* 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 75 - 80℃; for 8 h;
To the reaction bottle were added 913.5 g of toluene, 174 g of morpholine and 556 g of 3-bromopropanol, and 331.2 g of potassium carbonate was added under stirring,The reaction was heated at 75-80 ° C for 8 hours. After completion of the reaction, pressure filtration and concentration of the filtrate to remove toluene and unreacted raw materials, obtained light yellow278.4 g of N - (3-hydroxypropyl) morphorphine, a molar yield of 96percentGas purity was 98.5percent.
88.5%
at 80℃; for 4 h;
Morpholine 2a(3.1g, 36mmol) and 3-bromo-1-propanol (2.5g, 18mmol) were dissolved in 20mL of toluene at 80° C for 4 hours. The reaction was cooled to room temperature and the reaction was filtered. The filter cake was washed with ethyl acetate (2 mL X 2) and concentrated under reduced pressureThe filtrate gave the title product 3-morpholinopropan-1-ol 2b (2.3 g, yellow oil), yield: 88.5percent.
50%
at 50℃; for 18 h;
To a mixture of morpholine (33 mL, 371 mmol) and CH2C12(650 mL) was added 3-bromopropanol (25.8 g, 186 mmol), andthe mixture was heated at 50 °C for 18 h. The reaction wascooled, diluted with CH2C12/ and filtered. The filtrate waschromatographed (150 g SiC>2,; CH2C12 to 5percent 2 M NH3/MeOH inCH2C12) to give the title compound as a liquid (27.0 g,50percent) ..NMR (250 MHz, DMSO-dg) : 8 1.50(m, 2H) , 2.24(m, 6H), 3.36(t,J= 6.5 Hz, 1H) , 3.49(111, 2H) , 4.36(s, 1H) .FIA-MS, m/e: 146.1 (m+1).
Reference：
[1] Journal of Organic Chemistry, 1955, vol. 20, p. 855,858
[2] Journal of the American Chemical Society, 1942, vol. 64, p. 970,972
[3] Pharmazie, 1959, vol. 14, p. 201,202
[4] Journal of the American Chemical Society, 1949, vol. 71, p. 3366,3368
[5] Journal of the American Chemical Society, 1949, vol. 71, p. 3366,3368
[6] Journal of the American Pharmaceutical Association (1912-1977), 1951, vol. 40, p. 373,375
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6875 - 6884
[8] Patent: US2795581, 1955, ,
4
[ 20120-24-5 ]
[ 4441-30-9 ]
Reference：
[1] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 5, p. 644 - 648
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 1036 - 1040
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 40, p. 12796 - 12799
15
[ 110-91-8 ]
[ 20907-32-8 ]
[ 4441-30-9 ]
Reference：
[1] Yakugaku Zasshi, 1954, vol. 74, p. 763[2] Chem.Abstr., 1955, p. 11646
[3] Chemische Berichte, 1942, vol. 75, p. 123,129
16
[ 696-57-1 ]
[ 4441-30-9 ]
[ 2109-66-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 11-12, p. 565 - 570
17
[ 4441-30-9 ]
[ 7357-67-7 ]
Reference：
[1] Tetrahedron, 2007, vol. 63, # 52, p. 12903 - 12911
[2] Journal of the American Chemical Society, 1957, vol. 79, p. 5667,5670
[3] Pharmaceutical Chemistry Journal, 1967, p. 463 - 467[4] Khimiko-Farmatsevticheskii Zhurnal, 1967, p. 35 - 39
[5] Patent: US2009/124624, 2009, A1, . Location in patent: Page/Page column 22
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6875 - 6884
[7] Patent: US2795581, 1955, ,
18
[ 4441-30-9 ]
[ 39969-57-8 ]
[ 637-58-1 ]
Yield
Reaction Conditions
Operation in experiment
82.61%
With sodium hydride In tetrahydrofuran at 20℃; for 5 h; Reflux
A 500 ml reaction flask was added with 23.2 g (0.1 mol) of the above intermediate.3-morpholine-1-propanol 17.42g (0.12 mol) and 115 g of tetrahydrofuran, with stirring turned on, slowly add 60percent sodium hydride 4.8g (0.12 mol), temperature below 20°C, about 1~2 min after addition,The reaction was heated to reflux and monitored by TLC. After about 5 hours, the reaction was completed. The solution was concentrated under reduced pressure. 60 ml of water was added and the pH was adjusted to 1 to 2 with concentrated hydrochloric acid.Ethyl acetate (100 ml) was washed twice. The aqueous layer was adjusted to pH 11-12 with 40percent sodium hydroxide, and the mixture was extracted twice with 120 ml of ethyl acetate.Combine the organic layers, dry an appropriate amount of anhydrous sodium sulfate, decolorize with 2g of charcoal, concentrate at 40°C without concentration, and dissolve with 80ml of methanol.Concentrated hydrochloric acid to adjust the pH 1~2, vacuum concentration to no more, add acetone 40ml dissolved, stirring crystallization, continue to cool to -10 ° C, stirring crystallization about 6 ~ 8 hours;The mixture was filtered with suction, washed with cold acetone, and dried at 45-50° C. for 6-8 hours to obtain 27.25 g of a white crystalline solid with a yield of 82.61percent, a purity of 99.926percent, and a maximum single impurity of 0.046percent.
Reference：
[1] Patent: CN107892677, 2018, A, . Location in patent: Paragraph 0019; 0021
4.1. 4-(3-Chloropropyl)morpholine 1 g (6.9 mmol) of 4-(3-hydroxypropyl)morpholine is stirred at 0 C. and 2.5 mL (34.4 mmol) of thionyl chloride are added. The mixture is stirred for 6 hours at room temperature, poured slowly onto an ice-cold solution of 1 N NaOH and then extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. 1.1 g of an oily colorless product are obtained.1H NMR (DMSO-d6, 250 MHz) delta ppm: 1.8-1.95 (m, 2H); 2.3-2.4 (m, 6H); 3.5-3.6 (m, 4H); 3.65-3.70 (m, 2H).
With thionyl chloride; In toluene; for 2h;Reflux;
General procedure: 2-Chloro-1-ethanol (17) (0.05 mol, 3.4 ml) was added dropwise into the solution of imine (4a-4c) (0.1 mol) in toluene (20 ml) at 25 C, this mixture was refluxed gently for 3 h and then allowed to cool to room temperature. The mixture was filtered, washed with toluene. Then SOCl2 (10 ml) was added into the filtrate, this mixture was refluxed gently for 2 h, and concentrated under reduced pressure. The residue was recrystallized from anhydrous alcohol to afford 19a-19c as white solids which were then used directly in the next step. 24a-24b were synthesized from 1-chloro-3-hydroxypropan (22) and imine (4a-4c) in the same way of 19a-19c.
With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 0.5h;
Starting material: N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine was prepared according to the method in J. Med Chem 2009, 52, 6880-6888. [0321] 6-nitro-4-(3-chloro-4-fluorophenylamino)-7-fluoro-quinazoline (1 eq.) and morpholine-propanol (1.5 eq.) were dissolved in DMSO (10 ml), the solution was stirred for 5 mins with a water bath. A solution of potassium tert-butoxide (3.0 eq.) in DMSO (5 ml) was added slowly to the solution mentioned-above in drops, the mixture was stirred at room temperature for further 30 mins. After the reaction finished, the mixture was diluted with 100 ml water and pH was adjusted to neutral with concentrated hydrochloric acid, then stirred for 30 mins, large amount of yellow solid was precipitated, then filtering, the filter cake was washed with water twice and dried to give yellow solid of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine (yield 90%). [0322] 1H NMR (500 MHz, DMSO) delta 10.15 (s, 1H), 9.21 (s, 1H), 8.67 (s, 1H), 8.16 (dd, J1=7.0 Hz, J2=3.0 Hz, 1H), 7.82-7.78 (m, 1H), 7.49-7.45 (m, 2H), 4.34 (t, J=6.5 Hz, 2H), 3.58 (t, J=4.0 Hz, 4H), 2.46 (t, J=6.5 Hz, 2H), 2.38 (brs, 4H), 1.97-1.92 (m, 2H). HRMS (ESI): m/z calcd for (C21H21ClFN5O4+H)+: 462.1344. found: 462.1344.
With potassium tert-butylate; In dimethyl sulfoxide; at 25℃; for 0.5h;
General procedure: To a suspensionof N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (1.68 g, 5 mmol) and (S)-tetrahydrofuran-3-ol (0.66 g,7.5 mmol) in DMSO (10 mL) at 25 C was added t-BuOK (1.68 g,15 mmol). After a further 30 min reaction, sufficient water wasadded to ensure complete precipitation, and the solid was collectedby filtration, washed by water twice and dried to give thepure yellow solid.
With potassium carbonate; In toluene; at 75 - 80℃; for 8h;
To the reaction bottle were added 913.5 g of toluene, 174 g of morpholine and 556 g of 3-bromopropanol, and 331.2 g of potassium carbonate was added under stirring,The reaction was heated at 75-80 C for 8 hours. After completion of the reaction, pressure filtration and concentration of the filtrate to remove toluene and unreacted raw materials, obtained light yellow278.4 g of N - (3-hydroxypropyl) morphorphine, a molar yield of 96%Gas purity was 98.5%.
88.5%
In toluene; at 80℃; for 4h;
Morpholine 2a(3.1g, 36mmol) and 3-bromo-1-propanol (2.5g, 18mmol) were dissolved in 20mL of toluene at 80 C for 4 hours. The reaction was cooled to room temperature and the reaction was filtered. The filter cake was washed with ethyl acetate (2 mL X 2) and concentrated under reduced pressureThe filtrate gave the title product 3-morpholinopropan-1-ol 2b (2.3 g, yellow oil), yield: 88.5%.
50%
In dichloromethane; at 50℃; for 18h;
To a mixture of morpholine (33 mL, 371 mmol) and CH2C12(650 mL) was added 3-bromopropanol (25.8 g, 186 mmol), andthe mixture was heated at 50 C for 18 h. The reaction wascooled, diluted with CH2C12/ and filtered. The filtrate waschromatographed (150 g SiC>2,; CH2C12 to 5% 2 M NH3/MeOH inCH2C12) to give the title compound as a liquid (27.0 g,50%) ..NMR (250 MHz, DMSO-dg) : 8 1.50(m, 2H) , 2.24(m, 6H), 3.36(t,J= 6.5 Hz, 1H) , 3.49(111, 2H) , 4.36(s, 1H) .FIA-MS, m/e: 146.1 (m+1).
50%
In toluene;
Morpholine (94 g, 1.08 mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml) and the reaction then heated at 80 C. for 4 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was removed by filtration. The volatiles were removed from the filtrate and the resulting yellow oil was purified by distillation at 0.4-0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil. b.p. 68-70 C. (~0.5 mmHg) hu 1H NMR Spectrum: (DMSOd6) 1.65-1.78(m, 2H); 2.50(t, 4H); 2.60(t, 2H); 3.68(t, 4H); 3.78(t, 2H); 4.90(br d, 1H).
50%
In toluene;
Morpholine (94 g, 1.08 mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml) and the reaction then heated at 80 C. for 4 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was removed by filtration. The volatiles were removed from the filtrate and the resulting yellow oil was purified by distillation at 0.4-0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil. b.p. 68-70 C. (~0.5 mmHg) 1H NMR Spectrum: (DMSOd6) 1.65-1.78(m, 2H); 2.50(t, 4H); 2.60(t, 2H); 3.68(t, 4H); 3.78(t, 2H); 4.90(br d, 1H)
50%
In toluene;
Morpholine (94 g, 1.08 mol) was added dropwise to a solution of 3-bromo-1-propanol (75 g, 0.54 mol) in toluene (750 ml) and the reaction then heated at 80 C. for 4 hours. The mixture was allowed to cool to ambient temperature and the precipitated solid was removed by filtration. The volatiles were removed from the filtrate and the resulting yellow oil was purified by distillation at 0.4-0.7 mmHg to give 4-(3-hydroxypropyl)morpholine (40 g, 50%) as a colourless oil. b.p. 68-70 C. (~0.5 mmHg) 1H NMR Spectrum: (DMSOd6) 1.65-1.78(m, 2H); 2.50(t, 4H); 2.60(t, 2H); 3.68(t, 4H); 3.78(t, 2H); 4.90(br d, 1H)
In toluene; at 0 - 100℃; for 4h;
To a cooled (0C, ice bath) solution of morpholine (31.5 ml, 0.36 mole) in toluene (300 ml) was added 3-bromopropanol (25 g, 0.18 mole) under argon. The cooling bath was then removed, the resulting mixture was warmed to room temperature, and stirred at room temperature for 1 hr. The mixture was heated at 100C (bath temperature) for 3 hrs under argon. After cooling, the mixture was diluted with ethyl acetate. The organic layer was washed (brine), dried (MgSO4), and concentrated. The residue was chromatographed (silica gel, elution by 1 : 1 CH2Cl2-hexane) to give the title compound as a clear oil.
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃;
To a stirred suspension of 4-(2-fluoro-4-nitrophenoxy)-6- methoxyquinolin-7-ol: A solution of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6- methoxyquinoline (610 mg, 1.85 mmol) in 9.2 mL CH2Cl2 at room temperature under nitrogen was added 3-morpholinopropan-l-ol (307 uL, 2.22 mmol) followed by triphenylphosphine (775 mg, 2.96 mmol) and finally DEAD (465 uL, 2.96 mmol). After stirring overnight, the reaction was concentrated to a residue by rotovap and purified directly by silica gel flash column chromatography (9/1 EtOAc/MeOH). Product containing fractions were pooled and concentrated to a yellow solid (650 mg, 77%). 1H NMR (400 MHz, CDCl3) delta 8.58 (d, IH), 8.19 (dd, IH), 8.14 (m, IH), 7.48(s, IH), 7.43 (s, IH), 7.33 (dd, IH), 6.55 (d, IH), 4.29 (dd, 2H), 4.01 (s, 3H), 3.73 (m, 4H), 2.58 (dd, 2H), 2.49 (br m, 4H), 2.14 (m, 2H).
With triethylamine; In dichloromethane; at 0 - 20℃; for 3.25h;
Example 6; l-cyclohexyl-3-[4-(3-morpholin-4-yl-propoxy)phenyl]urea (45); Synthesis of 3-morpholinopropyl methanesulfonate (E-2); A solution of 4-(3 -hydro xypropyl)morpho line (E-I) (5.08 g, 35.0 mmol, 1.0 equiv),CH2Cl2 (175 rnL) and Et3N (5.85 rnL, 42.0 mmol, 1.2 equiv) was purged under nitrogen (2 min) and cooled to 0 0C. A mixture of methane sulfonyl chloride (2.98 mL, 38.5 mmol, 1.1 equiv.) in CH2Cl2 (25 mL) was added dropwise over a 15 min. period. The mixture was allowed to slowly warm to rt and stirred for 3 h. The mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and evaporated to provide 3- morpholinopropyl methanesulfonate (E-2) (7.47 g, 96%). LCMS m/z 224.1 [M + H]+. Due to the potential volatility of the product, it was only dried under high vacuum for 45 min. and then used in the next step without further purification.
93%
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;
14.5 g of 3-morpholino propanol was added to 200 ml of tetrahydrofuran,Then add 11g triethylamine,Cooling to 0 ,And then slowly adding 11.4 g of methanesulfonyl chloride,Natural warming to room temperature,The reaction was continued for 1 hour,TLC point board monitoring reaction is complete,Add dilute hydrochloric acid,Extraction,The organic phase was washed with saturated brine,Dried over anhydrous sodium sulfate,filter,Concentrated under reduced pressure,To give 20.7 g of compound II in a yield of 93%.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 15h;
EXAMPLE 68; Scheme for N5-lH-benzimidazol-2-yl-N4-{2-methyl-4-[(3-morpholin-4- ylpropyl)oxy]phenyl}-lH-imidazole-4,5-dicarboxamide; Synthesis of 3-morpholinopropyl methanesulfonate; [00282] A flask was charged with 3-morpholinopropan-l-ol (1.0 g, 6.9 mmol), DIEA (2.4 HiL, 14 mmol) and dichloromethane (100 mL). Mesylchloride (0.64 mL, 8.3 mmol) was added in a drop wise fashion to the dichloromethane mixture and the reaction mixture was stirred at room temperature for 15 hours. Concentration of the reaction mixture gave rise to a quantitative yield of 3-morpholinopropyl methanesulfonate, which was used in the next step without any further purification.
With triethylamine; In dichloromethane; at 20℃;
3-Morpholinopropan-1-ol (0.5g, 3.44 mmol) and triethylamine (0.72 ml, 5.17 mmol) are dissolved in dichloromethane (10 ml). Mesityl chloride (0.40 ml, 5.17 mmol) in dichloromethane (5 ml) is dropwise added and stirred overnight at room temperature. After usual work-up, 0.7 g of the final product are obtained as an oil, which is used in the next synthetic step without further purification.1H NMR (200 MHz, CHLOROFORM-d) delta ppm 1.83 - 2.11 (m, 2 H) 2.35 - 2.59 (m, 4 H) 3.03 (s, 3 H) 3.47 - 3.67 (m, 2 H) 3.67 - 3.80 (m, 2 H) 4.17 - 4.44 (m, 4 H)
In dichloromethane; at 0 - 20℃; for 2h;
Step 25 g 3-Morpholine-4-yl-propan-1 -ol was dissolved in dichloromethane, cooled to 0C, 3.25 mL methanesu lfonylch loride was added and the mixtu re was stirred for 2 h at ambient temperature. Then 7 g potassium carbonate and 3-hydroxy-4-methoxybenzonitrile were added and the reaction was stirred at 45C for 3 h. The mixture was concentrated and 70 mL dimethylacetamide was added and stirred at 120C for 3h. After this time, the mixture was diluted with dichloromethane and extracted with water, the organic phase was dried over magnesium sulfate und concentrated. Yield: 8.6 g (85% content, 77% of theory)
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere;
General procedure: To a solution of 3-morpholin-4-yl-propan-1-ol (412 mg, 2.82 mmol) and TEA (854 mg, 8.46 mmol) in THF (10 mL) was added MsC1 (356 mg, 3.1 mmol) at 0C under N2. After stirring at room temperature for 1 hr, the reaction mixture was filtered. The filtrate was concentrated to give methanesulfonic acid 3- morpholin-4-yl-propyl ester. The freshly prepared methanesulfonic acid 3 -morpholin-4-yl-propyl ester was mixed with 4-chloro-3-methyl-1H-pyrazolo[3,4-bjpyridine-5-carboxylic acid ethyl ester (404 mg, 1.69 mmol) and K2C03 (1.17 g, 8.46 mmol) in DMF (15 mL). The mixture was stirred at 65 C for 1 hr. The starting material was consumed almost completely by TLC. The mixture was poured into water (60 mL) and extracted with EA (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column (DCM/MeOHITEA = 20/1/0.2) to give 4-chloro-3 -methyl-i -(3 -morpholin-4-yl-propyl)- 1H-pyrazolo [3,4-blpyridine-5 -carboxylic acid ethyl ester (90 mg, yield: i5%) as a yellow oil.
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;
To a dichloromethane (CH2Cl2) solution of 4-(3-Hydroxypropyl)morpholine (5.0 g, 34.4 mmol) was added triethylamine (TEA) (7.20 mL, 51.7 mmol) and methanesulfonyl chloride (3.20 mL, 41.3 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 h and quenched with H2O (50 ml), followed by extraction with 10% MeOH/CH2Cl2(3 × 100 ml). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to obtain2as brown oil, which was used without further purification.Rf= 0.40 (MeOH/CH2Cl2, 0.5/9.5);1H NMR (400 MHz, CDCl3)delta3.74-3.68 (m, CH2, 4 piperazineH), 3.00 (s, CH3), 2.49-2.41 (m, CH2, 4 piperazineH), 1.95-1.88 (m, CH2).
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18.75h;
Example 1; 1- [4-(3-morpholin-4-yl-propoxy)cyclohexyl] -3-phenylur ea (62); Synthesis of 4-(3-bromopropyl)morpholine (A-2) A"1 A-2; 3-Morpholin-4-yl-propan-l-ol (A-I) (2.01 g, 13.9 mmol) and triphenylphosphine (3.89 g, 14.8 mmol) were dissolved in THF (29 mL) and the reaction mixture chilled in an ice-bath (0 0C) under a N2 atmosphere. Carbon tetrabromide (4.92 g, 14.8 mmol) was added in portions over ca. 15 minutes. After ca. 30 minutes, the mixture was allowed to <n="71"/>warm to ambient temperature. After ca. 18 h, the reaction was quenched with H2O (10 mL) and Et2O (30 mL). The layers were separated and the organic layer was extracted with 1 N HCl (2 x ca. 15 mL). The pH of the combined aqueous extracts was adjusted to 10-11 with 4 N NaOH. The aqueous phase was extracted with EtOAc (3 x ca. 30 mL), dried over Na2SO4, and evaporated to provide 4-(3-bromopropyl)morpholine (A-2) as a tan solid (2.53 g, 87%): 1H NMR indicated a purity of 72% (mixture of bromide A-2 and triphenylphosphine oxide). The crude material was used in the next step without additional purification.
63%
To a solution of 3-morpholinopropanol (1.20 g, 8.26 mmol) in anhydrous DCM (40 mL) cooled to -18 C was added tetrabromomethane (2.74 g, 8.26 mmol) in four equivalent portions. The mixture was stirred at -18 C for 15 minutes before the addition of triphenylphosphine (2.17 g, 8.26 mmol) in four equivalent portions. The reaction was brought to room temperature and stirred for 2.5 hours. Water (40 mL) was added, and the mixture was stirred vigorously for a few minutes. The layers were allowed to separate, and the organic phase was washed with 1N HC1 (50 mL). The acid layer was neutralized with 1N NaOH (50 mL), and then washed with EtOAc (100 mL). The organic phase was dried over anhydrous Na SCL and concentrated under reduced pressure to afford 46 as a white solid (1.09 g, 63% yield). Rf = 0.14 (hexanes/EtO Ac 50:50 v/v). 1H NMR (400 MHz, CDCl3) 5 3.7l (t, = 4.5 Hz, 4H), 3.47 (t, J= 6.6 Hz, 2H), 2.53-2.41 (m, 6H), 2.03 (app quint, J= 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) delta 67.1, 57.0, 53.8, 31.7, 29.7. MS (ESI+) calculated for [C7Hi5BrNO]+ [M+H]+, 208.0; found 208.0.
N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-fluoro-6-nitroquinazoline-4-amine[ No CAS ]
(3-chloro-4-fluoro-phenyl)-(3,4-dimethoxy-benzyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With sodium t-butanolate; In acetonitrile; at -20 - -10℃; for 4h;
[0136] Procedure B. (3-Chloro-4-fluoro-phenyl)-(3,4-dimethoxy-benzyl)-(7-fluoro-6-nitro-quinazolin-4-yl)-amine (40.6 g, 83.3 mmol) was dissolved in acetonitrile (400 mL). To the mixture was added morpholin-4-yl-propan-1-ol (12.1 g, 83.3 mmol) and the resulting orange-yellow solution was cooled to -15 C. Sodium t-butoxide (9.6 g, 100 mmol) was charged slowly as a solid to the reaction mixture and the resulting dark red solution was stirred for 4 h while maintaining the temperature between -20 C. and -10 C. Water (1 L) was charged to the reaction slowly while keeping the temperature less than 5 C. The resulting yellow suspension was stirred for 1 h. The precipitate was filtered and washed with water (125 mL). After drying at room temperature under nitrogen flow overnight, the crude cake was heated to 65 C. in i-Pr alcohol (700 mL) to obtain a dark homogenous solution. The mixture was slowly cooled to 0 C. to initiate crystallization (at about 35 C.), was held at 0 C. for about 1 h, then filtered and washed with cold i-Pr alcohol (2×60 mL). The cake was dried at 50 C. under vacuum for 24 h to give (3-chloro-4-fluoro-phenyl)-(3,4-dimethoxy-benzyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine as a yellow solid (34.0 g, 67%). Melting point 135-138 C.; 1H NMR (400 MHz, DMSO): delta 8.80 (s, 1H), 7.72 (m, 1H), 7.45 (m, 3H), 7.28 (m, 1H), 7.00 (s, 1H), 6.83 (d, 2H), 5.37 (s, 2H, BnCH2N), 4.30 (t, 2H, OCH2), 3.69 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.55 (t, 4H, O(CH2)2), 2.50 (t, 2H, NCH2), 2.43 (bs, 4H, N(CH2)2), 1.99 (bs, 2H, CH2CH2CH2).
49%
With potassium tert-butylate; In tetrahydrofuran; tert-butyl alcohol; at 5 - 20℃; for 13 - 19h;
[0135] Procedure A. (3-Chloro-4-fluoro-phenyl)-(3,4-dimethoxy-benzyl)-(7-fluoro-6-nitro-quinazolin-4-yl)-amine (0.20 g, 0.41 mmol) and morpholin-4-yl-propan-1-ol (0.060 g, 0.41 mmol) were suspended together in THF/t-BuOH (2:1, 3 mL) and cooled to 5 C. in an ice-salt bath. Potassium t-butoxide (0.05 g, 0.41 mmol) was added as a solid with vigorous stirring, resulting in an orange-brown colored mixture. The ice bath was removed after 1 h and the reaction mixture was stirred for 12 to 18 h at room temperature. The THF/t-BuOH was removed under reduced pressure; ethyl acetate and saturated aqueous sodium bicarbonate were added and the mixture was shaken. The layers then were separated and the aqueous layer was re-extracted with ethyl acetate. The pooled ethyl acetate layers were washed once with brine, and dried over magnesium sulfate. Filtration and evaporation of the solvent under reduced pressure provided the crude product as a bright yellow glass. Chromatography on a BIOTAGE 12M cartridge eluted with 5% MeOH in methylene chloride gave (3-chloro-4-fluoro-phenyl)-(3,4-dimethoxy-benzyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitro-quinazolin-4-yl]-amine (0.122 g, 49%). Melting point 129-132 C.; 1H NMR (400 MHz, CDCl3): delta 8.81 (s, 1H), 7.52 (s, 1H), 7.31 (s, 1H), 7.17 (m, 2H), 6.94 (m, 2H), 6.76 (m, 2H), 5.31 (s, 2H, BnCH2N), 4.25 (t, 2H, J=6.1 Hz, 0CH2), 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.74 (bs 4H, CH2OCH2), 2.54 (bd 6H, NCH2), 2.08 (bs, 2H, CH2CH2CH2); MS (APCI+) m/z 612.2 (M+1).
4-amino-2-(3-morpholino-propoxy)-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With sodium hydride; In 1-methyl-pyrrolidin-2-one; at 145℃; for 6.25h;
The starting material was prepared as follows: sodium hydride (2.0 g of an 85% dispersion in mineral oil, 60 mmol) was added to 4-(3-hydroxypropyl)morpholine (4.8 g, 30 mmol), (Tet. Lett. 1994, 35, 1715), in NMP (50 ml) and the mixture was stirred for 15 minutes. 3-Chloro-4-cyanoaniline (4.8 g, 30 mmol) was added and the mixture was heated at 145 C. for 6 hours.. The mixture was allowed to cool and was partitioned between ethyl acetate and water.. The organic layer was separated, washed with water and then brine and dried (MgSO4).. The solvent was removed by evaporation and the residue was purified by column chromatography eluding with ethyl acetate and then methylene chloride/methanol (9/1) to give 4-cyano-3-(3-morpholinopropoxy)aniline (2.0 g, 26%) as a yellow gum.
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 4h;
diethyl azodicarboxylate (120 mul, 0.76 mmol) was added dropwise to a solution of triphenylphosphine (200 mg, 0.76 mmol), <strong>[205448-31-3]4-chloro-7-hydroxy-6-methoxyquinoline</strong> (100 mg, 0.47 mmol), 3-morpholino-1-propanol (75 mg, 0.52 mmol), (Tet. Lett. 1994, 35, 1715), in methylene chloride (5 ml).. The mixture was stirred for 4 hours at ambient temperature, the solvent was removed by evaporation to dryness and purified by column chromatography eluding with methylene chloride/methanol (9/1) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (105 mg, 66%).
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; for 2h;
a) DI-TERT-BUTYL azodicarboxylate (1.44 g, 6.26 mmol) was added portionwise at room temperature to a stirred suspension of <strong>[574745-97-4]4-chloro-7-methoxyquinazolin-6-ol</strong> (1.20 g, 5.70 mmol), 3-MORPHOLIN-4-YLPROPAN-1-OL (0.91 g, 6.27 mmol) and triphenylphosphine (1.8 g, 6. 87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hours and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 5% methanol in dichloromethane to give 4-CHLORO-7-METHOXY-6- (3-MORPHOLIN-4- ylpropoxy) quinazoline (1. 28 g, 67% yield) as a pale yellow solid: 1H-NMR (CDC13) : 8. 86 (s, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 4.28 (t, 2H), 4.05 (s, 3H), 3.73 (m, 4H), 2.60 (t, 2H), 2.50 (m, 4H), 2.13 (quintet, 2H); MS (+ve ESI) : 338 (M+H) +.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 18 - 25℃;
Reference Example E-6 2-Chloro-4-(N-(3-morpholinopropyl)anilino)pyrimidine 2-Chloro-4-anilinopyrimidine (Reference Example A-9, 400 mg, 1.9 mmol) was dissolved in DCM (23 ml), triphenyl phosphine (612 mg, 2.3 mmol) and 3-N-morpholinopropanol (0.1 mg, 2.1 mmol) were added followed by dropwise addition of DTAD (537 mg, 2.3 mmol). The reaction mixture was stirred overnight at ambient temperature. The solvent was evaporated off and the residue was purified by flash chromatography using first DCM then EtOAc as the eluent. The solvent was evaporated to give the title product as a colourless oil (560 mg, 88%). NMR (400 MHz, 353K): 1.70 (m, 2H), 2.30 (m, 6H), 3.55 (m, 4H), 3.90 (m, 2H), 6.15 (m, 1H), 7.35-7.70 (m, 5H), 7.95 (m, 1H); m/z (ES+) 333 and 335 (MH+).
5-[7-ethyl-6-(3-morpholin-4-ylpropoxy)-1,4-dihydroindeno[1,2-c]pyrazol-3-yl]pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Example 249F (40 mg, 0. 092MMOL), polymer supported PH3P (3 MMOL/G, 46 mg, 0.139 MMOL), di-tert-butyl azodicarboxylate (32 mg, 0.139 mmol) and 3-MORPHOLIN-4-YLPROPAN-1-OL (27 mg, 0.184 mmol) were combined in THF (3 mL) and stirred overnight. Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixture of EtOH (5 mL) and CH2C12 (2 mL), treated with 4 N HC1 in dioxane (0.5 mL), stirred at 50C overnight and concentrated. The residue was purified by preparative HPLC. The title compound (33 mg) was obtained at 50% yield. MS (DCI/MH3) M/Z : 430.2 (M+H) +.
With hydrogenchloride In tetrahydrofuran; thionyl chloride; ethanol; N,N-dimethyl-formamide; toluene; <i>tert</i>-butyl alcohol
1 One-pot reaction for the preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (i)
EXAMPLE 1 One-pot reaction for the preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (i) 150 g 7-fluoro-6-nitroquinazolin-4(3H)-one (III) are suspended in 600 ml thionyl chloride and, after addition of 6 ml DMF, boiled under reflux for 24 hrs. A clear solution hereby results. About 350 ml thionyl chloride are distilled off in a vacuum. The resulting coarsely crystalline suspension is mixed with about 600 ml toluene. About 800 ml are distilled off in a vacuum. This distillation was further repeated 3 times with, in each case, 600 ml fresh toluene. In the case of the last distillation, the toluene is distilled off as far as possible. There results a coarsely crystalline suspension which, at all times, remains well stirrable. The almost dry residue is mixed with 1.2 l of a tetrahydrofuran/tert.-butanol mixture (7:3). The resulting suspension is cooled to about 10° C. With good stirring and cooling, a solution of 114 g 3-chloro-4-fluoroaniline and 258 g 3-morpholin-4-yl-propan-1-ol (VI) in 300 ml THF/tert.-butanol (7:3) is added dropwise over the course of about 20 min. so that the temperature in the reactor remains between 10° C. and 15° C. The initially yellowish suspension becomes thinner and colours orange in the course of the addition. One allows the reaction mixture slowly to come to room temperature and subsequently stirs it at room temperature for at least 24 hrs. To the yellow-orange suspension is added dropwise, with good stirring and gentle cooling during the course of about 20 min., a solution of 324 g potassium tert.-butylate in 1.86 l tetrahydrofuran so that the temperature in the reactor remains between 15° C. and 20° C. After addition of about 1/3 of the potassium tert.-butylate/THF solution, the whole reaction mixture becomes dark red coloured. After about 30 minutes of further stirring, the mixture is immediately stirred into a mixture of 5.4 kg ice, 6.0 l ethanol and 1.8 l hydrochloric acid (pH of the solution about 8). There hereby first results a yellow-orange solution. After brief stirring, a yellow product crystallises out. The resulting suspension is further stirred for about 5 hrs at about 0° C. and subsequently filtered with suction. The filter cake is washed twice with, in each case, 500 ml ice-cold ethanol. The product is pre-dried in a circulating air cabinet first at 40° C. and subsequently at 60° C. to constant weight (yield: 316.5 g=95.5%; HPLC purity: 98.48 rel. %; H2O (K.F.) 3.69% m.p. 257° C.
With hydrogenchloride In tetrahydrofuran; thionyl chloride; ethanol; N,N-dimethyl-formamide; toluene; <i>tert</i>-butyl alcohol
1 EXAMPLE 1
EXAMPLE 1 One-Pot Reaction for the Preparation of (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine (I). 150 g 7-fluoro-6-nitroquinazolin-4(3H)-one (III) are suspended in 600 ml thionyl chloride and, after addition of 6 ml DMF, boiled under reflux for 24 hrs. A clear solution hereby results. About 350 ml thionyl chloride are distilled off in a vacuum. The resulting coarsely crystalline suspension is mixed with about 600 ml toluene. About 800 ml are distilled off in a vacuum. This distillation was further repeated 3 times with, in each cape, 600 ml fresh toluene. In the case of the last distillation, the toluene is distilled off as far as possible. There results a coarsely crystalline suspension which, at all times, remains well stirrable. The almost dry residue is mixed with 1.2 l of a tetrahydrofuran/tert.-butanol mixture (7:3). The resulting suspension is cooled to about 10° C. With good stirring and cooling, a solution of 114 g 3-chloro-4-fluoroaniline and 258 g 3-morpholin-4-yl-propan-1-ol (VI) in 300 ml THF/tert.-butanol (7:3) is so added dropwise over the course of about 20 min. that the temperature in the reactor remains between 10° C. and 15° C. The initially yellowish suspension becomes thinner and colours orange in the course of the dropping in. One allows the reaction mixture slowly to come to room temperature and subsequently stirs at room temperature for at least 24 hrs. To the yellow-orange suspension is so added dropwise, with good stirring and gentle cooling during the course of about 20 min., a solution of 324 g potassium tert.-butylate in 1.86 l tetrahydrofuran that the temperature in the reactor remains between 15° C. and 20° C. After addition of about 1/3 of the potassium tert.-butylate/THF solution, the whole reaction mixture becomes dark red coloured. After about 30 minutes after-stirring, the mixture is immediately stirred into a mixture of 5.4 kg ice, 6.0 l ethanol and 1.8 l hydrochloric acid (pH of the solution about 8). There hereby first results a yellow-orange solution. After brief stirring, a yellow product crystallises out. The resulting suspension is after-stirred for about 5 hrs at about 0° C. and subsequently filtered off with suction. The filter cake is after-washed twice with, in each case, 500 ml ice-cold ethanol. The product is pre-dried in a circulating air cabinet first at 40° C. and subsequently at 60° C. to constant weight (yield: 316.5 g=95.5%; HPLC purity: 98.48 rel. %; H2O (K.F.) 3.69% m.p. 257° C.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 3h;
To a stirred solution of compound II (12 mg, 0.033 mmol) in THF (4.0 mL) was added 3-morpholinopropan-l-ol (10.0 muL, 0.072 mmol), triphenylphosphine (22.6 mg, 0.086 EPO <DP n="82"/>mmol) and diethyl azodicarboxylate (13.4 muL, 0.086 mmol). After stirring at room temperature for 3 h, the reaction mixture was concentrated. The residue was dissolved in THF/water (3:2, 1.2 mL), passed through a 0.45 mum filter, and purified by HPLC on a Varian Inertsil 5mu ODS-3 (250x100) reverse-phase HPLC column. Elution with 10% to 90% gradient of 0.1% AcOH in water/0.1 % AcOH in CH3CN over 40 min provided compound III (11 mg, 70% yield): LRMS m/z (M+H) calcd for C25H34NO9 492.2; obsd 492.2.
[0143] One hundred fifty g of 7-fluoro-6-nitroquinazolin-4(3H)-one was suspended in 600 mL of SOCl2 and, after addition of 6 mL of DMF, boiled under reflux for about 24 h, resulting in a clear solution. About 350 mL of SOCl2 was distilled off under vacuum, and the resulting coarse crystalline suspension was admixed with about 600 mL of toluene. Approximately 800 mL of the resultant solution was distilled off under vacuum. The distillation was repeated three times with, in each case, 600 mL of fresh toluene. In the last distillation, most of the toluene was distilled off, resulting in a coarse crystalline suspension. The nearly dry residue was mixed with 1.2 L of a THF/t-BuOH mixture (7:3 v/v), and the resulting suspension was cooled to about 10 C. A solution of 114 g of 3-chloro-4-fluoroaniline and 258 g of 3-morpholin-4-yl-propan-1-ol in 300 mL of a THF/ t-BuOH mixture (7:3 v/v) was added drop-wise with stirring and cooling over the course of about 20 min so that the temperature in the reactor remained at a temperature between 10 C. and 15 C. The initially yellowish suspension became less viscous and changed to a yellow-orange color during addition of the 3-chloro-4-fluoroaniline and 3-morpholin-4-yl-propan-1-ol solution. The resulting reaction mixture was allowed to slowly reach room temperature and was subsequently stirred at room temperature for at least 24 h. [0144] With stirring and cooling, a solution of 324 g of t-BuOK in 1.86 L of THF was added drop-wise to the yellow-orange suspension over the course of about 20 min so that the temperature in the reactor remained between 15 C. and 20 C. After the addition of about one-third of the t-BuOK/THF solution, the reaction mixture turned dark red. Once all of the t-BuOK/THF solution was added, the reaction mixture was stirred for an additional 30 min and subsequently stirred into a mixture of 5.4 kg of ice, 6.0 L EtOH and 1.8 L HCl (pH of the solution about 8). The reaction mixture was initially yellow-orange, but after brief stirring, a yellow product crystallized out. The resulting suspension was stirred for about 5 h at about 0 C. and subsequently filtered off with suction. The filter cake was washed twice with 500 mL aliquots of ice-cold EtOH. The product of the one-pot synthesis, (3-chloro-4-fluorophenyl)-[7-(3-morpholin-4-yl-propoxy)-6-nitroquinazolin-4-yl]-amine, was initially dried in a circulating air cabinet at 40 C. and was subsequently dried at 60 C. to constant weight (yield: 316.5 g=95.5%; HPLC purity: 98.48 rel. %; H2O (by K. F.) 3.69%; mp 257 C.).
With triethylamine; In tetrahydrofuran; at 0℃; for 2h;
14.5 g of 3-morpholinylpropanol was added to 200 ml of tetrahydrofuran,Then add 11g triethylamine, cool to 0 C,And then slowly add 19g p-toluenesulfonyl chloride, the natural temperature to room temperature, continue to stir the reaction for 2 hours, TLC point board monitoring reaction is complete, adding dilute hydrochloric acid, extraction and separation, organic phase and then saturated brine washing, Dried over sodium sulfate, filtered and concentrated under reduced pressure to give 28.7 g of compound II in a yield of 96%.
64%
With dmap; triethylamine; In dichloromethane; at 20℃;
Compound <strong>[4441-30-9]3-morpholinopropan-1-ol</strong> 30a (500 mg, 3.45 mmol) was dissolved in dichloromethane (100 ml), and then added 4-dimethylaminopyridine (42 mg, 0.34 mmol), triethylamine (1.04 g, 10.3 mmol) and p-toluenesulfonyl chloride (988 mg, 5.17 mmol), stirred at room temperature overnight, after the reaction is completed, the reaction solution was poured into water (50 mL), and then extracted with dichloromethane (50 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was removed by filtering, and the reaction system was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1), so as to obtain the title product 3-morpholinopropyl 4-methylbenzenesulfonate 30b (660 mg, yellow oily substance), and the yield was 64%. MS m/z (ESI): 300[M+1]
64%
With dmap; triethylamine; In dichloromethane; at 20℃;
The compound 3-morpholinopropane-1-ol 30a (500 mg, 3.45mmol) was dissolved in dichloromethane (100ml), 4-dimethylaminopyridine (42mg, 0.34mmol), triethylamine (1.04g, 10.3mmol) and p-toluenesulfonyl chloride (988mg, 5.17mmol) were added, Stir overnight at room temperature.After the reaction is completed, the reaction solution is poured into water (50mL) and extracted with dichloromethane (50mL × 3). The organic phases are combined and dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue is applied to a silica gel column. Chromatographic purification (petroleum ether / ethyl acetate = 2/1, the target product 3-morpholinopropyl 4-methylbenzenesulfonate 30b (660 mg, yellow oil) was obtained, yield: 64%.
43.5%
3-Morpholinopropan-1-ol 2b (1.45 g, 10 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine(2 · Olg, 20 mmol) and 4-dimethylaminopyridine (122 mg, 1 mmol) were added and reacted for 10 minutes. To the solution was added p-toluenesulfonyl chloride(2.86 g, 15 mmo 1) and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, a small amount of ethyl acetate was added to the residue, and the mixture was stirred for 10 minutesThe filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System A to give the title product 3-Morpholinopropyl 4-methylbenzenesulfonate 2c (1.3 g, yellow oil), yield: 43.5%.
With pyridine;dmap; at 20℃;
Example 30; 4-(3-Chloro-phenyl)-2-[6-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.30); Step 1; To a mixture of 0.145 g (1 mmole) of 3-morpholin-4-yl-propan-1-ol and 5 mL of pyridine was added 0.001 g of 4-dimethylaminopyridine and 0.210 g (1.1 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was taken up in 10 mL of dichloromethane and washed once with 5 mL of saturated sodium bicarbonate, twice with 5 mL of water, and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.22 g of toluene-4-sulfonic acid 3-morpholin-4-yl-propyl ester as a colorless oil.
4-{3-[(tributylstannyl)methoxy]propyl}morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
To a mixture of sodium hydride (60%, 278 mg, 6.96 mmol) and tetrahydrofuran (20 ml) was added N-(3-hydroxypropyl)morpholine (963 mul, 6.96 mmol) at room temperature. Then, the reaction mixture was stirred at 45C (external temperature) for 10 minutes. To the reaction mixture was added tributyl-iodomethyl-tin (2.0 g, 4.64 mmol) at 0C (external temperature). Then, the mixture was stirred at 45C for 1 hour. The reaction mixture was cooled at room temperature, diluted with ethyl acetate, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, heptane:ethyl acetate=9:1) to obtain the title compound (2.08 g, 6.96 mmol, 100%). 1H-NMR Spectrum (CDCl3) delta (ppm) : 0.81-0.97 (15H, m), 1.26-1.35 (6H, m), 1.42-1.54 (6H, m), 1.75 (2H, br s), 2.46 (6H, br s), 3.36 (2H, t, J=6.2Hz), 3.70(2H, t, J=7.0Hz), 3.64(4H, br s).
With potassium tert-butylate; In 1,4-dioxane; at 20℃; for 16h;
To a slurry of 790 mg (5.00 mmol) 3-fluoro-4-nitropyridine-1 -oxide and 762 mg4-(3-hydroxypropyl)-morpholine in 10 ml dioxane, 673 mg (6. 00 mmol) potassium tert- butylate were added and stirred at ambient temperature for 16 hrs. The reaction mixture was diluted with ethylacetate, filtered and the filtrate evaporated. The residue was chromatographed on a silica column with dichloromethane/methanol. This yielded 4-[3-(4- nitro-1-oxypyridin-3-yloxy)-propyl]-morpholine as a brownish oil; HPLC-MS: [M+H] 284.
With potassium tert-butylate; In 1,4-dioxane; at 20℃; for 16h;
EXAMPLE 5Synthesis of 2-(5-chloro-2-fluorophenyl)-[1,8]naphthyridin-4-yl]-[3-(3-morpholin-4-yl-propoxy)-pyridin-4-yl]-amine (no. 34) To a slurry of 790 mg (5.00 mmol) <strong>[769-54-0]3-fluoro-4-nitropyridine-1-oxide</strong> and 762 mg 4-(3-hydroxypropyl)-morpholine in 10 ml dioxane, 673 mg (6.00 mmol) potassium tert.-butylate were added and stirred at ambient temperature for 16 hrs. The reaction mixture was diluted with ethylacetate, filtered and the filtrate evaporated. The residue was chromatographed on a silica column with dichloromethane/methanol. This yielded 4-[3-(4-nitro-1-oxypyridin-3-yloxy)-propyl]-morpholine as a brownish oil; HPLC-MS: [M+H] 284.
General procedure: General Procedure for the Preparation of 7-Azaindenoisoquinolines 18-23 [0120] The appropriate 7-aza-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (15-17, 94-248 mg, 0.31-1.0 mmol, 1 equiv) and triphenylphosphine (262-786 mg, 1.0-3.0 mmol, 3 equiv) were diluted in THF (16-50 mL). The appropriate alcohol [3-dimethylamino-1-propanol (0.17-0.21 mL, 1.46-1.82 mmol, 3 equiv) or <strong>[4441-30-9]3-morpholinopropan-1-ol</strong> (145-435 mg, 1.0-3.0 mmol, 3 equiv)] was added, followed by DIAD (202-606 mg, 1.0-3.0 mmol, 3 equiv). The solution was stirred at room temperature for 64 h. As the reaction reached completion, all of the solid material dissolved. The reaction mixture was concentrated to dryness. The solid was purified by flash column chromatography (SiO2), eluting with 1% MeOH in CHCl3, to provide a dark-orange solid. The solid was further purified by treating it with 3 M HCl in methanol (15 mL) for 2 h at room temperature with stirring. The solution was concentrated to dryness. The orange solid was diluted in ethyl ether (50 mL). The hydrochloride salt of the product precipitated and was collected using vacuum filtration, washing with ethyl ether (3-15 mL), to provide an orange solid.; 7-Aza-5,6-dihydro-6-(3-morpholinopropyl)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline Hydrochloride (21) [0124] The general procedure provided the desired compound as an orange solid (255 mg, 62%): mp 316-318 C. IR (KBr) 1704, 1669, 1612, 1570, 1550, 1506, 779 cm-1; 1H NMR (DMSO-d6) delta 10.40 (s, 1H), 8.61 (d, J=4.5 Hz, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.92 (dd, J=7.2, 1.5 Hz, 1H), 7.86 (t, J=7.2 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.45 (dd, J=7.5 and 6.6 Hz, 1H), 4.91 (m, 2H), 3.90 (m, 2H), 3.69 (m, 2H), 3.37 (m, 2H), 3.05 (m, 4H), 2.24 (m, 2H). Anal. Calcd for C22H21N3O3.HCl.1.5H2O: C, 60.20; H, 5.74; N, 9.57. Found: C, 60.37; H, 5.83; N, 9.62.
5 g 3-Morpholine-4-yl-propan-1-ol was dissolved in dichloromethane, cooled to 0 C., 3.25 mL methanesulfonylchloride was added and the mixture was stirred for 2 h at ambient temperature. Then 7 g potassium carbonate and <strong>[52805-46-6]3-hydroxy-4-methoxybenzonitrile</strong> were added and the reaction was stirred at 45 C. for 3 h. The mixture was concentrated and 70 mL dimethylacetamide was added and stirred at 120 C. for 3h. After this time, the mixture was diluted with dichloromethane and extracted with water, the organic phase was dried over magnesium sulfate and concentrated.Yield: 8.6 g (85% content, 77% of theory)
7-Aza-5,6-dihydro-6-(3-(4-morpholino)propyl)-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (64) [0188] 7-Aza-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]-isoquinoline (61, 278 mg, 1 mmol) was added to a stirred solution of PPh3 (510 mg, 1.9 mmol) and diisopropyl azodicarboxylate (390 mg, 1.9 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 4 h. 4-(3-Hydroxypropyl)morpholine (280 mg, 1.9 mmol) was added dropwise to the resulting solution over the course of 15 min, and the reaction mixture was stirred at room temperature for 12 h. PPh3 (510 mg, 1.9 mmol) and diisopropyl azodicarboxylate (390 mg, 1.9 mmol) were added to the reaction mixture. The mixture was stirred for 6 h, and 4-(3-hydroxypropyl)morpholine (280 mg, 1.9 mmol) was added, forming an orange solution. The solution was stirred at room temperature for 24 h and evaporated to dryness under reduced pressure. The residue was subjected to flash column chromatography (silica gel), eluting with a gradient of 1% to 5% methanol in chloroform, to provide an orange solid (163 mg, 40%): mp 218-224 C. (dec). 1H NMR (300 MHz, DMSO-d6) delta 8.45 (d, J=8.2 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.61-7.45 (m, 2H), 4.82 (s, 2H), 3.92 (d, J=12.6 Hz, 5H), 3.74 (t, J=11.9 Hz, 2H), 3.39 (d, J=12.2 Hz, 2H), 3.21 (s, 2H), 3.03 (d, J=11.8 Hz, 2H), 2.22 (s, 2H); positive ion ESIMS m/z (rel intensity): 406 (MH+, 100); HRMS-ESI m/z: MH+ calcd for C21H21N3O3, 406.1767; found, 406.1773; HPLC purity: 97.30% [C-18 reverse phase, MeOH]; 98.60% [C-18 reverse phase, MeOH/H2O, 85:15].
7-Aza-5,6-dihydro-6-(3-(4-morpholino)propyl)-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (66) [0190] 7-Aza-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (62, 323 mg, 1 mmol) was added to a stirred solution of PPh3 (510 mg, 1.9 mmol) and diisopropyl azodicarboxylate (390 mg, 1.9 mmol) in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 4 h. 4-(3-Hydroxypropyl)morpholine (280 mg, 1.9 mmol) was added dropwise to the resulting solution over the course of 15 min, and the reaction mixture was stirred at room temperature for 12 h. PPh3 (510 mg, 1.9 mmol) and diisopropyl azodicarboxylate (390 mg, 1.9 mmol) were added to the reaction mixture. The mixture was stirred for 6 h, and 4-(3-hydroxypropyl)morpholine (280 mg, 1.9 mmol) was added, forming an orange solution. The solution was stirred at room temperature for 24 h and evaporated to dryness under reduced pressure. The residue was subjected to flash column chromatography (silica gel), eluting with a gradient of 1% to 5% methanol in chloroform, to provide 66 as a red solid (212 mg, 47%): mp 243-245 C. (dec). 1H NMR (300 MHz, DMSO-d6) delta 8.81 (s, 1H), 8.55 (s, 2H), 8.32 (d, J=2.5 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 4.84 (s, 2H), 3.96 (s, 3H), 3.79 (s, 4H), 3.21 (m, 6H), 2.22 (s, 2H); positive ion ESIMS m/z (rel intensity): 451 (MH+, 100); HPLC purity: 95.42% [C-18 reverse phase, MeOH]; 95.93% [C-18 reverse phase, MeOH/H2O, 85:15].
4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]propyl}morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With triphenylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 0 - 20℃;
In a 100 m L round-bottomed flask, t ri hen y I phosph i ne (1.25 g, 4.77 mmol, Eq: 1 .05 ), 3- morpholinopropan-l-ol (596 mg, 4.54 mmol, Eq: 1 .00) and 4-(4,4,5,5,-tetramethyl-l ,3,2- dioxaborolan-2-yl )phenol (1 g, 4.54 mmol, Eq: 1 .00) were combined with THF (25.0 ml ) to give a colorless suspension. Cooled the reaction to 0C, 1 . 1 '-(azodicarbonyl )dipiperidine ( 1 .2 g, 4.77 mmol, Eq: 1 .05 ) in THF (5 ml.) was added. The reaction mixture was slowly raised to room temperature and stirred overnight, concentrate the solution. The compound was purified by column chromatography ( Hexanes/EtOAc = 70/30) to give 0.90 g (57%) oil . MH+348.1
7-hydroxy-2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethanesulfonate[ No CAS ]
2,2-dimethyl-7-(3-morpholinopropoxy)-4-oxo-4H-benzo[d][1,3]dioxin-5-yl trifluoromethanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere;
A mixture of compound 44 (1.03 g, 3 mmol), 4-(3-hydroxypropyl)morpholine (498 muL, 3.6 mmol) and triphenylphosphine (1.57 g, 6 mmol) was dissolved in THF (15 mL). The solution was degassed well under argon and diisopropyl azodicarboxylate (883 mg, 4.5 mmol) was then added. The mixture was stirred at room temperature for 18 h under argon. The solvent was then removed under reduced pressure and the crude product was purified by column chromatography on silica gel (0-100% EtOAc in petro ether) to afford the title compound (30) (784 mg, 56%) as a colorless gum. 1H NMR (400 MHz, CDCl3) delta = 6.52 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 4.09 (t, J = 6.3 Hz, 2H), 3.73-3.69 (m, 4H), 2.53-2.43 (m, 6H), 2.03-1.95 (m, 2H), 1.73 (s, 6H); 13C NMR (100 MHz, CDCl3) delta = 165.0, 158.8, 157.0, 149.9, 118.7 (q, J = 321.1 Hz), 106.5, 105.6, 101.5, 100.8, 67.4, 66.9 (2C), 54.9, 53.7 (2C), 25.9, 25.5 (2C); MS (ESI): m/z 470 [M+H]+ (72%).
To a solution of <strong>[4441-30-9]3-morpholinopropan-1-ol</strong> (1.39 g, 9.50 mmol) in THF (35 mL) was added potassium tert-butoxide (1.65 g, 14.4 mmol) at 0C. The mixture was heated to rt and stirred for 30 minutes. Then the mixture was cooled to 0C again, and to it was added a mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (1.5 g, 6.5 mmol) in THF (25 mL) with stirring. The reaction mixture was stirred at rt overnight, quenched with water (10 mL), and then concentrated in vacuo. The residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium chloride solution (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) 20/1) to give the title compound as a yellow solid (1.65 g, 75%). The compound was characterized by the following spectroscopic data: ESI-MS (positive ion mode) m/z: 341.1 [M+1]+.
5-morpholino-7-(3-morpholinopropoxy)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
mixture of 5,7-difIuoroquinazoIin-4(3I--one (0.30 g, 1.65 mmol) and morpholine (0.29 mL, 3.30 mmol) in 2 mL of N,N-dimethylformamide was refluxed at 110 00 for 2 h. After the reaction solution was cooled down to room temperature, 3-morpholinopropan-1 -ol (0.26 g, 1 .82 mmol) and t-BuOK (0.74 g, 6.60 mmol) were added. The resulting reaction mixture was refluxed at 110 00 for 6 h. After removal of solvent in vacuo, the yellow solid residue was purified by column chromatography eluted with 0.5:5:94.5NH4OH :methanol:dichloromethane to afford 5-morpholino-7-(3- morpholinopropoxy)-quinazolin-4(3I--one as a yellow foamy solid in 32% yield(0.20 g). 1H NMR (300 MHz, 0D013): 7.94 (5, 1 H), 6.81 (d, J= 2.4 Hz, 1 H), 6.54 (d, J= 2.4 Hz, 1H), 4.15 (t, J= 6.3 Hz, 2H), 4.02-3.94 (m, 4H), 3.78-3.68 (m, 4H), 3.14 (brs, 4H), 2.58-2.40 (m, 6H), 2.08-1.96 (m, 2H).
3-morpholin-4-ylpropyl 5-{4-[4-([(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 60℃; for 3h;
Example 2743-morpholin-4-ylpropyl 5-{4-[4-([(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylateTo a stirred suspension of 5-{4-[4-([(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100mg, 0.22mmol) and N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC, 63mg, 0.33mmol) in 10ml of anhydrous tetrahydrofuran were added N-(3- hydroxypropyl)morpholine (64mg, 0.44mmol) and 4-dimethylaminopyridine (10mg, 0.08mmol). The mixture was heated at 60C for 3 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3~5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[4-([(2-fluoro-5- methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 72mg, 56%. LR MS (ES+): 574 (MH+) LR MS (ES-): 572 (M-H)
5-[(2S,3S)-1-{trans-4-[1-(tert-butoxycarbonyl)amino-2-fluoroethyl]cyclohexanecarbonyl}-3-cyclohexylpyrrolidine-2-carboxamide]-1-benzofuran-2-carboxylic acid[ No CAS ]
3-(morpholin-4-yl)propyl 5-[(2S,3S)-1-{trans-4-[1-(tert-butoxycarbonyl)amino-2-fluoroethyl]cyclohexanecarbonyl}-3-cyclohexylpyrrolidine-2-carboxamide]-1-benzofuran-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of the compound of Reference Example 50 (336.8 mg, 0.537 mmol) in DMF (3 mL), 1-hydroxybenzotriazole (164 mg, 1.08 mmol), WSC·HCl (206 mg, 1.08 mmol), triethylamine (224 muL, 1.61 mmol), and 3-morpholino propanol (117 mg, 0.806 mmol) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride twice and with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, then dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (300.6 mg, 74%). MS (ESI+) 755 (M+1, 100%)
5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid[ No CAS ]
5-(3-((1R,2R,3R,5R)-5-chloro-2-(3,5-dichlorophenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylic acid 3-(morpholin-4-yl)propyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetone; at 20℃; for 18h;
[091] To a solution of acid 1 (60 mg, 0.13 mmol), 4-dimethylaminopyridine (16.7 mg, 0.136 mmol), and 4-(3-hydroxypropyl)morpholine (0.18 ml, 1 .30 mmol) in DMF (2.0 ml) was added 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.5 mg, 0.143 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and diluted with ethyl acetate. The organic layer was washed with water, saturated aqueous NaCI, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was eluted through a flash column (silica gel 60, 230-400 mesh, 4% MeOH in EtOAc) to afford ester 6 (59.6 mg, 78%) as a light yellow oil.
6-chloro-3-((4-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazine[ No CAS ]
4-(3-((3-((4-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)oxy)propyl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60.67%
[00344] A mixture of N-hydroxypropyl morpholine (0.95 g, 6.55 mmol) in anhydrous THF (40 mL) was cooled to 0C, and t-BuOK (830 mg, 7.41 mmol) was added. After the addition, the reaction mixture was stirred for 20 minutes at rt and then cooled to 0C. A mixture of 6-chloro-3-((4-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazine (1.1 g, 3.69 mmol) in THF (30 mL) was added and then the reation mixture was warmed to rt and stirred overnight. After the reaction monitored by TLC was completed, water (2.0 mL) was added and the solvent was removed under vacuo. The residue was purified by silica gel column chromatography (CH2C12/MeOH (v/v) = 20/1) to give the title compound as a yellow solid (910 mg, 60.67%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 408.2 [M+lfb.
60.67%
N-hydroxypropylmorpholine (0.95 g, 6.55 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), cooled to 0 C, t-BuOK (830 mg, 7.41 mmol) was added and the mixture was stirred at rt for 20 min. Then, the temperature was further lowered to 0 C and 6-chloro-3-[(4-nitrophenyl)ethynyl]imidazo [1,2-b]pyridazine (1.1 g, 3.69 mmol) and 30 mL of tetrahydrofuran. After addition was complete, move to room temperature and react overnight. TLC monitoring of the reaction was complete, add water (2.0mL), the solvent was evaporated under reduced pressure, the residue was directly mixed with silica gel sample. Column chromatography (V (dichloromethane) / V (methanol) = 20/1) gave 910 mg of a yellow solid in a yield of 60.67%.
7-chloro-3-iodopyrazolo[1,5-a]pyrimidine[ No CAS ]
4-(3-((3-iodopyrazolo[1,5-a]pyrimidin-7-yl)oxy)propyl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
[00372] To a 50 mL one-neck flask were added t-BuOK (0.6 g, 5.0 mmol) and THF (50 mL). The mixture was cooled to 0C, and N-hydroxypropyl morpholine (0.78 g, 5.4 mmol) was added dropwise slowly, then the resulting mixture was stirred at 0 C for 30 minutes. Then 7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (1.0 g, 3.6 mmol) was added to the mixture while keeping the temperatureof the mixture ator below 10 C. After the addition, the reaction mixture was stirred at 0 C for 2 hours. The resulting mixture was quenched with water (50 mL) and concentrated in vacuo. The residue was dissolved in dichloromethane (300 mL), and the mixture was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a light yellow solid (1.3 g, 94%) which was used directly for the next step without further purification. The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 389.0 [M+lfb.
1.3 g
In a 50 mL single neck flask, t-BuOK (0.6 g, 5.0 mmol) was weighed and dissolved in tetrahydrofuran (50 mL). After cooling to 0 C, N-hydroxypropylmorpholine (0.78 g, 5.4 mmol) was slowly added dropwise and stirred at 0 C for 30 min. A solution of 7-chloro-3-iodopyrazolo[1,5-a]pyrimidine (1.0 g, 3.6 mmol) was slowly added and the temperature was kept at 10 C. The reaction mixture was quenched by adding water (50 mL), the reaction solution was concentrated, the residue was dissolved in dichloromethane (300 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. 1.3 g of a pale yellow solid was obtained in a yield of 94%. Without further purification, directly into the next reaction.
With potassium tert-butylate; In N,N-dimethyl-formamide; at 70 - 75℃; for 7h;
To the reaction flask were added 835 g of DMF, 184.7 g of 4-n-butoxychlorobenzene and 217.8 g of N- (3-hydroxypropyl) morpholine,After mixing, 134.4 g of potassium t-butoxide was added; the reaction solution was slowly raised to 70-75 C for 7 hours. After the reaction to concentrate,After the completion of the solvent distillation, the mixture was cooled to 30 C or lower and 350 g of water was added. The mixture was extracted with 350 g of ethyl acetate. The aqueous layer was extracted once more with 200 g of ethyl acetate. The combined organic layers were washed once with saturated brine. Powder after dryingActivated carbon decolorization, at 15-20 C to clarify the colorless solution obtained by hydrogen chloride gas to the solution pH value of 3 to 5; stirring half an hour after the re-measured solution pH value after stirring crystallization crystallization 2 hours, centrifugal drying to white 277.lg of pomocaine hydrochloride, liquid purity of 99.94%, molar yield of 84.0%.
4-(3-(4-nitro-2-(trifluoromethyl)phenoxy)propyl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of 1-methylpiperidin-4-ol (1.15 g, 10 mM) in DMF (10 mL) were added NaH (0.48 g, 12 mM) successively. The mixture was stirred at 0C for 0.5 h, followed by addition of the required 1-fluoro-4-nitro-2-(trifluoromethyl)benzene and heating to reflux for another 5 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100×2 mL) and water (40×2 mL). The organic layer was evaporated, the resulting residue 5a utilized as materials without further purification.
General procedure: To a solution of 1-methylpiperidin-4-ol (1.15 g, 10 mM) in DMF (10 mL) was added NaH (0.48 g, 12 mM) successively. The mixture was stirred at 0C for 0.5 h, followed by addition of the required 1-fluoro-4-nitro-2-(trifluoromethyl)benzene and heating to reflux for another 5 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (100×2 mL) and water (40×2 mL). The combined organic layers were evaporated, the resulting residue 1c utilized as materials without further purification.
3-fluoro-4-({2-[3-(morpholin-4-yl)propoxy]pyridin-4-yl}oxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium tert-butylate; In tetrahydrofuran; at 70℃; for 0.5h;Microwave irradiation;
The compound 41a (238 mg, 1 mmol)And 2-morpholine propanol (290 mg, 2 mmol) were dissolved in 1 mL of THF,Then potassium tert-butoxide (242 mg, 2 mmol) was added,Microwave 100w,70 under the conditions of reaction 30min.After completion of the reaction, the compound 41b (330 mg, 95%) was obtained by column chromatography after removal of the solvent.
tert-butyl 4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate[ No CAS ]
tert-butyl 4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- -4-yl]piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.6%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃; for 3h;Inert atmosphere;
A mixture of 3-morpholinopropan-l-ol (11.8 g, 81.1 mmol), tert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-<i]pyrimidin-4- yl)piperazine-l- carboxylate (18 g, 40.5 mmol), BINAP (5.05 g, 8.11 mmol), t-BuONa (9.74 g, 101 mmol) and Pd2(dba)3 (3.71 g, 4.05 mmol) in toluene (300 mL) was degassed and purged with N2 3 times, and the mixture stirred at 110 C for 3 hours under N2 atmosphere. The reaction mixture was poured into H20 (200 mL) and the aqueous layer extracted with ethyl acetate (3x300 mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated under vacuum to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 100/1 to 5/1) to give tert- Butyl 4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl] piperazine- 1 -carboxylate (14 g, 22.5 mmol). ES+APCI MS m/z 553.4 [M+H]+.
14 g
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 110℃; for 3h;Inert atmosphere;
A mixture of <strong>[4441-30-9]3-morpholinopropan-1-ol</strong> (11.8 g, 81.1 mmol), tert-butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazin- e-1-carboxylate (18 g, 40.5 mmol), BINAP (5.05 g, 8.11 mmol), t-BuONa (9.74 g, 101 mmol) and Pd 2(dba) 3 (3.71 g, 4.05 mmol) in toluene (300 mL) was degassed and purged with N 2 3 times, and the mixture stirred at 110° C. for 3 hours under N 2 atmosphere. The reaction mixture was poured into H 2O (200 mL) and the aqueous layer extracted with ethyl acetate (3 300 mL). The combined organics were washed with brine (200 mL), dried over anhydrous Na 2SO 4 and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=100/1 to 5/1) to give tert-Butyl 4-[7-benzyl-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- -4-yl] piperazine-1-carboxylate (14 g, 22.5 mmol). ES+APCI MS m/z 553.4 [M+H] +.
4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-(methylsulfonyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester[ No CAS ]
tert-butyl 4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.8%
To a mixture of 3-morpholinopropan-l-ol (5.46 g, 37.6 mmol, 2.00 eq) in THF (100 mL) was added NaH (2.26 g, 56.4 mmol, 60.0 % purity, 3.00 eq) in portions at 0 C. After the mixture was stirred at 0 C for 0.5 hour, a solution of tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (10.0 g, 18.8 mmol, 1.00 eq) in THF (100 mL) was added, and the reaction mixture was stirred at 0 C for 1.5 hours under N2. The mixture was poured into H4CI aqueous (300 mL), and extracted with DCM (2 x 200 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=50: l to 10: 1) to give tert-butyl 4- (4-benzyloxycarbonylpiperazin-l-yl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-7-carboxylate (7.70 g, 12.8 mmol, 67.8 % yield, 98.8 % purity) as a yellow oil. ESI MS m/z 597.4 [M+H]+ .
67.8%
To a mixture of <strong>[4441-30-9]3-morpholinopropan-1-ol</strong> (5.46 g, 37.6 mmol, 2.00 eq) in THF (100 mL) was added NaH (2.26 g, 56.4 mmol, 60.0% purity, 3.00 eq) in portions at 0° C. After the mixture was stirred at 0° C. for 0.5 hour, a solution of tert-butyl 4-(4-benzyloxycarbonylpiperazin-1-yl)-2-methylsulfonyl-6,8-dihydro-5H-pyr- ido[3,4-d]pyrimidine-7-carboxylate (10.0 g, 18.8 mmol, 1.00 eq) in THF (100 mL) was added, and the reaction mixture was stirred at 0° C. for 1.5 hours under N 2. The mixture was poured into NH 4Cl aqueous (300 mL), and extracted with DCM (2 200 mL). The combined organic layers were dried over Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=50:1 to 10:1) to give tert-butyl 4-(4-benzyloxycarbonylpiperazin-1-yl)-2-(3-morpholinopropoxy)-6,8-dihydro- -5H-pyrido[3,4-d]pyrimidine-7-carboxylate (7.70 g, 12.8 mmol, 67.8% yield, 98.8% purity) as a yellow oil. ESI MS m/z 597.4 [M+H] +.
benzyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
benzyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-(3-morpholinopropoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With caesium carbonate; In 1,4-dioxane; at 110 - 120℃;
Benzyl 4-((3 S.5R)-4-(tert-butoxycarbonylV3.5-dimethylpiperazin-l-vn-2-(3- mophiholinopropoxy -5,8-dihvdropyrido[3,4-d1pyrimidine-7(6H -carboxylate: A mixture of benzyl 4-((3 S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-l-yl)-2-chloro-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (400 mg, 0.775 mmol), 3- morpholinopropan-l-ol (400 mg, 2.33 mmol, 5 eq.), cesium carbonate (1.26 g, 3.88 mmol, 5 eq.) and dioxane (3 mL) in a 4-mL vial was purged with nitrogen. The vial was capped and the mixture stirred at 1 10C for 20h, then at 120C overnight. The reaction was cooled, diluted with EtOAc (10 mL), filtered through Celite and evaporated in vacuo. The product was purified by chromatography on silica, Redisep 40g, using 2 to 10% MeOH/DCM +0.2% H4OH as eluent to give a light-yellow amorphous solid (272 mg, 56%).
56%
With caesium carbonate; In 1,4-dioxane; at 110 - 120℃;Inert atmosphere;
A mixture of benzyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-2-chloro-5- ,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (400 mg, 0.775 mmol), <strong>[4441-30-9]3-morpholinopropan-1-ol</strong> (400 mg, 2.33 mmol, 5 eq.), cesium carbonate (1.26 g, 3.88 mmol, 5 eq.) and dioxane (3 mL) in a 4-mL vial was purged with nitrogen. The vial was capped and the mixture stirred at 110° C. for 20 h, then at 120° C. overnight. The reaction was cooled, diluted with EtOAc (10 mL), filtered through Celite and evaporated in vacuo. The product was purified by chromatography on silica, Redisep 40 g, using 2 to 10% MeOH/DCM+0.2% NH 4OH as eluent to give a light-yellow amorphous solid (272 mg, 56%).
With sodium hydride; In tetrahydrofuran; at 20.0℃; for 5.0h;Reflux;
A 500 ml reaction flask was added with 23.2 g (0.1 mol) of the above intermediate.3-morpholine-1-propanol 17.42g (0.12 mol) and 115 g of tetrahydrofuran, with stirring turned on, slowly add 60% sodium hydride 4.8g (0.12 mol), temperature below 20C, about 1~2 min after addition,The reaction was heated to reflux and monitored by TLC. After about 5 hours, the reaction was completed. The solution was concentrated under reduced pressure. 60 ml of water was added and the pH was adjusted to 1 to 2 with concentrated hydrochloric acid.Ethyl acetate (100 ml) was washed twice. The aqueous layer was adjusted to pH 11-12 with 40% sodium hydroxide, and the mixture was extracted twice with 120 ml of ethyl acetate.Combine the organic layers, dry an appropriate amount of anhydrous sodium sulfate, decolorize with 2g of charcoal, concentrate at 40C without concentration, and dissolve with 80ml of methanol.Concentrated hydrochloric acid to adjust the pH 1~2, vacuum concentration to no more, add acetone 40ml dissolved, stirring crystallization, continue to cool to -10 C, stirring crystallization about 6 ~ 8 hours;The mixture was filtered with suction, washed with cold acetone, and dried at 45-50 C. for 6-8 hours to obtain 27.25 g of a white crystalline solid with a yield of 82.61%, a purity of 99.926%, and a maximum single impurity of 0.046%.
4‐(3‐(morpholin-4-yl)propoxy)-3-nitrobenzoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Will be 10g (47mmol)Ethyl 4-fluoro-3-nitrobenzoate, potassium carbonate 20g (141mmol),Placed in 300ml DMF,34 g of 3-(morpholin-4-yl)-n-propanol (235 mmol) were added with stirring.Stir at room temperature overnight. Pour into 500ml of ice water,It was extracted with 500 ml of ethyl acetate, washed with water three times, and the organic layer was collected.Dry over anhydrous sodium sulfate, spin off the solvent,Column chromatography gave the product as a light yellow solid which was used directly for next step.
(3-morpholino)propyl 6-hydroxy-2,2-dimethyl-2H-benzo[h]chromen-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With toluene-4-sulfonic acid at 160℃; for 3h; Microwave irradiation; Inert atmosphere;
3.2. General Method A (6a-o)
General procedure: The mixture of mollugin (0.35 mmol), alcohol (3.52 mmol), and catalytic p-TsOH (0.035 mmol) in2 mL microwave vial was placed in the cavity of microwave reactor, and then stirred for 3 h at 160 °C.The produced brown mixture was dried under vacuum and subjected to purification (20 g silica gelcartridge, dichloromethane-MeOH) to give the title product.
3-morpholinopropyl-5-(4-fluorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.8%
General procedure: To a solution of 4a-4k (1 mmol) in CH2Cl2 (20 mL), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride(EDCHCl) (1.2 mmol), 1-Hydroxybenzotriazole (HOBt) (1.2 mmol)and 4-(dimethylamino)pyridine (DMAP) (0.5 mmol) were added insequence at 0 C. After half an hour of activation, morpholine andsubstituted morpholine (1.2 mmol) was added and stirred overnightat room temperature. The reaction mixture was washed withthe hydrochloric acid solution (1 mol/L, 10 mL), saturated Na2CO3solution (10 ml), distilled water (10 mL) three times. The combinedorganic extracts were dried with Na2SO4, The crude product waspurified by column chromatography (VAcOEt/VPE =1/1) to givecompounds A1-A41.4.5.1. 4- (5-(3-Fluorophenyl)-3-(thiomorpholine-4-carbonyl)-1Hpyrazol-1-yl)benzenesulfonamide(A1)White solid, yield 64.1%, m.p. 207.6-208.1 C,
39.8%
General procedure: Under stirring,Intermediates obtained in step 35-(3-chlorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylic acid(0.5 mmol), EDC.HCl (0.12 g, 0.6 mmol), HOBT (0.08 g, 0.6 mmol),DMAP (0.03 g, 0.25 mmol) was dissolved in anhydrous dichloromethane (10 mL).The reaction was stirred at 0 C for 1 h, and TCL followed the reaction.After the activation was completed, a morpholine derivative (1.2 mmol) was added.The reaction solution was stirred at room temperature overnight, and the reaction was carried out by TCL, and the solvent was evaporated (VPE:VAcOEt = 1:2). After the reaction was completed, anhydrous dichloromethane (15 mL) was added to the reaction mixture, and the organic layer was successively used 1 mol/L. hydrochloric acid,Washed with saturated sodium bicarbonate solution and distilled water three times.The organic phases were combined and the organic layer dried over anhydrous sodiumSilica gel column chromatography (eluent VPE:VAcOEt = 1:2),The target compound (E1) was obtained as a pale yellow solid in a yield of 87.2%.
3-morpholinopropyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.9%
General procedure: To a solution of 4a-4k (1 mmol) in CH2Cl2 (20 mL), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride(EDCHCl) (1.2 mmol), 1-Hydroxybenzotriazole (HOBt) (1.2 mmol)and 4-(dimethylamino)pyridine (DMAP) (0.5 mmol) were added insequence at 0 C. After half an hour of activation, morpholine andsubstituted morpholine (1.2 mmol) was added and stirred overnightat room temperature. The reaction mixture was washed withthe hydrochloric acid solution (1 mol/L, 10 mL), saturated Na2CO3solution (10 ml), distilled water (10 mL) three times. The combinedorganic extracts were dried with Na2SO4, The crude product waspurified by column chromatography (VAcOEt/VPE =1/1) to givecompounds A1-A41.4.5.1. 4- (5-(3-Fluorophenyl)-3-(thiomorpholine-4-carbonyl)-1Hpyrazol-1-yl)benzenesulfonamide(A1)White solid, yield 64.1%, m.p. 207.6-208.1 C,
58.9%
General procedure: Under stirring,Intermediates obtained in step 35-(3-chlorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylic acid(0.5 mmol), EDC.HCl (0.12 g, 0.6 mmol), HOBT (0.08 g, 0.6 mmol),DMAP (0.03 g, 0.25 mmol) was dissolved in anhydrous dichloromethane (10 mL).The reaction was stirred at 0 C for 1 h, and TCL followed the reaction.After the activation was completed, a morpholine derivative (1.2 mmol) was added.The reaction solution was stirred at room temperature overnight, and the reaction was carried out by TCL, and the solvent was evaporated (VPE:VAcOEt = 1:2). After the reaction was completed, anhydrous dichloromethane (15 mL) was added to the reaction mixture, and the organic layer was successively used 1 mol/L. hydrochloric acid,Washed with saturated sodium bicarbonate solution and distilled water three times.The organic phases were combined and the organic layer dried over anhydrous sodiumSilica gel column chromatography (eluent VPE:VAcOEt = 1:2),The target compound (E1) was obtained as a pale yellow solid in a yield of 87.2%.
3-morpholinopropyl-1-(4-sulfamoylphenyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.2%
General procedure: To a solution of 4a-4k (1 mmol) in CH2Cl2 (20 mL), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride(EDCHCl) (1.2 mmol), 1-Hydroxybenzotriazole (HOBt) (1.2 mmol)and 4-(dimethylamino)pyridine (DMAP) (0.5 mmol) were added insequence at 0 C. After half an hour of activation, morpholine andsubstituted morpholine (1.2 mmol) was added and stirred overnightat room temperature. The reaction mixture was washed withthe hydrochloric acid solution (1 mol/L, 10 mL), saturated Na2CO3solution (10 ml), distilled water (10 mL) three times. The combinedorganic extracts were dried with Na2SO4, The crude product waspurified by column chromatography (VAcOEt/VPE =1/1) to givecompounds A1-A41.4.5.1. 4- (5-(3-Fluorophenyl)-3-(thiomorpholine-4-carbonyl)-1Hpyrazol-1-yl)benzenesulfonamide(A1)White solid, yield 64.1%, m.p. 207.6-208.1 C,
54.2%
General procedure: Under stirring,Intermediates obtained in step 35-(3-chlorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylic acid(0.5 mmol), EDC.HCl (0.12 g, 0.6 mmol), HOBT (0.08 g, 0.6 mmol),DMAP (0.03 g, 0.25 mmol) was dissolved in anhydrous dichloromethane (10 mL).The reaction was stirred at 0 C for 1 h, and TCL followed the reaction.After the activation was completed, a morpholine derivative (1.2 mmol) was added.The reaction solution was stirred at room temperature overnight, and the reaction was carried out by TCL, and the solvent was evaporated (VPE:VAcOEt = 1:2). After the reaction was completed, anhydrous dichloromethane (15 mL) was added to the reaction mixture, and the organic layer was successively used 1 mol/L. hydrochloric acid,Washed with saturated sodium bicarbonate solution and distilled water three times.The organic phases were combined and the organic layer dried over anhydrous sodiumSilica gel column chromatography (eluent VPE:VAcOEt = 1:2),The target compound (E1) was obtained as a pale yellow solid in a yield of 87.2%.
3-morpholinopropyl-5-(4-ethoxyphenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.3%
General procedure: To a solution of 4a-4k (1 mmol) in CH2Cl2 (20 mL), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride(EDCHCl) (1.2 mmol), 1-Hydroxybenzotriazole (HOBt) (1.2 mmol)and 4-(dimethylamino)pyridine (DMAP) (0.5 mmol) were added insequence at 0 C. After half an hour of activation, morpholine andsubstituted morpholine (1.2 mmol) was added and stirred overnightat room temperature. The reaction mixture was washed withthe hydrochloric acid solution (1 mol/L, 10 mL), saturated Na2CO3solution (10 ml), distilled water (10 mL) three times. The combinedorganic extracts were dried with Na2SO4, The crude product waspurified by column chromatography (VAcOEt/VPE =1/1) to givecompounds A1-A41.4.5.1. 4- (5-(3-Fluorophenyl)-3-(thiomorpholine-4-carbonyl)-1Hpyrazol-1-yl)benzenesulfonamide(A1)White solid, yield 64.1%, m.p. 207.6-208.1 C,
65.3%
General procedure: Under stirring,Intermediates obtained in step 35-(3-chlorophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazole-3-carboxylic acid(0.5 mmol), EDC.HCl (0.12 g, 0.6 mmol), HOBT (0.08 g, 0.6 mmol),DMAP (0.03 g, 0.25 mmol) was dissolved in anhydrous dichloromethane (10 mL).The reaction was stirred at 0 C for 1 h, and TCL followed the reaction.After the activation was completed, a morpholine derivative (1.2 mmol) was added.The reaction solution was stirred at room temperature overnight, and the reaction was carried out by TCL, and the solvent was evaporated (VPE:VAcOEt = 1:2). After the reaction was completed, anhydrous dichloromethane (15 mL) was added to the reaction mixture, and the organic layer was successively used 1 mol/L. hydrochloric acid,Washed with saturated sodium bicarbonate solution and distilled water three times.The organic phases were combined and the organic layer dried over anhydrous sodiumSilica gel column chromatography (eluent VPE:VAcOEt = 1:2),The target compound (E1) was obtained as a pale yellow solid in a yield of 87.2%.
4-bromo-2-(4-methylpiperazin-1-yl)sulfonylphenol[ No CAS ]
4-[3-[4-bromo-2-(4-methylpiperazin-1-yl)sulfonylphenoxy]propyl]morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 0.5h;
PPh3 (85 mg, 0.323 mmol) and DEAD (0.051 mL, 0.323 mmol) were added to a solution of 4-bromo-2-(4-methylpiperazin-1-yl)sulfonylphenol (90 mg, 0.269 mmol) and 4-(3-hydroxypropyl)morpholine (0.045 mL, 0.323 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min and evaporated. The crude product was purified by chromatography on silica eluting with 2-12% (2M NH3 in MeOH) in DCM affording a brown solid (121 mg, 97%). M/z 462/464 (M+H)+.
With potassium hydroxide In N,N-dimethyl-formamide at 35 - 45℃;
2 Example two:
At room temperature, 3-(morpholin-4-yl)-1-propanol (4.35g, 30mmol) and solvent N,N-dimethylformamide (DMF) 100mL were added to the reaction flask,Potassium hydroxide (1.68g, 30mmol) was added with stirring until all were dissolved. Warm to 35-45°C and add 7-chloro-N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (II) (3.52g, 10mmol) with stirring, continue The reaction was stirred for 4-5 hours, and the reaction was completed by TLC. Reduce the temperature to 10-15°C, add water and adjust the pH to neutral with dilute hydrochloric acid, a solid precipitates out, slowly stir and crystallize at 0-5°C for 2-3 hours, filter with suction and dry under reduced pressure to obtain N-(3-chloro-4- fluorophenyl)-7-(3-morpholine-4-propoxy)-6-nitroquinazolin-4-amine (III) 3.78 g, yield 82.0%
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