold water. The organic layer was separated and the solvent was removed under reduced pressure to afford a viscous yellow liquid. The compound was further dried under high vacuum and subjected to various spectroscopic analyses. The characteristic peaks were compared with the literature values. The isolated yield of the compound was about 87percent. IR (cm-1): 1633.71 (C=O). 1H NMR (400 MHz, CDCl3): δ = 3.46-3.48 (t, N-CH2, 4H), 3.62 (m, O-CH2, 4H), 4.013 (s, C-CH2-Cl, 2H) ppm. 13CNMR (δ, 100 MHz, CDCl3): 40.55, 42.5, 46.73, 66.6, 165.4. Mass (EI, m/z): 163.17 (observed) (calculated: 163.6). A similar procedure was followed for the synthesis of 2-chloro-N,N-diethylacetamide (see Scheme 2 ).
78%
at -78 - 20℃; for 3 h;
PREPARATION 40; N-chloroacetyl-morpholine; To a solution of chloroacetyl chloride (2.0 mL, 2.5 mmol) in 20 mL CH2CI2 was slowly added a solution of morpholine (2.2 mL, 5.0 mmol) in 20 mL CH2CI2 at-78 °C. The reaction mixture was warmed to rt and stirred for 3 h. A white suspension solution resulted. The white precipitate was filtered off. The filtrate was washed with 1 N HCI, dried over sodium sulphate and concentrated to give the title compound (3.11 g, 78 percent) as colorless oil. 1H NMR (400 MHz, CDCI3) No. 4.12 (s, 2 H), 3.74 (br s, 4 H), 3.61 (br s, 2 H), 3.50 (br s, 2 H). MS m/z 164 [M+1].
76%
With triethylamine In dichloromethane at 0 - 20℃; for 0.75 h;
d) 2-Chloro- 1 -morpoholin-4-yl-ethanone; A solution of morpholine (0.50 g, 5.7 mmol) in CH2Cl2 (10 mL) was treated with Et3N and cooled to 0 0C. The mixture was treated with chloroacetyl chloride (0.50 mL, 6.3 mmol) as a solution in CH2Cl2 (2 mL). The reaction was stirred at 0 °C for 15 min and then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.72 g, 76 percent) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 4.06 (s, 2H), 3.73-7.67 (m, 4H), 3.62 (app t, 2H, J = 4.0 Hz), 3.52 (app t, 2H, J = 4.0 Hz).
76.6%
With triethylamine In tetrahydrofuran
Reference Example 116 Triethylamine (4.5 g, 44.5 mmol) was added to a tetrahydrofuran solution (60mL) of morpholine (3g, 32. 7 mmol), and a tetrahydrofuran solution (20 mL) of chloroacetyl chloride (3.9 g, 34.5 mmol) was added dropwise, gradually while the solution was ice-water-cooled. Ether was added to the residue; the precipitated triethylamine hydrochloride was removed by filtration; and the filtrate was concentrated under reduced pressure. The residue obtained was purified by distillation under reduced pressure (10 mm Hg, 110 to 112°C), to obtain 4-(chloroacetyl)morpholine (4.1 g, 76.6percent) as a pale yellow oil. 1H-NMR(CDCl3)δ:3.50-3.79(8H,m),4.07(2H,s)ppm
69.2%
With triethylamine In dichloromethane for 4 h;
To a stirred solution of morpholine (17.4 g,200 mmol) and triethylamine (24.24 g, 220 mmol) in CH2Cl2 (200 mL), acetyl chloride (24.00 g, 210mmol) in CH2Cl2 (volume) was added dropwise. The resulting reaction mixture was stirred at this temperature for a further 4 h, then poured into water, and the aqueous layer extracted twice with methylene chloride. The organic chloride phase was combined, washed with dilute hydrochloric acid and water, and dried over Na2SO4, and evaporated to dryness to give compound 20 (22.66 g, 69.2percentyield) as a pale yellow oil.
68%
at 20℃; for 1 h;
[0170] To morpholine (466 mg, 5.36 mmol) in DCM (13.4 mL) at 0 °C, was added 2- chloroacetyl chloride (300 mg, 2.68 mmol) in DCM. The mixture was then stirred at r.t. for 1 h. The precipitate was filtered and the filtrate was concentrated to provide the title compound as an oil (300 mg, 68percent). MS (ES+) m/e 164 (M+H)+.
64%
With triethylamine In tetrahydrofuran at 0℃; for 0.333333 h;
;4-(Chloroacetyl)morpholine To a solution of morpholine (3.6 mL, 41 mmol) and triethylamine (5.2 g, 51 mmol) in tetrahydrofuran (100 mL) was added chloroacetyl chloride (3.0 mL, 38 mmol) at 0°C, and the mixture was stirred at 0°C for 20 minutes. The reaction solution was concentrated and ethyl acetate was added thereto. The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated to obtain the title compound (4.0 g, yield 64percent) as an oily matter. 1H NMR (CDCl3) δ 3.52-3.55 (2H, m), 3.62-3.65 (2H, m), 3.69-3.75 (4H, m), 4.07 (2H, s).
64%
With potassium carbonate In toluene at 60℃; for 2.5 h;
0.45 mL of chloroacetyl chloride (5.78 mmol, 1.0 eq) was added to a suspension of 0.5 mL of morpholine (5.78mmol, 1.0 eq), 1.60 g of potassium carbonate (11.57 mmol, 2.0 eq) in 15 mL of abs. toluene. The mixture was stirred at 60 °C for 2.5 hours. The suspension was filtered and the solvent was removed under reduced pressure to give 0.78 g (64percent) of a yellow oil.
50%
With triethylamine In dichloromethane for 1 h; Cooling with ice
Take 870 microliters morpholine in 50ml round bottom flask, add 20ml methylene chloride to make it dissolve, slowly add 820 microliters chloroacetyl chloride slowly under ice-water bath, and slowly add 1.4ml triethylamine slowly, continue stirring 1 hour. The reaction was diluted with water and extracted three times with dichloromethane (15 ml each). The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 827 mg of intermediate A19 in a yield of 50percent
76%
With triethylamine In ethyl acetate
Preparation 24 4-(Chloroacetyl)morpholine [BM.1] To a stirring mixture of morpholine (1.00 g) and triethylamine (1.6 mL) in EtOAc (10 mL) at 0° C. is added chloroacetyl chloride (1.83 mL) dropwise. The mixture is stirred at 0° C. for 35 min., diluted with 10percent HCl (25 mL) and extracted with EtOAc (3*50 mL). The organic layer is dried over MgSO4, and the solvent removed. The residue is purified by SiO2 flash column chromatography (eluent 35percent EtOAc/hexane) to afford 1.42 g (76percent) of the title compound as a yellow liquid. Physical characteristics: 1H NMR (CDCl3) δ 3.54, 3.64, 3.72, 4.07; IR (liq.) 2859, 1654, 1463, 1438, 1302, 1270, 1251, 1233, 1115, 1069, 1040, 965, 790, 657, 604 cm-1; MS (ESI+) m/z 164 (M+H)+. Anal. Found: C, 43.66; H, 6.17; N, 8.58.
46.69 g
With triethylamine In dichloromethane at -10 - 20℃; for 3 h;
To a solution of chloroacetyl chloride (25 ml) in dry dichloromethane (125 ml) at -10°C was added dropwise a solution of morpholine (30 ml) and triethylamine (47.5 ml) in dry dichloromethane (125 ml) over approximately two hours keeping the internal temperature below 20°C. After addition, the reaction mixture was stirred for one hour then the reaction mixture was washed with 0.5N aqueous hydrochloric acid (200 ml) and water (2 x 200 ml). The combined aqueous was back extracted with dichloromethane (2 x 150 ml); the organic layers were combined, dried (MgS04) and evaporated to afford the title compound (46.69 g) as a brown oil. 1H-NMR (400 MHz, CDC13) δ (ppm): 3.49 - 3.57 (m, 2 H) 3.58 - 3.66 (m, 2 H) 3.71 (dt, J=9.84, 4.86 Hz, 4 H) 4.06 (s, 2 H)
Reference：
[1] Patent: EP1650194, 2006, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2012/72019, 2012, A1, . Location in patent: Page/Page column 71-72
[3] Molecules, 2015, vol. 20, # 11, p. 19984 - 20013
[4] Patent: WO2016/147144, 2016, A1, . Location in patent: Page/Page column 222
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6660 - 6671
[6] European Journal of Medicinal Chemistry, 1999, vol. 34, # 12, p. 1023 - 1034
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[8] Polyhedron, 2018, vol. 141, p. 215 - 222
[9] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1675 - 1678
[10] Patent: WO2005/66165, 2005, A1, . Location in patent: Page/Page column 91
[11] Patent: WO2006/47504, 2006, A1, . Location in patent: Page/Page column 132
[12] Patent: EP1820799, 2007, A1,
[13] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 87
[14] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2688 - 2703
[15] Journal of Pharmaceutical Sciences, 1980, vol. 69, # 8, p. 888 - 891
[16] Journal of Medicinal Chemistry, 2014, vol. 57, # 16, p. 7061 - 7072
[17] Molecules, 2014, vol. 19, # 2, p. 2004 - 2028
[18] Patent: WO2016/210330, 2016, A1, . Location in patent: Paragraph 0169-0170
[19] RSC Advances, 2013, vol. 3, # 3, p. 945 - 960
[20] Patent: EP1661898, 2006, A1, . Location in patent: Page/Page column 51
[21] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 503 - 523
[22] Russian Journal of General Chemistry, 2014, vol. 84, # 8, p. 1539 - 1542[23] Zhurnal Obshchei Khimii, 2014, vol. 84, # 8, p. 1316 - 1319,4
[24] Patent: CN107286098, 2017, A, . Location in patent: Paragraph 0191-0193
[25] Patent: US2768202, 1955, ,
[26] Farmaco, Edizione Scientifica, 1956, vol. 11, p. 113,115
[27] Roczniki Chemii, 1956, vol. 30, p. 1111,1114[28] Chem.Abstr., 1957, p. 8755
[29] Patent: US2692265, 1951, ,
[30] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 1, p. 119 - 123
[31] Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 727 - 734
[32] J. Appl. Chem. USSR (Engl. Transl.), 1988, vol. 61, # 6, p. 1246 - 1249[33] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1988, vol. 61, # 6, p. 1364 - 1367
[34] Pharmaceutical Research, 2001, vol. 18, # 5, p. 600 - 607
[35] Pesticide Science, 1994, vol. 40, # 1, p. 57 - 62
[36] Arzneimittel-Forschung/Drug Research, 2002, vol. 52, # 11, p. 817 - 821
[37] Journal of Organic Chemistry, 2004, vol. 69, # 10, p. 3554 - 3557
[38] Organic and Biomolecular Chemistry, 2005, vol. 3, # 11, p. 2129 - 2139
[39] Tetrahedron Asymmetry, 2006, vol. 17, # 14, p. 2154 - 2182
[40] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 14, p. 4820 - 4833
[41] Tetrahedron Letters, 2004, vol. 45, # 10, p. 2085 - 2088
[42] Patent: US2002/25960, 2002, A1,
[43] Patent: US2004/6123, 2004, A1,
[44] Patent: WO2004/65389, 2004, A1, . Location in patent: Page 45-46
[45] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 663 - 674
[46] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7310 - 7314
[47] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 21, p. 6310 - 6312
[48] Chemistry - A European Journal, 2013, vol. 19, # 39, p. 13017 - 13029
[49] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 338 - 347
[50] Patent: WO2014/13076, 2014, A1, . Location in patent: Page/Page column 71
[51] Organic Letters, 2014, vol. 16, # 7, p. 2003 - 2005
[52] RSC Advances, 2015, vol. 5, # 52, p. 41341 - 41351
[53] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3426 - 3435
[54] Angewandte Chemie - International Edition, 2015, vol. 54, # 21, p. 6236 - 6240[55] Angew. Chem., 2015, vol. 54, # 21, p. 6334 - 6338
[56] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4098 - 4101
[57] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6875 - 6884
[58] Journal of the Serbian Chemical Society, 2015, vol. 80, # 11, p. 1367 - 1374
[59] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 34 - 46
[60] Chemical Biology and Drug Design, 2016, vol. 87, # 6, p. 946 - 957
[61] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 608 - 621
[62] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4263 - 4271
[63] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 234 - 245
[64] New Journal of Chemistry, 2018, vol. 42, # 19, p. 16226 - 16236
[65] Patent: CN106349241, 2017, A, . Location in patent: Paragraph 0342; 0343; 0344
[66] Journal of Medicinal Chemistry, 2017, vol. 60, # 17, p. 7371 - 7392
[67] Applied Organometallic Chemistry, 2018, vol. 32, # 7,
[68] Patent: WO2004/111052, 2004, A1, . Location in patent: Page 50
2
[ 110-91-8 ]
[ 541-88-8 ]
[ 1440-61-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 20℃; for 1 h;
In a round-bottom flask containing 243 10 mL of chloroform was added morpholine (1 eq.), followed by chloroacetic anhydride 244 (1 eq.) in an ice bath. The reaction mixture was kept under magnetic stirring for one hour at room temperature. The solvent was removed under reduced pressure and the resulting 246 oil was diluted in 20 mL of AcOEt and washed with 15 mL of a saturated solution of 247 NaHCO3. The organic layer was dried with anhydrous magnesium sulfate and the solvent 248 was removed under reduced pressure to yield 4-(chloroacetyl)morpholine 17 as a yellow 249 oil, 95percent yield; IR (neat, cm-1) 1642, 1110; 1H NMR (200 MHz, CDCl3) δ 4.05 (s, 2H), 250 3.76 – 3.65 (m, 4H), 3.65 – 3.57 (m, 2H), 3.56 – 3.47 (m, 2H); 13C NMR (CDCl3, 50 251 MHz) δ 165.2, 66.5, 46.7, 42.4, 40.5.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 6, p. 1889 - 1900
Preparation of 4-(2-chloroacetyl)morpholine To an ice cold solution of chloroacetyl chloride (1.29 g, 11 mmol) in 10 mL of methylene chloride was added morpholine (1 g, 11 mmol) in 10 mL of methylene chloride containing triethylamine (2.32 g, 23 mmol). The reaction mixture was stirred at 5° C. for 30 minutes then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (100 mL) was added. The organic layer was separated, washed with 1N HCl (1*50 mL), saturated aqueous NaHCO3 (1*50 mL), brine (1*50 mL), dried over MgSO4, filtered and concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 0.52 g (28.8percent) of 4-(2-chloroacetyl)morpholine as a brown oil. 1 H NMR (300 MHz / CDCl3): δ 3.51-3.54 (m, 2H), 3.61-3.64 (m, 2H), 3.68-3.74 (m, 4H), 4.06 (s, 2H). HRMS: calcd for C6 H10 N1 O2 Cl1 164.0478, found 164.0498.
Reference：
[1] European Journal of Medicinal Chemistry, 2006, vol. 41, # 8, p. 985 - 990
8
[ 110-91-8 ]
[ 22118-09-8 ]
[ 1440-61-5 ]
Reference：
[1] Chemistry of Natural Compounds, 2013, vol. 48, # 6, p. 1047 - 1053[2] Khim. Prir. Soedin., 2012, vol. 48, # 6, p. 924 - 929,6
9
[ 110-91-8 ]
[ 15018-06-1 ]
[ 1440-61-5 ]
Reference：
[1] Farmaco, Edizione Scientifica, 1957, vol. 12, p. 1016,1021
10
[ 1440-61-5 ]
[ 348-57-2 ]
[ 51336-94-8 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
Stage #1: With magnesium In tetrahydrofuran at 30 - 35℃; for 2 h; Inert atmosphere Stage #2: at 40℃; for 2 h;
Prepare a dry, clean 1000mL glass four-port bottle, equipped with a suitable mechanical stirrer, condensing tube and thermometer, check the airtightness before feeding, and add 96.5g to the reaction flask under N2 protection. 2,4-Difluorobromobenzene (0.5mol, 1.0eq),25.5 g (0.525 mol, 1.05 eq) of magnesium bar, 500 mL of tetrahydrofuran, stirring was started, the temperature of the reaction solution was raised to 30-35° C., and the reaction was stirred for 2 h. After the reaction was completed, the reaction solution was slowly added dropwise 163.6 g (1.0 mol). , 2.0 eq.) of 4-(2-chloroacetyl)morpholine (Compound 4) in tetrahydrofuran (163.6 g dissolved in 360 ml of tetrahydrofuran), the temperature controlled during the additionAt 40°C, after the addition is complete, continue incubation at 40°C for 2 hours. After the reaction was completed, the reaction system was quenched with 100 mL of saturated ammonium chloride solution. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and then 500 mL of ethyl acetate was added for extraction. The separated ethyl acetate phase was washed with 300 mL of water and the organic phase was organic. It was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 92.0 g of compound 5 (yield: 96.5percent).
Reference：
[1] Patent: CN107746388, 2018, A, . Location in patent: Paragraph 0028; 0030; 0032; 0033; 0034; 0036; 0038; 0040
With potassium carbonate; In toluene; at 60℃; for 2.0h;
Step 1 A toluene (30 mL) solution of morpholine (1.00 mL, 11.5 mmol) was added with potassium carbonate (3.17 g, 22.9 mmol) and chloroacetyl chloride (0.91 mL, 11.4 mmol), followed by stirring at 60C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain N-chloroacetylmorpholine (1.87 g, quantitative yield). 1H-NMR (270 MHz, CDCl3) delta 3.51-3.54 (m, 2H), 3.62-3.65 (m, 2H), 3.68-3.74 (m, 4H), 4.07 (s, 2H).
100%
Chloroacetyl chloride (840 mg, 6.89 mmol) was added to a solution of morpholine (500 mg, 5.74 mmol) in anhydrous CH2CI2 (25 ml_) containing Et3N (1 .74 g, 17.22 mmol) at 0 C. The mixture was stirred and warmed to 27 C for 2 h. The mixture was washed with 1 M HCI(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give 2-chloro-1 -morpholinoethanone (1 .13 g, 100% yield). C6HnCINO2; brown oil; 1H NMR (400 MHz, CDCI3) delta 4.05 (2 H, s), 3.69 (4 H, m), 3.62 (2 H, m), 3.52 (4 H, m); 13C NMR (100 MHz, CDCI3) delta 164.4, 66.5, 66.4, 46.8, 42.5, 40.8; ESI-HRMS calcd for C6Hi2CIN02: 164.0478, found: m/z164.0478 [M + H]+.
99%
With triethylamine; In dichloromethane; at 0 - 20℃; for 6.0h;
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, 99%) as a light yellow liquid: 1H-NMR(CDCl3) delta 3.54 (t, J = 4.5 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H), 3.70-3.74 (m, 4H), 4.07 (s, 2H); 13C-NMR(CDCl3) delta 40.7, 42.5, 46.8, 66.6, 66.7, 165.3; LC-MS (ESI) m/z 164 ([M + 1]+).
96%
With triethylamine; In dichloromethane; at 25℃; for 1.0h;
To a solution of 2-chloroacetyl chloride (1.0 g, 8.8 mmol) and morpholine (771 mg, 8.85 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.34 g, 13.3 mmol). The reaction was stirred at25 00 for 1 h then concentrated and purified by column chromatography (silica gel, 30% ethyl acetate/petroleum ether) to give 2-chloro-1-morpholinoethanone (1.1 g, 96%) asyellow oil. 1H NMR (400 MHz, ODd3) O [ppm] 4.07 (5, 2H), 3.72 (td, J = 4.9,10.0 Hz, 4H), 3.67 - 3.60 (m, 2H), 3.59 - 3.48 (m, 2H).
94%
With triethylamine; In dichloromethane; at 0 - 10℃; for 1.0h;
General procedure: To the appropriate substituted amines (83a-h, 1 equiv) in DCM was added chloroacetyl chloride 84 (1.1 equiv) followed by the addition of TEA (2.8 equiv) at 0-10C. The reaction was continued at the same temperature for 1h. Then, the reaction mixture was washed with saturated NaHCO3 solution, HCl 2N, and brine solution. The excess of organic solvent was removed under reduced pressure and the crude compounds were purified by flash chromatography, eluting with Cyclohexane/EtOAc 1/1.
92%
With triethylamine; In dichloromethane; at 0℃; for 2.0h;
The morpholine (0.01 mol) was dissolved in 100 ml of dichloromethane solution.The ice bath is cooled to about 0 C, and triethylamine is added to the mixed solution under stirring.Subsequently, chloroacetyl chloride (1.2 eq) was added, and the mixture was stirred for 2 hours under ice-cooling, and then warmed to room temperature.The reaction end point was determined by TLC, and the reaction solution was washed twice with 100 ml of water and twice with dilute hydrochloric acid.The organic phase is dried over anhydrous magnesium sulfate, filtered and dried to give a crude product.Flash column separation (ethyl acetate / petroleum ether = 1 : 4) afforded 1.5 g of yellow solid.Yield: 92%.
87%
for 2.0h;Inert atmosphere; Cooling with ice;
The precursor, 2-chloro-1-morpholinoethanone was prepared by modified literature report [19] (see Scheme 1 ). 12.35?g (0.143?mol) of morpholine, diluted with 60?mL of diethyl ether was taken into two necked round bottomed flask. To that 8?g (0.072?mol) of chloroacetyl chloride diluted with 20?mL of diethyl ether was added drop wise at ice cooled condition under nitrogen atmosphere. The reaction mixture was stirred for 2?h. The reaction mixture was filtered to remove the white precipitate of morpholine hydrochloride salt and then diluted with 100?mL of ice cold water. The organic layer was separated and the solvent was removed under reduced pressure to afford a viscous yellow liquid. The compound was further dried under high vacuum and subjected to various spectroscopic analyses. The characteristic peaks were compared with the literature values. The isolated yield of the compound was about 87%. IR (cm-1): 1633.71 (C=O). 1H NMR (400?MHz, CDCl3): delta?=?3.46-3.48 (t, N-CH2, 4H), 3.62 (m, O-CH2, 4H), 4.013 (s, C-CH2-Cl, 2H) ppm. 13CNMR (delta, 100?MHz, CDCl3): 40.55, 42.5, 46.73, 66.6, 165.4. Mass (EI, m/z): 163.17 (observed) (calculated: 163.6). A similar procedure was followed for the synthesis of 2-chloro-N,N-diethylacetamide (see Scheme 2 ).
78%
In dichloromethane; at -78 - 20℃; for 3.0h;
PREPARATION 40; N-chloroacetyl-morpholine; To a solution of chloroacetyl chloride (2.0 mL, 2.5 mmol) in 20 mL CH2CI2 was slowly added a solution of morpholine (2.2 mL, 5.0 mmol) in 20 mL CH2CI2 at-78 C. The reaction mixture was warmed to rt and stirred for 3 h. A white suspension solution resulted. The white precipitate was filtered off. The filtrate was washed with 1 N HCI, dried over sodium sulphate and concentrated to give the title compound (3.11 g, 78 %) as colorless oil. 1H NMR (400 MHz, CDCI3) No. 4.12 (s, 2 H), 3.74 (br s, 4 H), 3.61 (br s, 2 H), 3.50 (br s, 2 H). MS m/z 164 [M+1].
76%
With triethylamine; In dichloromethane; at 0 - 20℃; for 0.75h;
d) 2-Chloro- 1 -morpoholin-4-yl-ethanone; A solution of morpholine (0.50 g, 5.7 mmol) in CH2Cl2 (10 mL) was treated with Et3N and cooled to 0 0C. The mixture was treated with chloroacetyl chloride (0.50 mL, 6.3 mmol) as a solution in CH2Cl2 (2 mL). The reaction was stirred at 0 C for 15 min and then at room temperature for 30 min. The reaction was diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.72 g, 76 %) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): delta 4.06 (s, 2H), 3.73-7.67 (m, 4H), 3.62 (app t, 2H, J = 4.0 Hz), 3.52 (app t, 2H, J = 4.0 Hz).
76.6%
With triethylamine; In tetrahydrofuran;
Reference Example 116 Triethylamine (4.5 g, 44.5 mmol) was added to a tetrahydrofuran solution (60mL) of morpholine (3g, 32. 7 mmol), and a tetrahydrofuran solution (20 mL) of chloroacetyl chloride (3.9 g, 34.5 mmol) was added dropwise, gradually while the solution was ice-water-cooled. Ether was added to the residue; the precipitated triethylamine hydrochloride was removed by filtration; and the filtrate was concentrated under reduced pressure. The residue obtained was purified by distillation under reduced pressure (10 mm Hg, 110 to 112C), to obtain 4-(chloroacetyl)morpholine (4.1 g, 76.6%) as a pale yellow oil. 1H-NMR(CDCl3)delta:3.50-3.79(8H,m),4.07(2H,s)ppm
76.6%
With triethylamine; In dichloromethane; at 0℃;
10 g of the compound of the formula I and 46.5 g of triethylamine were dissolved in 100 mL of dichloromethane, Stir well. 51.8 g of monochloroacetyl chloride was added dropwise at 0 C.The reaction was complete by TLC. add saturated sodium bicarbonate solution, extract with ethyl acetate and dry. concentration under reduced pressure to gave 14.4 g of 4-(2-chloroacetyl)morpholine, yield 76.6%.
69.2%
With triethylamine; In dichloromethane; for 4.0h;
To a stirred solution of morpholine (17.4 g,200 mmol) and triethylamine (24.24 g, 220 mmol) in CH2Cl2 (200 mL), acetyl chloride (24.00 g, 210mmol) in CH2Cl2 (volume) was added dropwise. The resulting reaction mixture was stirred at this temperature for a further 4 h, then poured into water, and the aqueous layer extracted twice with methylene chloride. The organic chloride phase was combined, washed with dilute hydrochloric acid and water, and dried over Na2SO4, and evaporated to dryness to give compound 20 (22.66 g, 69.2%yield) as a pale yellow oil.
68%
In dichloromethane; at 20℃; for 1.0h;
[0170] To morpholine (466 mg, 5.36 mmol) in DCM (13.4 mL) at 0 C, was added 2- chloroacetyl chloride (300 mg, 2.68 mmol) in DCM. The mixture was then stirred at r.t. for 1 h. The precipitate was filtered and the filtrate was concentrated to provide the title compound as an oil (300 mg, 68%). MS (ES+) m/e 164 (M+H)+.
64%
With triethylamine; In tetrahydrofuran; at 0℃; for 0.333333h;
4-(Chloroacetyl)morpholine To a solution of morpholine (3.6 mL, 41 mmol) and triethylamine (5.2 g, 51 mmol) in tetrahydrofuran (100 mL) was added chloroacetyl chloride (3.0 mL, 38 mmol) at 0C, and the mixture was stirred at 0C for 20 minutes. The reaction solution was concentrated and ethyl acetate was added thereto. The resulting mixture was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated to obtain the title compound (4.0 g, yield 64%) as an oily matter. 1H NMR (CDCl3) delta 3.52-3.55 (2H, m), 3.62-3.65 (2H, m), 3.69-3.75 (4H, m), 4.07 (2H, s).
64%
With potassium carbonate; In toluene; at 60℃; for 2.5h;
0.45 mL of chloroacetyl chloride (5.78 mmol, 1.0 eq) was added to a suspension of 0.5 mL of morpholine (5.78mmol, 1.0 eq), 1.60 g of potassium carbonate (11.57 mmol, 2.0 eq) in 15 mL of abs. toluene. The mixture was stirred at 60 C for 2.5 hours. The suspension was filtered and the solvent was removed under reduced pressure to give 0.78 g (64%) of a yellow oil.
50%
With triethylamine; In dichloromethane; for 1.0h;Cooling with ice;
Take 870 microliters morpholine in 50ml round bottom flask, add 20ml methylene chloride to make it dissolve, slowly add 820 microliters chloroacetyl chloride slowly under ice-water bath, and slowly add 1.4ml triethylamine slowly, continue stirring 1 hour. The reaction was diluted with water and extracted three times with dichloromethane (15 ml each). The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 827 mg of intermediate A19 in a yield of 50%
1.42 g (76%)
With triethylamine; In ethyl acetate;
Preparation 24 4-(Chloroacetyl)morpholine [BM.1] To a stirring mixture of morpholine (1.00 g) and triethylamine (1.6 mL) in EtOAc (10 mL) at 0 C. is added chloroacetyl chloride (1.83 mL) dropwise. The mixture is stirred at 0 C. for 35 min., diluted with 10% HCl (25 mL) and extracted with EtOAc (3*50 mL). The organic layer is dried over MgSO4, and the solvent removed. The residue is purified by SiO2 flash column chromatography (eluent 35% EtOAc/hexane) to afford 1.42 g (76%) of the title compound as a yellow liquid. Physical characteristics: 1H NMR (CDCl3) delta 3.54, 3.64, 3.72, 4.07; IR (liq.) 2859, 1654, 1463, 1438, 1302, 1270, 1251, 1233, 1115, 1069, 1040, 965, 790, 657, 604 cm-1; MS (ESI+) m/z 164 (M+H)+. Anal. Found: C, 43.66; H, 6.17; N, 8.58.
With potassium carbonate; In dichloromethane;
Intermediate: 4-(Chloroacetyl)morpholine Utilize a Quest 205 Parallel Synthesizer and to a mixture of morpholine (2.6 g, 30 mmol), dichloromethane (45 mL) and 2M K2CO3 slowly add chloroacetylchloride (3.73 g, 33 mmol) in dichloromethane (10 mL). Agitate the reaction overnight and filter off the organic layer. Extract the aqueous with dichloromethane (20 mL) and add it to the previously collected organic layer. Dry the organic phase (MgSO4) and concentrate under vacuum to obtain the title compound.
4-Chloroacetyl-morpholine was prepared from morpholine and chloroacetyl chloride using SCHOTTEN-BAUMANN conditions. A mixture of 9- (4, 5-DIMETHYL-THIAZOL-2-YL)-4-PIPERAZIN-1-YL-5, 6,7, 8-TETRAHYDRO- 1, 3, 4b-triaza-fluorene (102MG), 4-CHLOROACETYL-MORPHOLINE (45mg) and potassium carbonate (46mg) in DIMETHYLFORMAMIDE (ImL) was stirred at room temperature. After 2 hours the reaction mixture was diluted with ethyl acetate, washed with brine, dried (MGS04) and the solvent removed III vacuo to yield a gum, which was purified using flash chromatography (dichloromethane) to yield the title compound (58mg)
With triethylamine; In dichloromethane; at 0 - 10℃;
General procedure: To a series of substituted amines (1-7) in dichloromethane (0.05g/mL) was added chloroacetyl chloride (1.1equiv.) followed by the addition of triethylamine (2.5equiv.) at 0-10C. The reaction was continued at the same temperature for 30minto 1h. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with saturated NaHCO3 solution and washed with brine solution The excess organic solvent was removed under reduced pressure and the crude compound used for further reaction without purification.
46.69 g
With triethylamine; In dichloromethane; at -10 - 20℃; for 3.0h;
To a solution of chloroacetyl chloride (25 ml) in dry dichloromethane (125 ml) at -10C was added dropwise a solution of morpholine (30 ml) and triethylamine (47.5 ml) in dry dichloromethane (125 ml) over approximately two hours keeping the internal temperature below 20C. After addition, the reaction mixture was stirred for one hour then the reaction mixture was washed with 0.5N aqueous hydrochloric acid (200 ml) and water (2 x 200 ml). The combined aqueous was back extracted with dichloromethane (2 x 150 ml); the organic layers were combined, dried (MgS04) and evaporated to afford the title compound (46.69 g) as a brown oil. 1H-NMR (400 MHz, CDC13) delta (ppm): 3.49 - 3.57 (m, 2 H) 3.58 - 3.66 (m, 2 H) 3.71 (dt, J=9.84, 4.86 Hz, 4 H) 4.06 (s, 2 H)
In benzene; for 1.0h;Reflux;
General procedure: Chloroacetyl chloride 13 (0.06 mol, 4.0 ml) was added dropwise into the solution of imine (4a-4c) (0.06 mol) in benzene (20 ml) at 10 C. 30 min later, this mixture was refluxed gently for 1 h and then allowed to cool to room temperature. The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by vacuum distillation to afford the imino chlorides (14a-14c) which were then used directly in the next step.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.0h;
General procedure: To a stirred solution of triethylamine (17.2 mmol, 2.5 mL) and 17.2 mmol piperidine 1h(or morpholine 1i) in 10 mL CH2Cl2, 2-chloroacetyl chloride (17.2 mmol, 1.38 mL) wasadded dropwise at 0 C. Upon completion of the dropwise addition, the solution was broughtto room temperature and stirred for 2 h. Subsequently, the resulting solution was diluted with20 mL CH2Cl2 and successively washed with 20 mL water and 20mL brine. The CH2Cl2 layerwas separated and concentrated under reduced pressure to give crude 1h (or 1i) which wasfurther purified by chromatography to afford the desired 1h (or 1i) as a yellowish oil. Thephysical, analytical and spectral data of 2h and 2i are summarized in the Supplementarymaterial to this paper
With triethylamine; In dichloromethane; at 20℃; for 2.0h;
The compound Morpholine (2 g, 22.96 mmol),Triethylamine (9.6 mL, 68.87 mmol) was added to anhydrous dichloromethane (20 mL)Cooled to C,Chloroacetyl chloride (2.19 mL, 27.55 mmol) was added dropwise,After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 2 hours.After completion of the reaction, the crude product was washed with 1N hydrochloric acid solution, sodium bicarbonate solution, brine and dried to give crude 2-chloro-1-(morpholin-4-yl)ethan-1-one (1.7 g) in 45% yield.
4-Chloroacetyl-morpholine was prepared from chloroacetyl chloride and morpholine
In dichloromethane; at 20℃; for 24.0h;
Chloroacetyl chloride (0.57 g, 5 mmol) was dissolved in 20 mL of dichloromethane, and morpholine (0.96 g, 11 mmol) was added thereto.Stir the reaction at room temperature for 24 h, the reaction is completed, and add appropriate amount of water to wash.The organic layer was dried over anhydrous magnesium sulfate.Concentrated under reduced pressure to give N-chloroacetylmorpholine,It was used directly in the next step without purification.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2.0h;
General procedure: B23-B27 or B34-B361.0 mmol, 1.0 equiv) and Et3N (1.2 mmol,1.2 equiv) were dissolved in anhydrous tetrahydrofuran (THF), thena solution of chloroacetyl chloride (1.1 mmol, 1.1 equiv) in anhydrousTHF was added dropwise at 0 C. The reaction mixture wasthen stirred at room temperature for additional 2 h. Then water(30 mL) was added, extracted with ethyl acetate (3 10 mL). Theorganic phase was combined, dried over anhydrous Na2SO4,filtered, and concentrated to yield the crude azide substituents,which was purified by flash column chromatography to afford intermediatesC23eC27 and C34eC36. To a solution of the intermediatesin DMF were added sodium azide (1.2 mmol,1.2 equiv),and the mixture was stirred for 24 h at room temperature. Thenwater (30 mL) was added, extracted with ethyl acetate (3 10 mL).The organic phase was combined, dried over anhydrous Na2SO4,filtered, and concentrated to yield the target azide substituentsN23eN27 and N34eN36, which were used for the next stepwithout further purification.
With potassium carbonate; In tetrahydrofuran; at 100℃; for 24.0h;Heating / reflux;
Step 2 A THF (10 mL) solution of 4-hydroxybenzaldehyde (0.50 g, 4.09 mmol) was added with <strong>[1440-61-5]N-chloroacetylmorpholine</strong> (1.00 g, 6.12 mmol) obtained in Step 1 and potassium carbonate (1.70 g, 12.3 mmol), followed by heating under reflux at 100C for 24 hours. The reaction mixture was concentrated, and the residue was added with ethyl acetate and saturated brine, and then was extracted. The organic layer was dried over anhydrous sodium sulfate, and was concentrated to obtain N-(4-formylphenoxy)acetylmorpholine (1.24 g, quantitative yield). 1H-NMR (270 MHz, CDCl3) delta 3.51-3.74 (m, 8H), 4.80 (s, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H), 9.90 (s, 1H).
100%
With potassium carbonate; In tetrahydrofuran; for 24.0h;Reflux;
To a boiling suspension of 376 mg 4-hydroxybenzaldehyde (3.08 mmol, 1.0 eq), 1.28 g of potassium carbonate (9.23 mmol, 3.0 eq) in 5 mL of abs. tetrahydrofuran was added a solution of 755 mg of 2-chloro-1-morpholinethanone (4.62 mmol, 1.5 eq) in 10 mL of abs. tetrahydrofuran. The mixture was heated to reflux for 24 hours. The solvent was removed under reduced pressure. The residue was taken up in 20 mL of brine,extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried over Na2SO4, filtered and thesolvent was removed under reduced pressure to yield 780 mg (quant.) of a oily yellow solid.
85%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1.0h;
Take 244 mg of 4-hydroxybenzoic acid and 344 mg of intermediate A19 in a 50 ml round bottom flask,Add 10mlN, N_ dimethylformamide, another additional 828mg potassium carbonate, the reaction was stirred at 80 C oil bath for 1 hour, cooled to room temperature. The reaction solution was diluted with ethyl acetate and washed with water four timesThe layers were separated and the ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography using methylene chloride-methanol = 10: 1 as an eluent to obtain 433 mg of the intermediate, and A20 was obtained in a yield of 85%.
Stage #1: kumujian C With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: N-chloroacetylmorpholine In N,N-dimethyl-formamide at 65℃; for 24h;
4.a
EXAMPLE 4: Preparation of compound 1128 of Scheme 3.Step a: Preparation of 9-(2-morpholino-2-oxoethyl)-9H-pyrido[3,4-δ]indole-l-carbaldehyde: 4.00 mmol of cesium carbonate was added to the solution of 2.00 mmol of carboline aldehyde in 20 ml DMF. After stirring 1 hour at room temperature 3.00 mmol of N- (chloroacetyl)morpholine was added to the reaction mixture. The reaction mixture was heated to 65 0C for 24 hours and then poured to ice-water. The precipitate was filtered off, and washed with water and dried. The product was pure enough to use for the next step (75% yield). ESI+MS: m/z (rel intensity) 324.10 (100, [M+H]+). 1H-NMR (400 MHz, CDC13): δ 10.21 (s, IH), 8.66 (d, IH, J= 4.8 Hz), 8.20 (d, IH, J= 4.4 Hz), 8.17 (d, IH, 6.8 Hz), 7.64 (dt, IH, J= 1.2, 7.2 Hz), 7.38 (q, 2H, J= 7.2 Hz), 5.81 (s, 2H), 3.92 (t, 2H, J= 4.4 Hz), 3.74 (t, 4H, J= 4.8 Hz), 3.61 (t, 2H, J= 4.8 Hz).
With sodium azide; In water; acetonitrile; at 20℃; for 24.0h;
To a solution of alpha-chloroamide 15aa (1.41 g, 8.62 mmol) in acetonitrile (20 mL) and H2O (1 mL) was added sodium azide (700 mg, 10.77 mmol). The reaction mixture was stirred at room temperature for 1 day, and then diluted with EtOAc, washed with brine, dried over MgSO4 and filtered. The solvent was removed, and the residue was passed through a short plug of silica to give -azidoamide 16aa (1.40 g, 99%) as a colorless oil: 1H-NMR (CDCl3) delta 3.38 (t, J = 4.8 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H),3.67-3.71 (m, 4H), 3.92 (s, 2H); 13C-NMR (CDCl3) delta 42.3, 45.6, 50.6, 66.5, 66.8, 165.9; LC-MS (ESI) m/z171 ([M + 1]+).
79%
With sodium azide; In tetrahydrofuran; water; for 24.0h;Reflux;
In a round-bottom flask containing 254 3.3 mL of H2O and 6.6 mL of THF was added compound 17 (1 eq.), followed by sodium 255 azide (2 eq.). The reaction mixture was refluxed under magnetic stirring for 24h. The 256 solvent was partially removed under reduced pressure, followed by extraction with 20 257 mL of AcOEt. The organic layer was washed with 2x10 mL of H2O, dried with anhydrous 258 magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield 259 4-(azidoacetyl)morpholine 18 as a white solid, 79% yield; m.p. 67.8 - 69.0 C; IR (neat, 260 cm-1) 2106, 1635, 1110; 1H NMR (200 MHz, CDCl3) delta 3.92 (s, 2H), 3.67 (broad s, 6H), 261 3.50 - 3.20 (m, 2H); 13C NMR (CDCl3, 50 MHz) delta 165.7, 66.6, 66.3, 50.5, 45.4, 42.2.
With sodium azide; In N,N-dimethyl-formamide; at 20℃;
General procedure: To a mixture of 8-14 in dimethylformamide (0.067g/mL) was added sodium azide (3.0equiv.) at room temperature and the reaction allowed to proceed for 8-12h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was subjected to an extraction with ethyl acetate with saturated NaHCO3 solution, and the organic extracts washed with brine solution and finally water. The organic solvent was removed under reduced pressure and the crude compounds were used for further reaction without any purification, based on a high-level purity (>95%) by 1H NMR spectroscopy.
With sodium azide; In N,N-dimethyl-formamide; at 20℃; for 24.0h;
General procedure: B23-B27 or B34-B36 (1.0 mmol, 1.0 equiv) and Et3N (1.2 mmol,1.2 equiv) were dissolved in anhydrous tetrahydrofuran (THF), thena solution of chloroacetyl chloride (1.1 mmol, 1.1 equiv) in anhydrousTHF was added dropwise at 0 C. The reaction mixture wasthen stirred at room temperature for additional 2 h. Then water(30 mL) was added, extracted with ethyl acetate (3 10 mL). Theorganic phase was combined, dried over anhydrous Na2SO4,filtered, and concentrated to yield the crude azide substituents,which was purified by flash column chromatography to afford intermediatesC23eC27 and C34eC36. To a solution of the intermediatesin DMF were added sodium azide (1.2 mmol,1.2 equiv),and the mixture was stirred for 24 h at room temperature. Thenwater (30 mL) was added, extracted with ethyl acetate (3 10 mL).The organic phase was combined, dried over anhydrous Na2SO4,filtered, and concentrated to yield the target azide substituentsN23eN27 and N34eN36, which were used for the next stepwithout further purification.
4-Fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile. To a solution of intermediate 129, <strong>[186590-01-2]4-fluoro-2-hydroxybenzonitrile</strong>, (685 mg, 5 mmol) in dimethylformamide (8 mL, Sure Seal; Aldrich) was added NaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich), and the mixture stirred for 5 min under an anhydrous nitrogen atmosphere. To this was added 4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; Avocado Organics), and stirring continued at room temperature for 21 hrs. The reaction was quenched by careful addition of water (30 mL). The resulting mixture was extracted with CH2Cl2 (25 mL×2). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of the title compound as a white solid: 1H NMR (CDCl3, 500 MHz) delta ppm: 3.63 (2H, t, J=4 Hz, NCH2), 3.67 (1H, m, OCH), 3.72 (1H, m, OCR), 4.86 (2H, s, OCH2), 6.80-6.86 (2H, m, Ar-Hs), 7.61 (1H, dd, J=8.5 Hz, 6.1 Hz, Ar-H); 13C NMR (CDCl3, 125.77 Hz) delta ppm: 42.63, 46.04, 66.80, 68.33, 98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57, 161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C13H14N2O3F (M+H) 265.0988. found 265.0998.
83%
4-Fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile. To a solution of intermediate 129, <strong>[186590-01-2]4-fluoro-2-hydroxybenzonitrile</strong>, (685 mg, 5 mmol) in dimethylformamide (8 mL, Sure Seal; Aldrich) was added NaH (200 mg, 5 mmol; 60% oil dispersion; Aldrich), and the mixture stirred for 5 min under an anhydrous nitrogen atmosphere. To this was added 4-(2-chloroacetyl)morpholine (900 mg, 5.5 mmol, 1.1 eq.; Avocado Organics), and stirring continued at room temperature for 21 hrs. The reaction was quenched by careful addition of water (30 mL). The resulting mixture was extracted with CH2Cl2 (25 mLx2). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was triturated to obtain 1.10 g (4.17 mmol, Yield 83%) of the title compound as a white solid: 1H NMR (CDCl3, 500 MHz) 5 ppm: 3.63 (2H, t, J = 4 Hz, NCH2), 3.67 (IH, m, OCH), 3.72 (IH, m, OCH), 4.86 (2H, s, OCH2), 6.80-6.86 (2H, m, Ar-Hs), 7.61 (IH, dd, J = 8.5 Hz, 6.1 Hz, Ar-H); 13C NMR (CDCl3, 125.77 Hz) delta ppm: 42.63, 46.04, 66.80, 68.33, 98.45, 98.47, 101.57, 101.79, 109.56, 109.74, 115.42, 135.48, 135.57, 161.26, 161.35, 114.79, 165.23, 167.28. HRMS calcd for C13H14N2O3F (M+H) 265.0988, found 265.0998.
Example 39a 2-Chloro-1-(5-methylthiazol-2-yl)ethanone Isopropylmagnesium bromide (CAS 920-39-8, 1 M in THF, 12.1 mL, 12.1 mmol) was added dropwise to a solution of <strong>[41731-23-1]2-bromo-5-methylthiazole</strong> (CAS 41731-23-1, 2.056 g, 11.55 mmol) in THF (20 mL) at 0 C. and the resulting solution was stirred for 15 min at 0 C. A solution of 2-chloro-1-morpholinoethanone (CAS 1440-61-5, 2.078 g, 12.70 mmol) in THF (5 mL) was added dropwise and the mixture was stirred at 0 C. for 45 min and then at room temperature for 1.5 h. The reaction was quenched by the addition of sat. aq. NH4Cl and the mixture was diluted with diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with citric acid, water and sat. aq. NaHCO3, dried over MgSO4 and concentrated to give 2-chloro-1-(5-methylthiazol-2-yl)ethanone (1.48 g, 73%). MS m/z 176, 178 [M+H]+.
36%
[00349] 2-Chloro-l-(5-methylthiazol-2-yl)ethanone. Isopropylmagnesium chloride (2 M in Et20, 2.67 mL, 5.35 mmol) was added dropwise to a solution of <strong>[41731-23-1]2-bromo-5-methylthiazole</strong> (1.0 g, 5.62 mmol, 1.05 equiv.) in THF (10 mL) at 0C. The resulting solution was stirred for 15 min at 0C. A solution of 2-chloro-l-morpholinoethanone (959 mg, 5.88 mmol, 1.1 equiv.) in THF (3 mL) was added dropwise and the mixture was stirred at 0 C for 45 min and then at room temperature for 1.5 h. The reaction was quenched by the addition of sat. aq. NH4CI and the mixture was diluted with diethyl ether. The phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with water and sat. aq. NaHCC>3, dried over MgS04 and concentrated to give 2-chloro-l-(5- methylthiazol-2-yl)ethanone. The crude product was purified using automated flash chromato raphy in 36 % isolated yield. ESI-MS (m/z): 176.1 [M+H]+.
4-[(2R,3S,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(3-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid 2-morpholin-4-yl-2-oxoethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h;Sealed tube;
In a 15 mL pressure tube, <strong>[1229705-06-9]4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid</strong> (prepared as described in US20100152190A1, 100 mg, 162 mumol) and cesium carbonate (63.4 mg, 195 mumol) were combined with dry dimethyl formamide (5 mL). 2-Chloro-1-morpholinoethanone (26.5 mg, 21.1 muL, 162 mumol) was added to the mixture with stirring. The tube was capped and heated at 50 C. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2*). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-morpholin-4-yl-2-oxo-ethyl ester as an off-white solid (104 mg, 86% yield) as product. LCMS (ES+) m/z calcd. for C37H39Cl2F2N4O6[(M+H)+]: 743. found: 743
1-morpholino-2-[(1S)-1-(trityloxymethyl)allyloxy]ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 0 - 5℃; for 19.0h;Large scale;
Preparation 2 1-Morpholino-2-[(1S)-1-(trityloxymethyl)allyloxy]ethanone Scheme 2, step A: Add tetrabutyl ammonium hydrogen sulfate (83.2 g, 245.0 mmol) and 4-(2-chloroacetyl)morpholine (638.50 g, 3902.7 mmol) to a solution of 1-trityloxybut-3-en-2-ol (832.4, 2519 mmol) in toluene (5800 mL) that is between 0 and 5 C. Add sodium hydroxide (1008.0 g, 25202 mmol) in water (1041 mL). Stir for 19 hours between 0 and 5 C. Add water (2500 mL) and toluene (2500 mL). Separate the layers and wash the organic extract with water (2*3500 mL). Concentrate the organic extract under reduced pressure to dryness. Add toluene (2500 mL) to the residue and then add n-heptane (7500 mL) slowly. Stir for 16 hours. Collect the resulting solids by filtration and wash with n-heptane (1200 mL). Dry the solid under vacuum to obtain the title compound (1075.7 g, 98%).
98%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 0 - 5℃; for 19.0h;Large scale;
Add tetrabutyl ammonium hydrogen sulfate (83.2 g, 245,0 mmol) and 4-(2-chloroacetyl)morpholine (638.50 g, 3902.7 mmol) to a solution of 1- trityloxybut-3-en-2-o] ( 832.4, 2519 mmol) in toluene (5800 mL) that is between 0 and 5 C. Add sodium hydroxide (1008.0 g, 25202 mmol) in water (1041 mL). Stir for 19 hours between 0 and 5 C, Add water (2500 mL) and toluene (2500 mL). Separate the layers and wash the organic extract with water (2 chi 3500 mL). Concentrate the organic extract under reduced pressure to dryness. Add toluene (2500 ml.) to the residue and then add n-heptane (7500 mL) slowly. Stir for 16 hours. Collect the resulting solids by filtration and wash with n-heptane (1200 mL). Dr the solid under vacuum to obtain the title compound (1075.7 g, 98%).
98%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 0 - 5℃; for 19.0h;Large scale;
Add tetrabutyl ammonium hydrogen sulfate (83.2 g, 245.0 mmol) and 4-(2-chloroacetyl)morpholine (638.50 g, 3902.7 mmol) to a solution of 1- trityloxybut-3-en-2-ol ( 832.4 , 2519 mmol) in toluene (5800 mL) that is between 0 and 5 C. Add sodium hydroxide (1008.0 g, 25202 mmol) in water (1041 mL). Stir for 19 hours between 0 and 5 C. Add water (2500 mL) and toluene (2500 mL). Separate the layers and wash the organic extract with water (2 chi 3500 mL). Concentrate the organic extract under reduced pressure to dryness. Add toluene (2500 mL) to the residue and then add n-heptane (7500 mL) slowly. Stir for 16 hours. Collect the resulting solids by filtration and wash with n-heptane (1200 mL). Dry the solid under vacuum to obtain the title compound (1075.7 g, 98%).
98%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 0 - 5℃; for 19.0h;Large scale;
Scheme la, step A: Add tetrabutyl ammonium hydrogen sulfate (83.2 g, 245.0 mmol) and 4-(2-chloroacetyl)morpholine (638.50 g, 3902.7 mmol) to a solution of 1- trityloxybut-3-en-2-ol ( 832.4, 2519 mmol) in toluene (5800 mL) that is between 0 and 5 C. Add sodium hydroxide (1008.0 g, 25202 mmol) in water (1041 mL). Stir for 19 hours between 0 and 5 C. Add water (2500 mL) and toluene (2500 mL). Separate the layers and wash the organic extract with water (2 x 3500 mL). Concentrate the organic extract under reduced pressure to dryness. Add toluene (2500 mL) to the residue and then add n-heptane (7500 mL) slowly. Stir for 16 hours. Collect the resulting solids by filtration and wash with n-heptane (1200 mL). Dry the solid under vacuum to obtain the title compound (1075.7 g, 98%).
91%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 5℃; for 19.0h;
To a solution of 1-40 (15.31 g, 46.34 mmol) in toluene (104.25 mL) at 5 C were added tetrabutylammonium hydrogen sulfate (1.57 g, 4.63 mmol), 4-(2-chloroacetyl)morpholine (9.35 mL, 71.82 mmol) and a solution ofNaOH (18.53 g, 463.35 mmol) in water (25 mL). The r.m. was stirred for 19 h, while allowing the temperature to reach rt, then water (15 mL) and toluene (5 mL) were added. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-41(19.3 g, 91%) as a solid, which was used in the subsequent step without further purification.
5-(4-nitrophenyl)amino-1,3,4-thiadiazole-2(3H)-thione[ No CAS ]
1-(morpholin-4-yl)-2-[(5-((4-nitrophenyl)amino)-1,3,4-thiadiazol-2-yl)thio]ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate; In acetone; at 20℃; for 8.0h;
General procedure: A mixture of N-(alkyl/aryl)-2-chloroacetamide/4-(chloroacetyl)morpholine (2 mmol) and 5-(4-nitrophenyl)amino-1,3,4-thiadiazole-2(3H)-thione (2) (2 mmol) in acetone was stirred at room temperature for 8 h in the presence of potassium carbonate. The reaction mixture was filtered. The residue was washed with water and crystallized from ethanol.
3,6-di-(morpholinyl-carbonylmethoxy)xanthone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.6%
With potassium carbonate In acetone for 3h; Reflux;
Synthesis of xanthone derivatives (XD) 1-10
General procedure: K2CO3 (4.14 g, 30 mmol) and N-substituted or N,N-disubstituted-a-chloroacetamide (2 mmol) were added to a solution of3,6-dihydroxy-4-methylxanthone (484 mg, 2 mmol) or 3.6-dihydroxyxanthone(456 mg, 2 mmol) in acetone (60 mL). The mixturewas stirred under reflux for 3 h, after which more N-substituted orN,N-disubstituted-a-chloroacetamide (2 mmol) were added. Then,the mixture was stirred under reflux overnight. The solid was filteredout and washed with acetone. The residual left after theremoval of the acetone by a rotavapor was purified by dry-columnflash chromatography to afford XD1-10.
1-morpholino-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;
[0172] A mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (300 mg, 1.36 mmol), 2-chloro-l-morpholinoethan-l-one (223 mg, 1.36) and K2CO3 (283 mg, 2.04 mmol) in DMF (4.5 mL) was heated at 90 C overnight, diluted with EtO Ac, washed with water (2x) and brine, dried over Na2S04, concentrated, and purified by chromatography with EtO Ac/Hex to provide the title compound (201 mg, 42%) as a white solid. MS (ES+) m/e 348 (M+H)+.
N-(4-fluorobenzyl)-1,2-dimethyl-5-hydroxy-1H-indole-3-carboxamide[ No CAS ]
N-(4-fluorobenzyl)-1,2-dimethyl-5-[2-(morpholin-4-yl)-2-oxoethoxy]-1H-indole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.9%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16.0h;
General procedure: A solution of 5a, 5b, 5c or 5d (0.0034 mol), 2-chloroacetamide (0.017 mol), anhydrous potassium carbonate (4.70 g, 0.034 mol), potassium iodide (0.06 g, 0.00034 mol) in N,N-dimethylformamide (DMF, 20 mL) was stirred at 80C for 16 h. Water (100 mL) was added and the reaction mixture was stirred for 4 h. The mixture was filtered and the residue was purified by column chromatography on silica gel using petroleum ether/ ethyl acetate (5/1, v/v) as eluent to afford the corresponding products (6a-6x).
75.9%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16.0h;
General procedure: A solution of 5a, 5b, 5c or 5d (0.0034 mol), 2-chloroacetamide (0.017 mol), anhydrous potassium carbonate (4.70 g, 0.034 mol), potassium iodide (0.06 g, 0.00034 mol) in N,N-dimethylformamide (DMF, 20 mL) was stirred at 80 C for 16 h. Water (100 mL) was added and the reaction mixture was stirred for 4 h. The mixture was filtered and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (5/1, v/v) as eluent to afford the corresponding products (6a-6l).
N-benzyl-2-methyl-1-ethyl-5-hydroxy-1H-indole-3-carboxamide[ No CAS ]
N-benzyl-1-ethyl-2-methyl-5-[2-(morpholin-4-yl)-2-oxoethoxy]-1H-indole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.7%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16.0h;
General procedure: A solution of 5a, 5b, 5c or 5d (0.0034 mol), 2-chloroacetamide (0.017 mol), anhydrous potassium carbonate (4.70 g, 0.034 mol), potassium iodide (0.06 g, 0.00034 mol) in N,N-dimethylformamide (DMF, 20 mL) was stirred at 80C for 16 h. Water (100 mL) was added and the reaction mixture was stirred for 4 h. The mixture was filtered and the residue was purified by column chromatography on silica gel using petroleum ether/ ethyl acetate (5/1, v/v) as eluent to afford the corresponding products (6a-6x).
77.7%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16.0h;
General procedure: A solution of 5a, 5b, 5c or 5d (0.0034 mol), 2-chloroacetamide (0.017 mol), anhydrous potassium carbonate (4.70 g, 0.034 mol), potassium iodide (0.06 g, 0.00034 mol) in N,N-dimethylformamide (DMF, 20 mL) was stirred at 80 C for 16 h. Water (100 mL) was added and the reaction mixture was stirred for 4 h. The mixture was filtered and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (5/1, v/v) as eluent to afford the corresponding products (6a-6l).
2-(but-3-en-2-yloxy)-1-morpholinoethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: 2-hydroxy-3-butene With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water; toluene at 10 - 20℃; for 0.25h;
Stage #2: N-chloroacetylmorpholine In water; toluene at 10 - 20℃; for 1h;
2 <2-(but-3-en-2-yloxy)-1-morpholinoethanone>
A reactor was charged with tetra-butylammonium hydrogen sulfate (0.10 eq) and toluene (4.0 V). The mixture was cooled to 10-20 °C. While maintaining the internal temperature below 20 °C, 50 wt% aqueous sodium hydroxide (2.2 V, 9.7 eq) and then 3-buten-2-ol (0.66 V, 1.25 eq) were added. The mixture was stirred at 10-20 °C for 15 minutes. 4-(chloroacetyl)morpholine (1.0 Wt, 1.00 eq) was added while maintaining the internal temperature between 10-20 °C, After the addition, the mixture was stirred between 10-20 °C for 1h and monitored the reaction for complete consumption of 4-(chloroacetyl)morpholine (target >98% conversion). The reactor was charged with water (3.0 V) and MTBE (6,00 V) while maintaining the internal temperature between 10-20 °C. The biphasic mixture was stirred vigorously for 15 minutes, and then allowed to partition. The aqueous layer was extracted with MTBE (3.0 V). The combined organic layers were washed with water twice (1.5V each). The water wash was extracted with MTBE twice (1.6 V each). The organic layers were combined and concentrated under reduced pressure (T < 40 C). Heptane (1.0 V) and MTBE (1.0 V) were added. The solution was filtered to remove particulates, rinsing with additional heptane:MTBE as necessary to clear the product. The solution was returned to the reactor and concentrated under reduced pressure to give amide 12 (77%) as oil.
66.4%
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water; toluene for 1h; Large scale;
4-(3,4-dimethoxybenzyl)-3-(3-methoxy-4-(2-morpholino-2-oxoethoxy)benzyl) dihydrofuran-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
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%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20.0℃; for 20.0h;
The above N-chloroacetylmorpholine was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl) was added to the above solution.Amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) and anhydrous K2CO3 (0.69 g, 5 mmol), stirred at room temperature20h, after the reaction is completed, pour into an appropriate amount of ice water, and filter by suction to obtain a crude product, which is dried.Silica gel column chromatography (dichloromethane:methanol = 3:1) gave the title compound as a yellow solid powder, yield 57%.
ethyl 2-(3-methoxy-4-(2-morpholin-2-oxoethoxy)phenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate; In acetone; for 12h;Reflux;
Take intermediate A1 (0.01 mol) and intermediate B1 (0.01 mol)Add to 100 ml of acetone solution, add potassium carbonate solid to the stirred solution,The reaction was carried out under reflux for 12 h, and the reaction mixture was evaporated to dryness.Wash 100 ml of water three times, dry over anhydrous magnesium sulfate, filter, and spin dry to give the initial product.Flash column separation (ethyl acetate / petroleum ether = 1 : 4) afforded 2.Yield: 88%.
1-morpholino-2-(1-phenyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In acetonitrile;Reflux;
General procedure: A solution of tetrahydrocarboline 4(1.2 mmol), K2CO3 (1.5 eq) and alkyl halide (1.2 eq)in 10 mL of acetonitrile was stirred at reflux. After completion (reactionmonitored by TLC) some ice was added and the precipitate filtered to providethe desired compound.
2-[4-(4-fluorophenyl)-1H-imidazol-1-yl]-1-(morpholin-4-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: 4-(4-fluorophenyl)-1H-imidazole With sodium hydride In tetrahydrofuran for 0.25h; Cooling with ice;
Stage #2: N-chloroacetylmorpholine In tetrahydrofuran at 0 - 20℃; for 4h;
1.2 Synthesis of 2-[4-(4-fluorophenyl)-1H-imidazol-1-yl]-1-(morpholin-4-yl)ethan-1-one / Intermediate 43-1
NaH (60%, 95 mg, 2.37 mmol) was added to an ice-cold solution of 4-(4-fluorophenyl)-1H- imidazole (350 mg, 2.16 mmol) in anhydrous THF (7 mL). The reaction was stirred for 15 min before 2-chloro-1-morpholino-ethanone (0.28 mL, 2.16 mmol) was added, and the reaction was stirred at 0 °C for 2 h and at RT for 2 additional h. The reaction was carefully quenched into water, extracted with EtOAc (2x), washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by flash chromatography (25 g, silica), eluting with 0-6% MeOH/DCM and the resulting product was triturated with DCM to yield the title compound as a white solid (253 mg, 40% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.79 - 7.73 (m, 2H), 7.59 (d, J = 1.1 Hz, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.21 - 7.14 (m, 2H), 5.05 (s, 2H), 3.65 (t, J = 4.7 Hz, 2H), 3.60 (t, J = 4.7 Hz, 2H), 3.51 (t, J = 4.6 Hz, 2H), 3.47 (t, J = 4.6 Hz, 2H). LCMS (Analytical Method F) Rt = 0.47 min, MS (ESIpos): m/z 290.1 [M+H]+, Purity = 100%
2-(5-(benzyloxy)-1H-indol-1-yl)-1-morpholinoethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: 5-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h;
Stage #2: N-chloroacetylmorpholine 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.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
HazMat Fee +
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
