* 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; triethylamine In N,N-dimethyl-formamide at 80℃; for 2 h;
Step first, 80g p-hydroxybenzaldehyde, 128g potassium carbonate, DMF 150mL and 10mL isopropyl stirred, and then added the 101g of 2-(dimethylamino) chloroethane hydrochloride into DMF, then added the 80g solution of triethylamine, stirred at 80 ° C and carry on reaction for 2 h, the reaction solution is cooled at room temperature, poured into 700mL of water and extracted with 500mL of chloroform, into the chloroform added the 2 mol ·L-1 sulfuric acid 300mL extraction, under ice water, added the 200mL sodium hydroxide solution into aqueous phase with mass fraction 20percent, and then extracted with 1000mL of ethyl acetate, dried over anhydrous sodium sulfate, the ethyl acetate is recovered under reduced pressure and distilled under reduced pressure, then collect bp142-144 ° C / 0.533kPa fractions, and then obtained 110.2g of 4-(2-Dimethylaminoethoxy) benzaldehyde, yield 86.3percent, 100g solution of 4-(2-Dimethylaminoethoxy) benzaldehyde is dissolved in 150 ml of methanol, then under ice bath added the 26.5g sodium borohydride, TLC detection until the end of the reaction, excessive the sodium borohydride with ammonium chloride vanished, under reduced pressure remove the methanol, the crude product is added with 300 ml of water and extracted with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product has been distilled under reduced pressure then obtains 87.9 g of a colorless liquid, yield is 87percent;
85.33%
Stage #1: With sodium hydroxide In water; toluene Stage #2: With tetrabutylammomium bromide; potassium carbonate In ethyl acetate; toluene for 5 h; Heating / reflux
17.5 kg of 2-dimethylaminoethylchloride hydrochloride, 75 kg of deionized water and 2.50 kg of toluene are charged into a batch, 17.5 kg of 30percent sodium hydroxide are then dropped into. The mixture obtained is kept under stirring until complete solution of the solid. The aqueous phase is removed while the organic phase is used for the following preparation. 10 kg of 4-hydroxy-benzaldehyde, 12.5 kg of potassium carbonate, 0.27 kg of tetrabutylammonium bromide and 70 kg of ethyl acetate are charged into a reactor. The mixture obtained is heated under reflux and then the aforesaid toluene solution is added dropwise. The mixture is kept under stirring and reflux for at least 5 hours. 50 kg of deionized water are then added, the mixture obtained is stirred for at least 5 minutes, the aqueous phase is removed and the organic phase is distilled, to obtain an oily residue. The residue is cooled to 20-30°C and 35 kg of 80percent acetic acid are added dropwise. The reaction mixture is then stirred for 5 minutes until complete solution. A solution containing 13.5 kg of 4-(2-dimethylaminoethoxy)-benzaldehyde is obtained. Reaction yield referred to 4-hydroxybenzaldehyde: 85.33percent
72%
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
A mixture of 4-hydroxybenzaldehyde (6.0 g, 49.1 mmol), 2-chloro-N,N- dimethylethanamine hydrochloride (10.61 g, 73.70 mmol) and potassium carbonate (20.37 g, 147.4 mmol) in N,N-dimethylformamide (60 mL) was stirred overnight at 90 °C The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulphate and the solvent evaporated to yield the title compound (7.25 g, 72percent) as a brown oil. LRMS (m/z): 194 (M+1 )+
72%
With potassium carbonate In N,N-dimethyl-formamide at 90℃;
A mixture of 4-hydroxybenzaldehyde (6.0 g, 49.1 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (10.61 g, 73.70 mmol) and potassium carbonate (20.37 g,147.4 mmol) in N,N-dimethylformamide (60 mL) was stirred overnight at 90 °C. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate and the solvent evaporated to yield the title compound (7.25 g, 72percent) as a brownoil.LRMS (mlz): 194 (M+1).
49%
Stage #1: With potassium carbonate In acetone for 2 h; Reflux Stage #2: at 20℃; Reflux
The title compound was obtained as a colorless oil in 49 percent yield by following the general procedure B. UV (EtOH) mm: 219 and 276 nm. IR (nujol): 2945, 2822, 2727, 1685, 1597, 1510, 1466, 131 1,1258, 1216 1 160, 1030 and 834 cm '. NMR (300 MHz, CDCI3): δ 2.37 (6H, s, 2 x NC3/4), 2.81(2H, t, J = 5.1Hz, -NCH2), 4. 1 1 (2H, t, J = 5.4 Hz, OCH2), 6.99 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.81 (2H, d, J = 7.8 Hz, 2 x Ar-H), 9.85 (1H, s, CHO). 13C NMR (75.5 MHz, CDC13): δ 45.68 (2 x NC3/4), 57.90 (NCH2), 66.08 (OCH2), 1 14.82 (C-2 C-6), 130.04(C-1), 13 1.92 (C-3 & C-5), 163.72 (C-4), 190.75 (C=0). HRMS m/z calculated for CH,&5N02 [M+H]+ 194.1 176, observed [M+Hf 194. 1 168. In a dried single-neck round bottom flask, 4-hydroxylbenzaldehyde (40 mmol), potassium carbonate (122 mmol) and dry acetone (160 ml) were taken and the contents refluxed for 2 h. The reaction mixture was brought to room temperature and catalytic amount of potassium iodide was added, followed by the gradual addition of the appropriate dialkylaminoethyl chloride hydrochloride (45 mmol) dissolved in dry acetone (50 ml) through a pressure-equalizing addition funnel and the reaction mixture was allowed to reflux again. The contents were regularly monitored for reaction progress by TLC using 10 percent methanol/dichloromethane as the solvent system. The reaction was generally complete in 10-13 h. At this point, reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8 percent methanol in dichloromethane, v/v as eluent) to afford the six pure 4-dialkylaminoethoxybenzaldehydes as colorless oils in 49-92 percent yields. The structures of these products were unambiguously established from the analysis of their spectral data (IR, NMR, l3C NMR and mass spectra).
10%
With potassium carbonate In DMF (N,N-dimethyl-formamide) for 12 h; Heating / reflux
To a mixture [OF 4-HYDROXYBENZALDEHYDE (1.] 34 g, 10.97 [MMOL)] and 2- dimethylaminoethyl chloride hydrochloride (1.95 g, 13.54 [MMOL)] in DMF (12 mL) was added KzCOs (6.04 g, 3.23 [MMOL).] The mixture was heated at reflux for 12 h. The residue was partitioned between [HZ0] and EtOAc. The organic layer was dried [(MGSO4),] filtered, and concentrated. The crude material was purified by flash chromatography [(10percent] [MEOH/CH2CI2) TO YIELD 4-[2-(DIMETHYLAMINO) ETHOXYBENZALDEHYDE] (220 mg, 10percent) as an orange liquid. 'H NMR (400 MHz, CDCl3) 8 9. 87 (s, 1H), 7. [82 (D, 2H),] 7.01 (d, [2H),] 4.16 (t, [2H),] 2. [79 (T,] 2H), 2. 37 (s, 6H).
Reference：
[1] Patent: CN106518706, 2017, A, . Location in patent: Paragraph 0009
[2] Patent: WO2006/51079, 2006, A1, . Location in patent: Page/Page column 5
[3] Patent: WO2015/91531, 2015, A1, . Location in patent: Page/Page column 52
[4] Patent: WO2015/86693, 2015, A1, . Location in patent: Page/Page column 65
[5] Patent: WO2012/79154, 2012, A1, . Location in patent: Page/Page column 76; 77
[6] Organic Process Research and Development, 2013, vol. 17, # 7, p. 981 - 984
[7] Patent: WO2004/9602, 2004, A1, . Location in patent: Page 79
[8] European Journal of Medicinal Chemistry, 2010, vol. 45, # 12, p. 5965 - 5978
[9] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3858 - 3866
[10] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 327 - 335
[11] Synlett, 2018, vol. 29, # 17, p. 2257 - 2264
2
[ 123-08-0 ]
[ 107-99-3 ]
[ 15182-92-0 ]
Yield
Reaction Conditions
Operation in experiment
75.9%
Stage #1: With potassium carbonate In acetone at 60℃; for 2 h; Stage #2: at 60℃; for 2 h;
General procedure: To a solution of 4-hydroxybenzaldehyde (0.4 g, 3.275 mmol) in acetone (13 mL) was added K2CO3 (1.38 g, 10 mmol). The reaction mixture was vigourously stirred with heating at 60 °C for 2 h. The reaction mixture was then cooled to room temperature, followed by the addition of appropriate chlorides (4.585 mmol) dissolved in acetone. The reaction mixture was allowed to stir again with heating at 60 °C for 2 h. The reaction mixture was then filtered to remove K2CO3. The filtrate was evaporated to dryness to yield crude products which were subjected to column chromatography to obtain pure 4-O-alkylated benzaldehydes.
Reference：
[1] European Journal of Inorganic Chemistry, 2006, # 22, p. 4621 - 4628
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 195 - 210
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3617 - 3629
[4] Patent: US2879293, 1957, ,
[5] Patent: US2747766, 1954, ,
[6] Patent: US3969527, 1976, A,
[7] Patent: DE1007774, 1955, ,
3
[ 506-59-2 ]
[ 52191-15-8 ]
[ 15182-92-0 ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium carbonate In N,N-dimethyl-formamide at 80℃;
A2 was synthesized according to the literature with a little change [2]. Briefly, A1 (1 g, 4.4 mmol), dimethylamine hydrochloride (5 g, 61.7 mmol) and potassium carbonate (14 g, 101.5 mmol) were added to DMF and the mixture was heated to 80 and stirred overnight. On cooling, the mixture was filtered and evaporated under vacuum. The crude product was purified by column chromatography using EtOH/DCM (1:10) as eluent to yield 0.71 g (84percent) of A2 as brown liquid.
Reference：
[1] Chinese Chemical Letters, 2016, vol. 27, # 12, p. 1740 - 1744
4
[ 327077-87-2 ]
[ 506-59-2 ]
[ 15182-92-0 ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium carbonate In acetonitrile at 90℃; for 16 h;
[00324] To a solution of compound 3 (750.00 mg, 2.34 mmol) in acetonitrile (8.00 ml) was added dimethylamine hydrochloride (229.07 mg, 2.81 mmol) and K2C03 (1.62 g, 11.70 mmol, 5.00 eq). The mixture was stirred at 90C for 16 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (PE:EA=l : l~DCM:MeOH=20: l) to afford 4-[2-(dimethylamino)ethoxy]benzaldehyde (EW3861-140) (260mg, 57percent) as a yellow oil. LCMS (method H): retention time 0.36min, M/z = 194 (M + 1).
Reference：
[1] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 2, p. 195 - 200
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 112 - 116
6
[ 44929-30-8 ]
[ 123-08-0 ]
[ 15182-92-0 ]
Yield
Reaction Conditions
Operation in experiment
49%
With potassium carbonate In DMF (N,N-dimethyl-formamide) for 4 h; Heating / reflux
To a solution of 4-hydroxybenzaldehyde (500 mg, 4 [MMOL)] and [K2CO3] (662 mg, 4.8 [MMOL)] in anhydrous DMF, N, N-dimethyl-2-metilsulphonilethylamine (775 mg, 4.4 [MMOL)] was added. The reaction mixture was heated to reflux, under magnetic stirring, for 4 hours, then poured in water to obtain a suspension from which the solid was isolated by filtration. The crude product was purified by chromatography on silica gel (ethyl acetate), to give 379 mg of pure product of the title (yield 49percent). [APOS;H-NMR] : (300 MHz, [DMSO-D5)] : 9.86 [(1H,] s), 8.78 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 3.28 (2H, t, 5.5 Hz), 2.97 (2H, t, J=5.5 Hz), 2.71 (6H, s) [EL-MS] : 193.25 Th [[CLLHL5N021APOS;]
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 16, p. 5488 - 5495
9
[ 123-08-0 ]
[ 15182-92-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 112 - 116
[2] Chinese Chemical Letters, 2016, vol. 27, # 12, p. 1740 - 1744
10
[ 15182-92-0 ]
[ 20059-73-8 ]
Yield
Reaction Conditions
Operation in experiment
84.7%
Stage #1: With hydroxylamine hydrochloride In water; acetic acid at 0 - 5℃; for 2 h; Stage #2: With acetic acid; zinc In water at 45 - 70℃; for 7 h;
27 kg of 80percent acetic acid are charged into a reactor, 5.3 kg of hydroxylamine hydrochloride are added, the mixture is cooled to 0-5 °C and the solution prepared in the previous step containing 13.5 kg of 100percent 4-(2-dimethylaminoethoxy)- benzaldehyde in acetic solution is added. The reaction mixture is kept at 0-5°C for at least 2 hours. EPO <DP n="7"/>When the reaction is complete, 10.8 kg of powdered zinc are added in portions, allowing the temperature to rise up to a maximum of 50 °C.This mixture is kept under stirring at 45-50°C for at least 5 hours, and then heated to 65-70°C for at least 2 hours. Upon completion of the reaction, the reaction mixture is distilled to obtain a dense but stirrable residue.20.3 kg of deionized water are then added to the residue thus treated, the mixture thus obtained is cooled to 20-30°C and 54 kg of 30percent ammonia are added dropwise. The reaction mixture is then stirred at 20-30°C for at least 10 minutes, the pH is checked to ensure it is above 9.5. The reaction mixture is then extracted at 20-25 °C with 40.5 kg of methylene chloride. The organic phase is separated while the aqueous phase is reextracted with 27 kg of methylene chloride and the mixture is stirred for at least 5 minutes; the organic phase is added to the previous organic phase. Then the solvent is removed until an oily residue is obtained. 54 kg of sec-butanol and 20.3 kg of N, N - dimethylformamide are added. The solution thus obtained contains 11.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine Yield: 84.7percent.
Reference：
[1] Patent: WO2006/51079, 2006, A1, . Location in patent: Page/Page column 5-6
[2] Patent: US2879293, 1957, ,
[3] Organic Process Research and Development, 2013, vol. 17, # 7, p. 981 - 984
[4] Patent: KR101819771, 2018, B1, . Location in patent: Paragraph 0023; 0045-0052
11
[ 15182-92-0 ]
[ 554-92-7 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 7, p. 981 - 984
[2] Organic Process Research and Development, 2013, vol. 17, # 7, p. 981 - 984
27 kg of 80% acetic acid are charged into a reactor, 5.3 kg of hydroxylamine hydrochloride are added, the mixture is cooled to 0-5 C and the solution prepared in the previous step containing 13.5 kg of 100% 4-(2-dimethylaminoethoxy)- benzaldehyde in acetic solution is added. The reaction mixture is kept at 0-5C for at least 2 hours. EPO <DP n="7"/>When the reaction is complete, 10.8 kg of powdered zinc are added in portions, allowing the temperature to rise up to a maximum of 50 C.This mixture is kept under stirring at 45-50C for at least 5 hours, and then heated to 65-70C for at least 2 hours. Upon completion of the reaction, the reaction mixture is distilled to obtain a dense but stirrable residue.20.3 kg of deionized water are then added to the residue thus treated, the mixture thus obtained is cooled to 20-30C and 54 kg of 30% ammonia are added dropwise. The reaction mixture is then stirred at 20-30C for at least 10 minutes, the pH is checked to ensure it is above 9.5. The reaction mixture is then extracted at 20-25 C with 40.5 kg of methylene chloride. The organic phase is separated while the aqueous phase is reextracted with 27 kg of methylene chloride and the mixture is stirred for at least 5 minutes; the organic phase is added to the previous organic phase. Then the solvent is removed until an oily residue is obtained. 54 kg of sec-butanol and 20.3 kg of N, N - dimethylformamide are added. The solution thus obtained contains 11.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine Yield: 84.7%.
1) Preparation of Hydroxylamine Ethanol Solution (Solution A) 15 mmol of hydroxylamine hydrochloride was dissolved in 80% acetic acid In 50mlAnd then stored at -10 C. 2) Preparation of APA ethanol solution (B solution) 10 mmol of APA was dissolved in 50 ml of 80% acetic acid and stored at -10 C. 3) Production of APDA Solution A and solution B were respectively pumped and mixed at a T-junction maintained at -10 C and passed through a column reactor filled with zinc powder at 100 C. . 4) Reaction termination and separation The reaction mixture was added with 30% ammonia water to complete the reaction. After confirming that the pH was 9 or more, the organic layer was collected three times using CH2Cl2. The organic layer was washed once with brine, dehydrated with MgSO4 and filtered. The final filtrate was distilled under reduced pressure to remove the organic solvent to obtain an off-white APDA.
N-((S)-3-{6-[1-[4-(2-Dimethylamino-ethoxy)-phenyl]-meth-(E)-ylidene]-5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide[ No CAS ]
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 4h;Heating / reflux;
To a solution of 4-hydroxybenzaldehyde (500 mg, 4 [MMOL)] and [K2CO3] (662 mg, 4.8 [MMOL)] in anhydrous DMF, N, N-dimethyl-2-metilsulphonilethylamine (775 mg, 4.4 [MMOL)] was added. The reaction mixture was heated to reflux, under magnetic stirring, for 4 hours, then poured in water to obtain a suspension from which the solid was isolated by filtration. The crude product was purified by chromatography on silica gel (ethyl acetate), to give 379 mg of pure product of the title (yield 49%). ['H-NMR] : (300 MHz, [DMSO-D5)] : 9.86 [(1H,] s), 8.78 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 3.28 (2H, t, 5.5 Hz), 2.97 (2H, t, J=5.5 Hz), 2.71 (6H, s) [EL-MS] : 193.25 Th [[CLLHL5N021']
5,10,15-tris-[4-(2-N,N-dimethylaminoethoxy)phenyl]-[20-(4-decyloxy)phenyl]porphyrin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
To a solution of [4-DECYLOXYBENZALDEHYDE] coming from step c) (505 mg, 2 [MMOL),] [4-(N, N-DIMETHYLAMINOETHOXY) BENZALDEHYDE] prepared as described in step b) (1160 mg, 6 [MMOL)] and pyrrole (537 mg, 8 [MMOL)] in anhydrous [CH2C12,] trifluoroacetic acid (570 mg, 6.7 [MMOL)] was added and the mixture was kept under magnetic stirring, at room temperature, under nitrogen atmosphere, for 20 hours. Then p-chloranil (1650 mg, 6.7 [MMOL)] was added and the final mixture stirred for additional 4 hours. Work-up: washing with Na2CO3 saturated solution, drying on [NA2SO4,] and removing solvent by evaporation. The crude product was finally purified by reverse phase chromatography on C18 silica gel [(WATER/ACETONITRILE] 3/1), to give 245 mg of the title product (yield 12%). 1H NMR (300 MHz, CDCl3) : 8.85 (8H, m), 8.11 (8H, m), 7.29 (8H, m), 4.40 (6H, t, J = 5.6 Hz), 4.25 (2H, t, J = 6.3 Hz), 2.99 (6H, t, J = 5.6 Hz), 2.53 (18H, s), 1.97 (2H, tt, J = 7.2 Hz), 1.65-1. 32 (14H, m), 0.91 (3H, t, J = 6.6 Hz);-2. 77 (2H, s). 13C NMR (75 MHz, [CECI3,] selected data): 163.4, 163.0, 161.8, 135.6, 131.1, 118.0, 112.7, 77,2, 68.3, 66.8, 58.1, 49.1, 44.4, 37.7, 31.9, 29.6, 29.4, 29.3, 26.2, 22.6, 14.0. ESI-MS : m/z 1032.5 Th [C66H78N7O4]+.
With potassium carbonate; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 2h;
Step first, 80g p-hydroxybenzaldehyde, 128g potassium carbonate, DMF 150mL and 10mL isopropyl stirred, and then added the 101g of 2-(dimethylamino) chloroethane hydrochloride into DMF, then added the 80g solution of triethylamine, stirred at 80 C and carry on reaction for 2 h, the reaction solution is cooled at room temperature, poured into 700mL of water and extracted with 500mL of chloroform, into the chloroform added the 2 mol ·L-1 sulfuric acid 300mL extraction, under ice water, added the 200mL sodium hydroxide solution into aqueous phase with mass fraction 20%, and then extracted with 1000mL of ethyl acetate, dried over anhydrous sodium sulfate, the ethyl acetate is recovered under reduced pressure and distilled under reduced pressure, then collect bp142-144 C / 0.533kPa fractions, and then obtained 110.2g of 4-(2-Dimethylaminoethoxy) benzaldehyde, yield 86.3%, 100g solution of 4-(2-Dimethylaminoethoxy) benzaldehyde is dissolved in 150 ml of methanol, then under ice bath added the 26.5g sodium borohydride, TLC detection until the end of the reaction, excessive the sodium borohydride with ammonium chloride vanished, under reduced pressure remove the methanol, the crude product is added with 300 ml of water and extracted with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product has been distilled under reduced pressure then obtains 87.9 g of a colorless liquid, yield is 87%;
85.33%
17.5 kg of 2-dimethylaminoethylchloride hydrochloride, 75 kg of deionized water and 2.50 kg of toluene are charged into a batch, 17.5 kg of 30% sodium hydroxide are then dropped into. The mixture obtained is kept under stirring until complete solution of the solid. The aqueous phase is removed while the organic phase is used for the following preparation. 10 kg of 4-hydroxy-benzaldehyde, 12.5 kg of potassium carbonate, 0.27 kg of tetrabutylammonium bromide and 70 kg of ethyl acetate are charged into a reactor. The mixture obtained is heated under reflux and then the aforesaid toluene solution is added dropwise. The mixture is kept under stirring and reflux for at least 5 hours. 50 kg of deionized water are then added, the mixture obtained is stirred for at least 5 minutes, the aqueous phase is removed and the organic phase is distilled, to obtain an oily residue. The residue is cooled to 20-30C and 35 kg of 80% acetic acid are added dropwise. The reaction mixture is then stirred for 5 minutes until complete solution. A solution containing 13.5 kg of 4-(2-dimethylaminoethoxy)-benzaldehyde is obtained. Reaction yield referred to 4-hydroxybenzaldehyde: 85.33%
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;
A mixture of 4-hydroxybenzaldehyde (6.0 g, 49.1 mmol), 2-chloro-N,N- dimethylethanamine hydrochloride (10.61 g, 73.70 mmol) and potassium carbonate (20.37 g, 147.4 mmol) in N,N-dimethylformamide (60 mL) was stirred overnight at 90 C The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulphate and the solvent evaporated to yield the title compound (7.25 g, 72%) as a brown oil. LRMS (m/z): 194 (M+1 )+
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;
A mixture of 4-hydroxybenzaldehyde (6.0 g, 49.1 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (10.61 g, 73.70 mmol) and potassium carbonate (20.37 g,147.4 mmol) in N,N-dimethylformamide (60 mL) was stirred overnight at 90 C. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate and the solvent evaporated to yield the title compound (7.25 g, 72%) as a brownoil.LRMS (mlz): 194 (M+1).
49%
The title compound was obtained as a colorless oil in 49 % yield by following the general procedure B. UV (EtOH) mm: 219 and 276 nm. IR (nujol): 2945, 2822, 2727, 1685, 1597, 1510, 1466, 131 1,1258, 1216 1 160, 1030 and 834 cm '. NMR (300 MHz, CDCI3): delta 2.37 (6H, s, 2 x NC¾), 2.81(2H, t, J = 5.1Hz, -NCH2), 4. 1 1 (2H, t, J = 5.4 Hz, OCH2), 6.99 (2H, d, J = 8.1 Hz, 2 x Ar-H), 7.81 (2H, d, J = 7.8 Hz, 2 x Ar-H), 9.85 (1H, s, CHO). 13C NMR (75.5 MHz, CDC13): delta 45.68 (2 x NC¾), 57.90 (NCH2), 66.08 (OCH2), 1 14.82 (C-2 & C-6), 130.04(C-1), 13 1.92 (C-3 & C-5), 163.72 (C-4), 190.75 (C=0). HRMS m/z calculated for C?H,5N02 [M+H]+ 194.1 176, observed [M+Hf 194. 1 168. In a dried single-neck round bottom flask, 4-hydroxylbenzaldehyde (40 mmol), potassium carbonate (122 mmol) and dry acetone (160 ml) were taken and the contents refluxed for 2 h. The reaction mixture was brought to room temperature and catalytic amount of potassium iodide was added, followed by the gradual addition of the appropriate dialkylaminoethyl chloride hydrochloride (45 mmol) dissolved in dry acetone (50 ml) through a pressure-equalizing addition funnel and the reaction mixture was allowed to reflux again. The contents were regularly monitored for reaction progress by TLC using 10 % methanol/dichloromethane as the solvent system. The reaction was generally complete in 10-13 h. At this point, reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 x 60 ml). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8 % methanol in dichloromethane, v/v as eluent) to afford the six pure 4-dialkylaminoethoxybenzaldehydes as colorless oils in 49-92 % yields. The structures of these products were unambiguously established from the analysis of their spectral data (IR, NMR, l3C NMR and mass spectra).
10%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 12h;Heating / reflux;
To a mixture [OF 4-HYDROXYBENZALDEHYDE (1.] 34 g, 10.97 [MMOL)] and 2- dimethylaminoethyl chloride hydrochloride (1.95 g, 13.54 [MMOL)] in DMF (12 mL) was added KzCOs (6.04 g, 3.23 [MMOL).] The mixture was heated at reflux for 12 h. The residue was partitioned between [HZ0] and EtOAc. The organic layer was dried [(MGSO4),] filtered, and concentrated. The crude material was purified by flash chromatography [(10%] [MEOH/CH2CI2) TO YIELD 4-[2-(DIMETHYLAMINO) ETHOXYBENZALDEHYDE] (220 mg, 10%) as an orange liquid. 'H NMR (400 MHz, CDCl3) 8 9. 87 (s, 1H), 7. [82 (D, 2H),] 7.01 (d, [2H),] 4.16 (t, [2H),] 2. [79 (T,] 2H), 2. 37 (s, 6H).
General procedure: In a dried single-neck round bottom flask, 4-hydroxylbenzaldehyde (40 mmol), potassium carbonate (122 mmol) and dry acetone (160 ml) were taken and the contents refluxed for 2 h. The reaction mixture was brought to room temperature and catalytic amount of potassium iodide was added, followed by the gradual addition of appropriate dialkylaminoethyl chloride hydrochloride (45 mmol) dissolved in dry acetone (50 ml) through a pressure-equalizing addition funnel and the reaction mixture was allowed to reflux again. The contents were regularly monitored for reaction progress by TLC using 10% methanol/dichloromethane as the solvent system. The reaction was generally complete in 10-13 h. At this point, reaction mixture was filtered under suction and the solid inorganic salts were washed with acetone (3 × 60 ml). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel (6-8% methanol in dichloromethane, v/v as eluent) to afford the pure aldehydes 4a-f as colorless oils in 49-92% yields. The structures of 4a-f were unambiguously established from the comparison of their spectral data with reported values [13,24,25]. The spectroscopic data of compound 4b which is not reported in literature is being included here.
With potassium carbonate; In butanone; for 6h;Reflux;
General procedure: Requisite alkylaminoethyl chloride hydrochloride, chlorobromopropane and cyclopentyl bromide (6.0mmol) were added to a stirred and refluxing slurry of 4-hydroxybenzaldehyde (1.0g, 8.19mmol) in ethyl methyl ketone (C4H8O) (40ml) in the presence of anhydrous potassium carbonate (2.0g, 14.47mmol). The reaction mixture was further refluxed for 6h with continuous stirring. The completion of the reaction was monitored by TLC. On completion, the reaction mixture was cooled, filtered and the solvent was removed under reduced pressure to obtain an oily residue of corresponding aldehyde 3-9, which was used as such for further reaction.
With potassium carbonate; In ethyl acetate; at 80℃;
A mixture of the 4-hydroxybenzaldehyde (100g, 0.82mol) and anhydrous K2CO3 (330g,2.5mol) in EtOAc (1000mL) was stirring at 80 C till the disappearance of the startingmaterials 4-hydroxybenzaldehyde. Then 2-chloro-N, N-dimethylethanaminehydrochloride (118.69g, 0.83mol) was added into the reaction system and continued tostir until the reaction finished. After reaction, the mixture was filtered and the filtratewas washed with water and dried with Na2SO4. The extraction was filtered and thefiltrate was evaporated under reduced pressure to recycle the ethyl acetate and give thecrude mass which was further evaporated under high vacuum (bp142 -144oC/0.533 kPa)to give pale yellow oil(181.42g, 94%).
With hydrogenchloride; potassium carbonate; In N-methyl-acetamide; methanol; hexane; di-isopropyl ether; water; ethyl acetate;
Example 1 Preparation of bis(2,5-dimethyl-4-hydroxyphenyl)[4-(2-dimethylamino-1-ethoxy)phenyl]methane (Compound 1) Dimethylformamide (2 ml), 4-hydroxybenzaldehyde (0.5 g, 4.094 mmol), potassium carbonate (1.23 g, 8.90 mmol), 1-dimethylamino-2-chloroethane (0.66 g, 6.18 mmol), and diisopropyl ether (0.25 ml) were introduced into a reaction vessel, and stirred at 60 C. for 1 hour and 30 minutes. After standing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over magnesium sulfate, and the solvent was evaporated. The resultant residue (0.77 g) was distilled under reduced pressure (110 C./1-3 mmHg) to yield 4-(2-dimethylamino-1-ethoxy)benzaldehyde (0.45 g, 57%). 4-(2-Dimethylamino-1-ethoxy)benzaldehyde (0.15 g, 0.776 mmol) was mixed with 2,5-dimethylphenol (0.227 g, 1.86 mmol), methanol (0.4 g) and 35% aqueous hydrochloric acid (40 mg), stirred at 40 C. for 10 hours. To the reaction mixture, 35% aqueous hydrochloric acid (85 mg) was further added, and stirred at 60 C. for 8 hours and 30 minutes. The reaction was then left overnight to cool, during which crystals precipitated. To the semicrystals collected by decantation, 1.5 ml of hexane was added, and decanted. Furthermore, 1.5 ml of ethyl acetate was added, and stirred. Crystals precipitated were then filtered, and washed (twice with each 1 ml of ethyl acetate, and once with 1 ml of hexane) to yield crystals (0.333 g, 94%) of the aimed product, bis(2,5-dimethyl-4-hydroxyphenyl)[4-(2-dimethylamino-1-ethoxy)phenyl]methane (Compound 1): 1H NMR [270 MHz, CDCl3, TMS, delta (ppm)] 2.03 (6H, s), 2.04 (6H, s), 2.98 (6H, s), 3.58 (2H, m), 4.32 (2H, m), 5.43 (1H, s), 6.37 (2H, s), 6.59 (2H, s), 6.87-6.98 (4H, m).
By the same method, using 4-(2-dimethylamino)ethoxybenzaldehyde in place of the abovementioned aldehyde, (3Z)-1-acetyl-3-(4-(2-dimethylamino)ethoxybenzylidene)-2,5-piperazinedione was prepared.
With methanol; sodium tetrahydroborate;Cooling with ice;
Step first, 80g p-hydroxybenzaldehyde, 128g potassium carbonate, DMF 150mL and 10mL isopropyl stirred, and then added the 101g of 2-(dimethylamino) chloroethane hydrochloride into DMF, then added the 80g solution of triethylamine, stirred at 80 C and carry on reaction for 2 h, the reaction solution is cooled at room temperature, poured into 700mL of water and extracted with 500mL of chloroform, into the chloroform added the 2 mol ·L-1 sulfuric acid 300mL extraction, under ice water, added the 200mL sodium hydroxide solution into aqueous phase with mass fraction 20%, and then extracted with 1000mL of ethyl acetate, dried over anhydrous sodium sulfate, the ethyl acetate is recovered under reduced pressure and distilled under reduced pressure, then collect bp142-144 C / 0.533kPa fractions, and then obtained 110.2g of 4-(2-Dimethylaminoethoxy) benzaldehyde, yield 86.3%, 100g solution of 4-(2-Dimethylaminoethoxy) benzaldehyde is dissolved in 150 ml of methanol, then under ice bath added the 26.5g sodium borohydride, TLC detection until the end of the reaction, excessive the sodium borohydride with ammonium chloride vanished, under reduced pressure remove the methanol, the crude product is added with 300 ml of water and extracted with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product has been distilled under reduced pressure then obtains 87.9 g of a colorless liquid, yield is 87%;
76%
With methanol; sodium tetrahydroborate; at 20℃;
The title compound was obtained as a colorless oil in 76 % yield. UV (EtOH) chi: 224, 269 nm. IR (nujol): 3244, 2947, 2864, 2828, 161 1, 15 12, 1465, 1299, 1243, 1 173, 1032, 1009 and 819 cm"1. NMR(300 MHz, CDC1,): delta 2.36 (6H, s, 2 x NCH3), 2.77 (2H, t, J = 5.4 Hz, -NCH2), 4.06 (2H, t, J = 5.4 Hz, OCH2), 4.61 (2H, s, CH2OH), 6.89 (2H, d, J - 8.4Hz, 2 x Ar-H), 7.29 (2H, d, J = 8. 1 Hz, 2 x Ar-H). I3C NMR (75.5 MHz, CDCI3): delta 45.70 (2 x NCH3), 58.10 (NCH2), 64.99 (CH2OH), 65.78 (OCH2), 1 14.59 (C-2 & C-6), 128.77 (C-3 & C-5), 133.56(C-1), 158.24 (C-4). HRMS rn/z calculated for C| ,Hl 7N02 [M+Hf 196.1332, observed [M+H]+ 196.1329.In a round bottom flask, a solution of appropriate 4- dialkylaminoethoxybenzaldehyde (4.5 mmol) in methanol (25 ml) was taken and sodium borohydride (3.1 mmol) was added in small lots at room temperature. The reaction was monitored by TLC using 10% methanol/dichloromethane as the solvent system. The reaction was completed in 3-5 h. After completion of reaction, the methanol was removed under reduced pressure. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (3 x 50 ml). The organic layer was washed with water (3 x 50 ml) and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and dried under high vacuum to afford the desired benzyl alcohols as colorless oils in 76-95 % yields. The structures of these products were unambiguously established from the analysis of their spectral data (IR, NMR, 1 'C NMR and mass spectra).
5.25 g (88%)
With sodium borohydrid; In methanol;
EXAMPLE 7 4-(2-dimethylamino-ethoxy)-benzyl alcohol (3c) To a stirred solution of the aldehyde 2c (5.9 g, 0.031 mol, 1.0 eq.) in methanol (20 mL) at 22 C. sodium borohydride (0.58 g, 0.015 mol, 0.5 eq.) is added in portions. The reaction is stirred for 30 min. TLC at this point shows no starting material, mostly product (EtOAc/hexane/triethylamine 5:5: 1). The reaction mixture is diluted with water (50 mL), extracted with methylene chloride (3*40 mL), and dried over MgSO4. The solution is concentrated on a rotary evaporator to give 5.25 g (88%) of the alcohol 3c as a thick oil. 1 H NMR (CDCl3 /TMS): 7.25 (d, 2H, J=8.64 Hz), 6.85 (d, 2H, J=8.64 Hz), 4.52 (s, 2H), 3.99 (t, 2H, J=5.88 Hz), 2.67 (t, 2H, J=5.79 Hz), 2.29 (s, 6H)
With sodium tetrahydroborate; In methanol; at 20℃;
General procedure: In a round bottom flask, a solution of the compound 4a-h (4.5 mmol) in methanol (25 ml) was taken and sodium borohydride (3.1 mmol) was added in small lots at room temperature. The reaction was monitored by TLC using 10% methanol/dichloromethane as the solvent system. The reaction was completed in 3-5 h. After completion of reaction, the methanol was removed under reduced pressure. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (3 × 50 ml). The organic layer was washed with water (3 × 50 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and dried under high vacuum to afford the desired alcohols 5a-h as colorless oils in 76-95% yields. The structures of the compounds 5a-h were unambiguously established by comparing their spectral data with reported values [14]. Compound 5g was found to be new to chemical literature; its spectral data is reported below.
With sodium tetrahydroborate; In ethanol; at -5 - 20℃;
2. Synthesis of (4-(2-(dimethylamino)ethoxy)phenyl)methanol (3)To the stirring solution of the <strong>[15182-92-0]4-(2-(dimethylamino)ethoxy)benzaldehyde</strong> (100g,0.52mol) in EtOH (300mL) was added NaBH4 (14.7g, 0.39mol) slowly at -5C and thestirring was continued at an ambient temperature till the complete reduction(TLC). Theexcess amount of NaBH4 was quenched with aq.NH4Cl at 0oC and the reaction mixturewas evaporated under reduced pressure to remove the solvent. The crude product, thusobtained was extracted with ethyl acetate/water (200ml/300ml). The organic layer wasdried over anhydrous Na2SO4 and concentrated to give a crude mass, which wasevaporated under high vacuum to afford colorless liquid (98g, 97%).
EXAMPLE 63 32 g of [1-(4,4-dimethyl-6-thiochromanyl)ethyl]triphenylphosphonium bromide were suspended in 130 ml of tetrahydrofuran and treated at 0 C. with 37 ml of n-butyllithium (1.6 molar in hexane). After stirring at 0 C. for 45 minutes, a solution of 10 g of <strong>[15182-92-0]4-(2-dimethylaminoethoxy)benzaldehyde</strong> in 60 ml of tetrahydrofuran was added dropwise to the orange reaction mixture. The mixture was stirred at room temperature for an additional 1 hour, poured on to ice/water and extracted with ether. The organic phases were washed with water, dried and evaporated. After filtration of the crude product over neutral Alox (eluding agent ether) and recrystallization from hexane/ether, there were obtained 8.7 g of 2-[p-[(E)-2-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)propenyl]phenoxy]-N,N-dimethylethylamine, melting point 81-82 C.
2-[[4-[2-(Dimethylamino)ethoxy]phenyl]methylene]2,3-dihydro-1H-inden-1-one, hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
B. 2-[[4-[2-(Dimethylamino)ethoxy]phenyl]methylene]2,3-dihydro-1H-inden-1-one, hydrochloride (1:1) The reaction between 31 g (0.23 mole) of 1-indanone and 45 g (0.23 mole) of material from part A according to a procedure described for example 1, part A, gives 58.5 g of yellow crystals, mp 95-97, s. 92. Crystallization from 130 ml of MeCN yields 53.2 g (75%) of cream-colored crystals, mp 107-109. A solution of 6.0 g of the above in 50 ml of warm MeCN is treated with one equivalent of ethanolic HCl to give 6.4 g of light yellow solid, mp 237-239. Crystallization from 30 ml of methanol yields 5.49 g of nearly colorless crystals, mp 234-238 (solvated with methanol). The above is recrystallized from a solution containing 22.5 ml of MeCN and 2.5 ml of H2 O to give 4.8 g (68%) of a cream-colored hydrated product, mp 237-239, s. 233.
2-[[4-[2-(dimethylamino)ethoxy]phenyl]methylene]-2H-1,4-benzothiazin-3(4H)-one, hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium methylate; In N-methyl-acetamide; methanol; ethanol; chloroform;
EXAMPLE 4 2-[[4-[2-(Dimethylamino)ethoxy]phenyl]methylene]-2H-1,4-benzothiazin-3(4H)-one, hydrochloride (1:1) A solution of 25 g. (0.15 mole) of 1,4-benzothiazin-3(4H)-one in 125 ml. of dimethylformamide is reacted with 48.5 g. (0.25 mole) of <strong>[15182-92-0]4-(2-dimethylaminoethoxy)benzaldehyde</strong> and 10.2 g. (0.18 mole) of sodium methoxide according to the procedure of example 1 to yield 36.8 g. of crude yellow product; m.p. 134-137. Crystallization from 100 ml. of ethanol yields 28.1 g. of material; m.p. 158-160, s. 145. Recrystallization from 50 ml. of dimethylformamide yields 22.8 g. of yellow crystalline (2-[[4-[2-(dimethylamino)ethoxy]phenyl]methylene]2H-1,4-benzothiazin-3(4H)-one; m.p. 177-179. A solution of 5 g. of the above product in 50 ml. of chloroform is treated with one equivalent of hydrochloric acid in ethanol to yield 4.8 g. of yellow product; m.p. 222-224. Recrystallization from 30 ml. of methanol yields 4.6 g. of yellow crytalline 2-[[4-[2 -(dimethylamino)ethoxy]phenyl]methylene]-2H-1,4-benzothiazin-3(4H)-one, hydrochloride (1:1); m.p. 224-226.
With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h;
Example 52-(4-(6-bromo-7-(4-((5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5- ib]pyridin-2-yl)phenoxy)-lambda/,lambda/-dimethylethanamineTo a mixture of 5-bromo-4-(4-((5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-3- nitropyridin-2-amine (0.060 g, 0.14 mmol) in EtOH (2.4 mL) and DMF (0.33 ml_), 4-(2- dimethylaminoethoxy)benzaldehyde (0.031 g, 0.16 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1 M; 0.44 mL, 0.44 mmol). The reaction mixture was heated at 85 0C for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 90:10) to give the title compound as a off-white solid (0.005 g, 6%); 1H-NMR (500Mz, DMSO-d6): delta (NMe2 and CH2N masked under DMSO peak), 2.60-2.69 (m, 4H, piperazine N(CH2)2), 3.64-3.70 (m, 6H), 4.13-4.22 (m, 2H, OCH2), 7.11 (d, J = 9.0 Hz, 2H, ArH, C6H4), 7.69-7.75 (m, 1 H, py 4-H), 8.13 (d, J = 9.0 Hz, 2H1 ArH, C6H4), 8.21 (s, 1 H, imidazo[4,5Hb]pyridine 5-H)1 8.45-8.47 (m, py 2-H ), 8.49 (d, 1H, J = 2.5 Hz, py 6-H)1 13.35 (br s, 1H, imidazo[4,5- jb]pyridine N-H); LC (Method B) - MS (ESI, m/z) 2.32 min - 554/556 [(M+H) Br isotopic pattern]. ESI-HRMS: Found: 554.1679, calculated for C26H30FBrN7O (M+H)+: 554.1674.
With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h;
Example 132-(4-(6-Bromo-7-(4-((2-methylthiazol-4-yl)nnethyl)piperazin-1-yl)-3H-imidazo[4,5- b]pyridin-2-yl)phenoxy)-lambda/,lambda/-dimethylethanamineTo a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3- nitropyridin-2-amine (0.062 g, 0.14 mmol) in EtOH (2.6 ml_) and DMF (0.35 ml_), 4-(2- dimethylaminoethoxy)benzaldehyde (0.032 g, 0.16 mmol, 1.1 eq) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml_, 0.44 mmol). The reaction mixture was heated at 85 0C for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 90:10) to give the title compound as an off-white solid (0.007 g, 8.9%); 1H-NMR (500Mz, DMSO-c/6): delta 2.27 (s, 6H, NMe2), 2.63-2.75 (m, 9H, piperazine N(CH2)2, CH3-thiazole, CH2N), 3.64-3.70 (m, 6H), 3.61-3.69 (m, 6H, piperazine N(CH2)2, CH2N), 4.11-4.17 (m, 2H, OCH2), 7.10 (d, J = 9.0 Hz, 2H, ArH, C6H4), 7.33 (s, 1 H, 5H-thiazole), 8.12 (d, J = 9.0 Hz, 2H, ArH, C6H4), 8.20 (s, 1 H, imidazo[4,5-/b]pyridine 5-H)1 13.39 (br s, 1 H, imidazo[4,5- 6]pyridine N-H); LC (Method B) - MS (ESI, m/z) 2.06 min - 556/558 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 556.1488, calculated for C25H31BrN7O (M+H)+: 556.1489.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;
General procedure: To a stirred solution of substituted benzaldehydes3-8 (3.79 mmol) in 15 mL DMF was added K2CO3 (7.58 mmol) and desired amines (4.54 mmol). The reaction mixture was then stirred at 80 C for 6 h and progress of reaction was monitored by TLC. After completion, it was cooled on ice bath and then extracted with CHCl3. The organic layer was washed with water and dried over Na2SO4. Excess solvent was evaporated under reduced pressure to obtain oily residue of corresponding amino substituted aldehydes (9-33), which were used as such for further reaction.
With sodium dithionite; In ethanol; water; N,N-dimethyl-formamide; at 85℃; for 24h;
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.050 g, 0.13 mmol, 1 eq), EtOH (2.2 mL) and DMF (0.29 mL), <strong>[15182-92-0]4-(2-dimethylaminoethoxy)benzaldehyde</strong> (0.027 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85 C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.010 g, 15%); 1H-NMR (500 Mz, DMSO-d6): 2.24 (s, 6H, NMe2), 2.66 (t, J=5.5 Hz, 2H, CH2NMe2), 2.75-2.80 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.70-3.76 (m, 4H), 4.13 (t, J=5.8 Hz, 2H, CH2O), 7.10 (d, J=8.5 Hz, 2H, ArH C6H4), 7.23 (d, J=4.0 Hz, 1H) and 7.49 (d, J=3.50 Hz, 1H) (thiazole H-4, H-5), 8.04-8.11 (m, 3H, imidazo[4,5-b]pyridine 5-H and ArH C6H4), 11.88 (br s, 1H, NHCO), 13.24 (br s, 1H, imidazo[4,5-b]pyridine N-H); LC (Method B)-MS (ESI, m/z) 3.63 min-587/589 [(M+H)+, Cl isotopic pattern].
With toluene-4-sulfonic acid; at 125℃;Microwave irradiation; Neat (no solvent);
General procedure: A mixture of 2-naphthol (12 mmol), 4-hydroxypiperidine (12 mmol), appropriate (dialkylamino)ethoxybenzaldehydes (10 mmol) and catalytic amount of p-TSA (50 mg) were irradiated in Discover S-Class CEM microwave oven for 7-10 min. (2.5 min × 3 or 4, to avoid overheating). The reaction mixture was cooled and purified by column chromatography over silica gel using methanol-dichloromethane (8-10%) as eluent to afford the pure compounds 2a-f in 38-47% yields. The structures of compounds 2a-f were unambiguously established from the analysis of their spectral data (IR, 1H, 13C NMR and mass spectra). It should be noted that the peak for the two -NCH2 carbons of the 4-hydroxypiperidine ring were consistently not seen at room temperature due to the molecular dynamics as mentioned in the Results and Discussion section.
With piperidine; In methanol; at 100℃; for 0.5h;Microwave irradiation;
General procedure: Equimolar amounts (0.3 mmol) of 5-chlorooxindole/oxindole and aldehyde were dissolved in methanol (1 ml), a drop of piperidine (30 mul) was added and the mixture heated at 100C under microwave irradiation for 30 min. The reaction mixture was cooled to room temperature and the resulting precipitate was removed by filtration, carefully washed with methanol and recrystallized at least once from methanol to give the desired product in good yield.
With pyridine; In methanol; at 100℃; for 0.5h;Microwave irradiation;
General procedure: A suspension of indolinone (0.3mmol), aldehyde (0.3mmol) and pyridine (30muL) in methanol (1mL) were heated under microwave irradiation at 100 C for 30 minutes. The reaction mixture was cooled to room temperature and the resulting precipitate was removed by filtration, carefully washed with methanol and dried in vacuo. When no precipitate was observed methanol was removed under vacuum and the residue was purified by silica gel chromatography to give the desired product.
General procedure: To a solution of amino substituted benzaldehydes9-33 (15 mmol) in MeOH (5 ml) was added cyclic ketone (7.5 mmol). The solution was allowed to stir for 15 min at room temperature, followed by dropwise addition of 20% (w/v) aq. NaOH solution. The reaction mixture was stirred at room temperature and progress of reaction was monitored by TLC. After completion of reaction, saturated solution of NH4Cl was added to the reaction mixture. The precipitate formed was washed with water, cold methanol and finally with cold acetone. It was then dried and recrystallized with ethanol/water system to obtain corresponding curcumin derivatives 34-76.
General procedure: A mixture of an aldehyde (1.0 eq) and an amine (1.0 eq) was heated in a sealed tube at 60 C for 6 h. The crude material was dried under vacuum over phosphorus(V) oxide to give quantitatively the imine which was used in the next step without further purification.
General procedure: To a stirred solution of 5,6-diamino-1,3-dimethyluracil (2) (1.0g, 5.87mmol) in MeOH-AcOH (4:1, 40mL) was slowly added the solution of the above obtained oily residue of the relevant aldehyde 3-9 in methanol (24ml). The reaction mixture was further stirred overnight at room temperature. The completion of the reaction was monitored by TLC. The residue obtained after removal of solvent under reduced pressure was dissolved in ice-cold water and made alkaline with sodium hydroxide. The resultant turbid solution was cooled in ice for complete precipitation. The precipitate obtained was filtered off, washed with ice cold water and dried to obtain the corresponding benzylidene derivatives 10-16, which were used as such for further reaction.
(Z)-2-(4-(2-(dimethylamino)ethoxy)benzylidene)-6-hydroxybenzofuran-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In methanol; water; at 50 - 60℃;
General procedure: To a solution of 1-12 in methanol (100 mg, 0.67 mmol, 10 ml/mmol) was added the suitably functionalized benzaldehydes (0.67 mmol), followed by a solution of KOH 50% in water (1.5 ml/mmol). The solution is heated at 50-60 C for 2-3 h. The reaction mixture was concentrated in vacuo and diluted with distilled water.The reaction mixture was adjusted to pH 7 with 1 N HCl. The aqueous layer was extracted with ethyl acetate and dried (Na2SO3).The organic phase was evaporated in vacuo to yield crude products which were subjected to column chromatography by using chloroform:methanol (8:2) to yield pure Series 1 aurones.
(Z)-2-(4-(2-(dimethylamino)ethoxy)benzylidene)-6-methoxybenzofuran-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In ethanol; water; at 20℃; for 2h;
General procedure: To a solution of 2-12 in ethanol (100 mg, 0.62 mmol, 13 ml/mmol) was added the suitably functionalized benzaldehydes (0.62 mmol), followed by a solution of KOH 20% in water (0.8 ml/mmol). The solution is stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and diluted with distilled water. The aqueous layer was extracted with ethyl acetate and dried (Na2SO3). The organic phase was evaporated in vacuo to yield crude products which were subjected to column chromatography by using amino silica gel as adsorbent and solvent system of hexane: ethyl acetate (7:3) followed by silica gel column chromatography by using chloroform: methanol (9.5:0.5) to yield Series 2 derivatives except for 2-6 and 2-9.
N,N-dimethyl-2-(4-(piperazin-1-ylmethyl)phenoxy)ethanamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
A mixture of <strong>[15182-92-0]4-[2-(dimethylamino)ethoxy]benzaldehyde</strong> (Preparation 35a, 7.25 g, 37.5 mmol), tert-butyl piperazine-1 -carboxylate (6.98 g, 37.5 mmol) and sodium triacetoxyborohydride (9.54 g, 45.0 mmol) in dichloromethane (30 mL) was stirred at room temperature for 48h. The reaction mixture was washed with 2N aqueous solution of sodium hydroxide and with 0.1 N aqueous solution of hydrogen chloride. The solvent was evaporated, 4.0 M solution of hydrogen chloride in 1 ,4-dioxane (94 mL) was added to the crude and the resulting mixture was stirred at ambient temperature for 1 h. The solvent was evaporated and the residue was co-evaporated with 1 ,4-dioxane and toluene to dryness to yield the title compound (1 1 .05 g, 71 %) as an hydrochloride salt. LRMS (m/z): 264 (M+1 )+ 1H-NMR delta (300 MHz, CD3OD): 3.0 (s, 6H), 3.6 (s, 10H), 4.3 - 4.5 (m, 4H), 7.2 (d, 2H), 7.6 (d, 2H).
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 48h;
A mixture of <strong>[15182-92-0]4-[2-(dimethylamino)ethoxy]benzaldehyde</strong> (Preparation 18a, 7.25 g, 37.5mmol), tert-butyl piperazine-1-carboxylate (6.98 g, 37.5 mmol) and sodiumtriacetoxyborohydride (9.54 g, 45.0 mmol) in dichloromethane (30 mL) was stirred at room temperature for 48 hours. The reaction mixture was washed with a 2N aqueous solution of sodium hydroxide and with a 0.1 N aqueous solution of hydrogen chloride. The solvent was evaporated to dryness, 4.0 M solution of hydrogen chloride in 1,4-dioxane (94 mL) was added to the residue and the resulting mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was coevaporated with 1 ,4-dioxane and toluene to dryness to yield the title compound (11.05 g, 71%) as a hydrochloride salt.LRMS (mlz): 264 (M+1).1H-NMR (300 MHz, CD3OD): 3.0 (s, 6H), 3.6 (s, 1OH), 4.3 - 4.5 (m, 4H), 7.2 (d, 2H), 7.6 (d, 2H).
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 96h;
Sodium triacetoxyborohydride (0.32 g, 1 .51 mmol) was added to a solution of tert-butyl (3R,5S)-3,5-dimethylpiperazine-i -carboxylate (0.28 g, 1 .30 mmol) and 4-[2-(dimethyl amino)ethoxy]benzaldehyde (Preparation 18a, 0.25 g, 1.29 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was washed with 2M aqueous solution of sodium hydroxide and theorganic layer was separated, dried over magnesium sulfate and the solvent evaporated to dryness. 4M Solution of hydrochloric acid in 1,4-dioxane was added to the residue and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness to yield the hydrochloride salt of the title compound (299 mg, 45%) as a solid.LRMS (mlz): 292 (M+i).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
A2 was synthesized according to the literature with a little change [2]. Briefly, A1 (1 g, 4.4 mmol), dimethylamine hydrochloride (5 g, 61.7 mmol) and potassium carbonate (14 g, 101.5 mmol) were added to DMF and the mixture was heated to 80 and stirred overnight. On cooling, the mixture was filtered and evaporated under vacuum. The crude product was purified by column chromatography using EtOH/DCM (1:10) as eluent to yield 0.71 g (84%) of A2 as brown liquid.
With potassium carbonate; In acetonitrile; at 90℃; for 16h;
[00324] To a solution of compound 3 (750.00 mg, 2.34 mmol) in acetonitrile (8.00 ml) was added dimethylamine hydrochloride (229.07 mg, 2.81 mmol) and K2C03 (1.62 g, 11.70 mmol, 5.00 eq). The mixture was stirred at 90C for 16 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (PE:EA=l : l~DCM:MeOH=20: l) to afford 4-[2-(dimethylamino)ethoxy]benzaldehyde (EW3861-140) (260mg, 57%) as a yellow oil. LCMS (method H): retention time 0.36min, M/z = 194 (M + 1).
β-dimethylaminoethyl chloride hydrochloride[ No CAS ]
[ 123-08-0 ]
[ 15182-92-0 ]
Yield
Reaction Conditions
Operation in experiment
1) Preparation of 4-hydroxybenzaldehyde solution (solution A) 10 ml of 4-hydroxybenzaldehyde was dissolved in 100 ml of ethyl acetate and stored at -10 C .2) Preparation of 2-chloro-N, N-dimethylethanamine solution (solution B) 10 ml of 2-chloro-N, N-dimethylethanamine hydrochloride and 20 mol of K2CO3 were added to 100 ml of ethyl acetate and sonicated for 30 minutes. -N, N-dimethylethanamine hydrochloride was completely dissolved, and the remaining salt was removed by filtration. The separated filtrate was stored at -10 & lt; 0 & gt; C.3) Production of APA Solution A and solution B were pumped, respectively, and mixed at a T-junction maintained at -10 C. K 2 CO 3 at 150 CAnd passed through a filled column reactor.4) When the reaction termination and separation were completed, the reaction was terminated by adding saturated aqueous NH4Cl solution and the whole solution was transferred to the separating funnel. The water layer was washed three times with ethyl acetate, and the combined ethyl acetate layers were washed once with brine, dehydrated with MgSO4 and filtered.The final filtrate was distilled under reduced pressure to remove the organic solvent to obtain brown APA.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
