* 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.
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414
2
[ 39061-97-7 ]
[ 105-53-3 ]
[ 79965-62-1 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 10, p. 1149 - 1157[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 10, p. 1385 - 1393
3
[ 50332-66-6 ]
[ 39061-97-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With thionyl chloride In dichloromethane; N,N-dimethyl-formamideReflux; Cooling with ice
The Intermediate 3-nitro-4-hydroxyquinoline 70 (18.7 g, 98.4 mmol) was suspended in dichloromethane (150 mL). Thionyl chloride (17.2 mL, 236 mmol) and N,N-dimethylformamide (9.2 mL, 118 mmol) were added. The reaction mixture was then heated at reflux overnight. The reaction mixture was then poured in ice. The layers were separated and the organic layer was washed with NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue (20.52 g, yield 93percent) was used for the next step without any further purification. Methyl 4-((3-nitroquinolin-4-ylamino)methyl)benzoate:
93%
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide
4-chloro-3-nitroquinoline The Intermediate 3-nitro-4-hydroxyquinoline 15 (18.7 g, 98.4 mmol) was suspended in dichloromethane (150 mL). Thionyl chloride (17.2 mL, 236 mmol) and DMF (9.2 mL, 118 mmol) were added. The reaction mixture was then heated at reflux overnight. The reaction mixture was then poured in ice. The layers were separated and the organic layer was washed with NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue (20.52 g, yield 93percent) was used for the next step without any further purification.
81%
for 0.5 h; Heating / reflux
3-Nitro-4-chIoroquinoIine (compound 6); Compound 6 was prepared as described elsewhere [Van Galen, P. J. M. et. al. 1- H-imidazo[4,5-c]quinolin-4-amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202-1206]. In brief, 3-Nitro-4-hydroxyquinoline 5 (5.7 g, 30 mmol) was added to phosphorus oxychlσride (70.0 g, 41.2 ml, 450 mmol) with stirring. <n="22"/>The mixture was refluxed for 30 minutes. After cooling the solvent was poured over crushed ice while stirring. After 1 hour the solid that was formed was filtered off, washed with cold water and dissolved in ethyl acetate. The solution was extracted with ice-cold NaOH (1 M) till ρH= 8-9 and dried over MgSO4. The solvent was evaporated and the residue was dried. Yield: 5.05 g (81percent). Mp.: 118M19 αC. 1H NMR (DMSO- d6): δ 7.94-8.11 (m, 2H, Ar); 8.25 (d, IH5 J= 8.0 Hz5 Ar); 8.47 (d, IH, J= 9.5 Hz, Ar); 9.42 (s, IH, Ar).
2.3 g
With trichlorophosphate In N,N-dimethyl-formamide at 100℃; for 0.25 h;
Phosphorus oxychloride (2.5 mL, 27 mmol) was added dropwise to a mixture of 3-nitroquinolin-4-ol (4.6 g, 24 mmol) and 100 mL of DMF. The mixture was heated at 100 °C for 15 min, and then poured onto stirred ice. The slurry was neutralized with solid NaHC03, and the precipitate was filtered and washed with saturated NaHC03 and H20. The filtrate was taken up in DCM, dried over anhydrous Na2S04, and concentrated to give 2.3 g of solid.
Reference：
[1] Patent: EP2674170, 2013, A1, . Location in patent: Paragraph 0228
[2] Patent: US2014/141033, 2014, A1, . Location in patent: Page/Page column
[3] Journal of Medicinal Chemistry, 1991, vol. 34, # 3, p. 1202 - 1206
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3354 - 3361
[5] Patent: WO2007/89507, 2007, A1, . Location in patent: Page/Page column 20-21
[6] RSC Advances, 2016, vol. 6, # 81, p. 77717 - 77734
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2211 - 2214
[8] Journal of the Chemical Society, 1948, p. 1284,1290
[9] Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414
[10] Yakugaku Zasshi, 1952, vol. 72, p. 767,770[11] Chem.Abstr., 1954, p. 2711
[12] Journal of the American Chemical Society, 1947, vol. 69, p. 365,370
[13] Yakugaku Zasshi, 1952, vol. 72, p. 1109[14] Chem.Abstr., 1953, p. 6946
[15] Pharmaceutical Bulletin, 1957, vol. 5, p. 56,60
[16] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[17] Journal of Medicinal Chemistry, 2005, vol. 48, # 10, p. 3481 - 3491
[18] Patent: WO2003/97641, 2003, A2, . Location in patent: Page/Page column 51
[19] Patent: WO2005/18551, 2005, A2, . Location in patent: Page/Page column 206-207
[20] Patent: US6348462, 2002, B1, . Location in patent: Page column 21
[21] Patent: US6348462, 2002, B1, . Location in patent: Page column 34
[22] Patent: US2011/136801, 2011, A1, . Location in patent: Page/Page column 21
[23] Patent: WO2014/120995, 2014, A2, . Location in patent: Page/Page column 173
[24] Patent: JP5837549, 2015, B2, . Location in patent: Paragraph 0101
[25] Patent: WO2017/184735, 2017, A1, . Location in patent: Page/Page column 63; 64
[26] Patent: CN108003153, 2018, A, . Location in patent: Paragraph 0064; 0070
[27] Patent: WO2005/18551, 2005, A2, . Location in patent: Page/Page column 206-207
4
[ 611-36-9 ]
[ 39061-97-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 10, p. 3481 - 3491
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414
[3] Patent: US2011/136801, 2011, A1,
[4] Patent: EP2674170, 2013, A1,
[5] Patent: WO2014/120995, 2014, A2,
[6] Patent: JP5837549, 2015, B2,
[7] Patent: WO2017/184735, 2017, A1,
[8] Patent: CN108003153, 2018, A,
5
[ 121845-92-9 ]
[ 39061-97-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3354 - 3361
[2] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[3] Journal of the American Chemical Society, 1947, vol. 69, p. 365,370
6
[ 118-92-3 ]
[ 39061-97-7 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 365,370
7
[ 125836-07-9 ]
[ 39061-97-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2844 - 2851
8
[ 2099-63-0 ]
[ 39061-97-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3354 - 3361
9
[ 56-57-5 ]
[ 39061-97-7 ]
Reference：
[1] Pharmaceutical Bulletin, 1957, vol. 5, p. 56,60
10
[ 39061-97-7 ]
[ 99010-24-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 10, p. 3481 - 3491
[2] Patent: WO2014/120995, 2014, A2,
11
[ 39061-97-7 ]
[ 99010-64-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 10, p. 3481 - 3491
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide;Reflux; Cooling with ice;
The Intermediate <strong>[50332-66-6]3-nitro-4-hydroxyquinoline</strong> 70 (18.7 g, 98.4 mmol) was suspended in dichloromethane (150 mL). Thionyl chloride (17.2 mL, 236 mmol) and N,N-dimethylformamide (9.2 mL, 118 mmol) were added. The reaction mixture was then heated at reflux overnight. The reaction mixture was then poured in ice. The layers were separated and the organic layer was washed with NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue (20.52 g, yield 93%) was used for the next step without any further purification. Methyl 4-((3-nitroquinolin-4-ylamino)methyl)benzoate:
93%
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide;
4-chloro-3-nitroquinoline The Intermediate <strong>[50332-66-6]3-nitro-4-hydroxyquinoline</strong> 15 (18.7 g, 98.4 mmol) was suspended in dichloromethane (150 mL). Thionyl chloride (17.2 mL, 236 mmol) and DMF (9.2 mL, 118 mmol) were added. The reaction mixture was then heated at reflux overnight. The reaction mixture was then poured in ice. The layers were separated and the organic layer was washed with NaHCO3 solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue (20.52 g, yield 93%) was used for the next step without any further purification.
81%
With trichlorophosphate; for 0.5h;Heating / reflux;
3-Nitro-4-chIoroquinoIine (compound 6); Compound 6 was prepared as described elsewhere [Van Galen, P. J. M. et. al. 1- H-imidazo[4,5-c]quinolin-4-amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202-1206]. In brief, 3-Nitro-4-hydroxyquinoline 5 (5.7 g, 30 mmol) was added to phosphorus oxychl?ride (70.0 g, 41.2 ml, 450 mmol) with stirring. <n="22"/>The mixture was refluxed for 30 minutes. After cooling the solvent was poured over crushed ice while stirring. After 1 hour the solid that was formed was filtered off, washed with cold water and dissolved in ethyl acetate. The solution was extracted with ice-cold NaOH (1 M) till rhoH= 8-9 and dried over MgSO4. The solvent was evaporated and the residue was dried. Yield: 5.05 g (81%). Mp.: 118M19 alphaC. 1H NMR (DMSO- d6): delta 7.94-8.11 (m, 2H, Ar); 8.25 (d, IH5 J= 8.0 Hz5 Ar); 8.47 (d, IH, J= 9.5 Hz, Ar); 9.42 (s, IH, Ar).
79%
With trichlorophosphate; at 90℃;
(0673) <strong>[50332-66-6]3-nitro-4-quinolinol</strong> (95 mg, 0.50 mmol) was stirred in POCl3 (5 mL) at 90 C overnight. The reaction was then quenched with saturated sodium carbonate solution and extracted with ethyl acetate (50 mLx3). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: dichloromethane/ethyl acetate, 10-100%) to give the title compound as a white solid (82 mg, (0674) 79%). 1H NMR (400 MHz, chloroform-d) delta 9.28 (s, 1H), 8.45 (ddd, J = 8.5, 1.4, 0.6 Hz, 1H), 8.23 (ddd, J = 8.5, 1.3, 0.7 Hz, 1H), 7.97 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.87 - 7.80 (m, 1H).
50%
With trichlorophosphate; at 60 - 120℃; for 3h;
POCl3 (661 mL, 7.21 mol, 18.3 eq) was heated at 60C and 3-nitroquinolin-4- ol (75 g, 0.39 mol) was added in portions. The resulting suspension was then stirred at 120C for 3 h, then cooled down to room temperature and the solvent was removed under reduced pressure. The crude residue was poured on a mixture of ice (1 kg) and CH2C12 (500 mL). The aqueous layer was discarded and a solid crystallized from the organic phase during the evaporation. The resulting solid was filtered off and washed with CH2C12 to give 40.4 g (50%) of the desired substance as a light beige solid. No further purification. (0125) MS (ESI+) m/z 209.0 211.0 [M+H]+
50%
With trichlorophosphate; at 60 - 120℃;
Step 2: POC (661 mL, 7.21 mol, 18.3 eq) was heated at 60 C and 3-nitroquinolin-4- ol (75 g, 0.39 mol) was added in portions. The resulting suspension was then stirred at 120C for 3 h, then cooled down to room temperature and the solvent was removed under reduced pressure. The crude residue was poured on a mixture of ice (1 kg) and CH2CI2 (500 mL). The aqueous layer was discarded and a solid crystallized from the organic phase during the evaporation. The resulting solid was filtered off and washed with CH2CI2 to give 40.4 g (50%) of the desired substance as a light beige solid. No further purification. (0126) MS (ESI+) m/z 209.0 21 1.0 [M+H]+
With trichlorophosphate; at 130℃; for 2h;
5. 5g (29 mmol) <strong>[50332-66-6]3-nitro-quinolin-4-ol</strong> (Example 1a) in 25ml POCl3 are heated for 2 h to keep at 130 C. The mixture is cooled to rt and poured into ice-water. The precipitate is filtered off, washed with ice-cold water, and dissolved in CH2CI2. The organic phase is washed with cold 0. 1N NaOH (1x) and with cold water (2x). After drying over MgS04, the solvent is evaporated to dryness. The residue is stirred in hexane. The title compound is isolated as a powder and is dried at 60C under vacuum. mp: 121-122 C ; NMR (CDCI3) : 9.26/s (1 H), 8.44/d and 8.21/d (2H), 7.95/t and 7.82/t (2H); HPLC: tret=11. 64 min (Grad 1).
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 2h;Heating / reflux;
4-Hydroxy-3-nitroquinoline (19.0 g, 0.10 mol) was suspended in methylene chloride (250 mL). Thionyl chloride (8.0 mL, 0.11 mol) was combined with dimethylformamide (8.5 mL, 0.11 mol) and slowly added to the suspension. The resulting mixture was stirred and heated at reflux for about 2 hours.
With thionyl chloride; N,N-dimethyl-formamide;
Using the general method of Example 41, <strong>[50332-66-6]4-hydroxy-3-nitroquinoline</strong> (19 g, 0.10 mole) was chlorinated.
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 2.5h;Reflux;
To a stirred solution of <strong>[50332-66-6]3-nitroquinolin-4-ol</strong> (30 g) in DCM (250 mL) was added DMF (6 mL) and thionyl chloride (13.9 mL) and the reaction mixture was refluxed for 2.5 h when all solids dissolved. The solution was cooled to 0 C. and a solution of (3-aminopropyl)-carbamic acid tert-butyl ester (45.6 g) and Et3N (67 mL) in DCM (250 mL) was added dropwise. The reaction mixture was stirred overnight and then evaporated. Potassium carbonate solution and MTBE were added to the residue and stirred for 1 h. The product was filtered and washed with water and MTBE and dried to give the subtitle compound (50.7 g). Yield: 94%1H NMR delta (CDCl3) 9.66 (1H, s), 9.36 (1H, s), 8.31-8.29 (1H, m), 7.98-7.95 (1H, m), 7.77-7.72 (1H, m), 7.48-7.44 (1H, m), 4.67 (1H, s), 4.00-3.96 (2H, m), 3.34-3.29 (2H, m), 2.03-1.96 (2H, m), 1.41 (9H, s)MS: ESI 347 (M+1)
2.3 g
With trichlorophosphate; In N,N-dimethyl-formamide; at 100℃; for 0.25h;
Phosphorus oxychloride (2.5 mL, 27 mmol) was added dropwise to a mixture of <strong>[50332-66-6]3-nitroquinolin-4-ol</strong> (4.6 g, 24 mmol) and 100 mL of DMF. The mixture was heated at 100 C for 15 min, and then poured onto stirred ice. The slurry was neutralized with solid NaHC03, and the precipitate was filtered and washed with saturated NaHC03 and H20. The filtrate was taken up in DCM, dried over anhydrous Na2S04, and concentrated to give 2.3 g of solid.
With trichlorophosphate; In N,N-dimethyl-formamide; at 50℃; for 0.5h;
Phosphorus oxychloride (1.2 eq.) was added slowly to well stirred suspension of compound of formula 1 obtained in step I in N,N-dimethylformamide. The reaction mixture was further heated to 50 with stirring for 30 min. The resulting solution was cooled at ambient temperature and poured into an ice/water mixture. A solid was collected by filtration and dried to afford 4-chloro-3-nitro-quinoline.
With N,N-dimethyl-formamide; trichlorophosphate; In dichloromethane; at 45℃; for 4h;Inert atmosphere;
Into a 100-mL round-bottom flask, purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 3 -nitroquinolin-4-ol (1.9 g, 10.00 mmol,1.00 equiv), N,N-dimethylformamide (876 mg, 12.00 mmol, 1.20 equiv) and POC13(3.648 g, 23.79 mmol, 2.00 equiv) in dichloromethane (20 mL). The resulting solutionwas stirred for 4 h at 45C in an oil bath. The reaction was then quenched by the addition of ice/water. The resulting solution was extracted with dichloromethane (3x50 mL) and washed with aqueous NaHCO3 (1x50 mL), dried over Na2SO4 and concentrated under vacuum. This resulted in 2.295 g of crude 4-chloro-3-nitroquinoline as a yellow solid.LC-MS: (ES, m/z): [M+H] = 209.0
With oxalyl dichloride; In dichloromethane; at 40℃; for 0.5h;
The second step: Dissolve <strong>[50332-66-6]4-hydroxy-3-nitroquinoline</strong> (2 g, 10.53 mmol) of formula V-1 in dichloromethane. Oxalyl chloride (4.5 mL, 52.65 mmol) was then slowly added dropwise, and when the formation of bubbles was moderated, it was heated to 40C; After half an hour, the reaction solution was concentrated to give the white solid of 4-chloro-3-nitroquinoline of Formula IV-1.
With trichlorophosphate; In N,N-dimethyl-formamide; for 0.25h;Heating;
Part A Phosphorous oxychloride (84.3 g, 0.55 mol) was added to a stirred suspension of <strong>[50332-66-6]3-nitroquinolin-4-ol</strong> (95.0 g, 0.50 mol) in DMF (500 mL), and an exotherm was observed. After the addition was complete, the solution was heated on a steam bath for 15 minutes. The solution was poured over ice to precipitate 4- chloro-3-nitroquinoline. The 4-cliloro-3-nitroquinoline was isolated by filtration, washed with water, and pressed dry. The 4-chloro-3-nitroquinoline was dissolved in dichloromethane (1 L) and the solution was dried over magnesium sulfate and filtered. 2-(2-AMINOETHOXY) ETHANOL (60.7 g, 0.6 mol) and triethylamine (104 ML, 0.75 mol) were added to the filtrate. The resulting solution was heated at reflux for 30 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in dilute aqueous hydrochloric acid and filtered. Ammonium hydroxide was added to the filtrate and a yellow solid formed. The solid was isolated by filtration, washed with water, and dried to provide 104.5 g OF2- {2- [ (3- nitroquinolin-4-yl) amino] ethoxy} ethanol as a yellow solid.
With triethylamine In dichloromethane at 10 - 20℃; for 2h;
2 Example 2: Synthesis of 2-methyl-1-(3-nitroquinoline-4-monolamino)propane-2-ol
Using the method of Scheme 3 below, 2-methyl-1- (3-nitroquinoline-4-ylamino) propane-2-ol (compound 2) was synthesized. More specifically, 1-amino-2-methylpropane-2-ol (14 g) and tetraethylamine (9.6 g) were added to dichloromethane (450 ml) with the addition of compound 1 (30 g) at 10-20 ° C., and the mixture was prepared by stirring for 2 hours. And after evaporating the solvent in a vacuum to concentrate the mixture, it was authored using methyltert-butyl ether (150 ml). The authored mixture was separated using a filter and concentrated at low pressure to obtain compound 2 (32 g, 85.2%, yellow solid).
In dichloromethane Heating;
With triethylamine In hydrogenchloride; dichloromethane
1 EXAMPLE 1
EXAMPLE 1 Preparation of a Compound of Formula IV. To a stirred solution of 150 ml of dichloromethane, 10 ml of triethylamine and 6.7 g (0.075 mole) of 1-amino-2-methyl-2-propanol was added 10.4 g (0.05 mole) of 4-chloro-3-nitroquinoline. The solution was heated on a steam bath for about one hour then evaporated to remove the solvent. The residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was made basic with concentrated ammonium hydroxide to reprecipitate the product. The product was separated by filtration and recrystallized twice from ethanol to provide the novel yellow solid 2-methyl-1-[(3-nitro-4-quinolinyl)amino]-2-propanol, m.p. 244°-246° C. (dec.). Analysis: Calculated for C13 H15 N3 O3: %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N 16.1.
With triethylamine In hydrogenchloride; dichloromethane
1 Preparation of a Compound of Formula IV
EXAMPLE 1 Preparation of a Compound of Formula IV To a stirred solution of 150 mL of dichloromethane, 10 mL of triethylamine and 6.7 g (0.075 mole) of 1-amino-2-methyl-2-propanol was added 10.4 g (0.05 mole) of 4-chloro-3-nitroquinoline. The solution was heated on a steam bath for about one hour then evaporated to remove the solvent. The residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was made basic with concentrated ammonium hydroxide to reprecipitate the product. The product was separated by filtration and recrystallized twice from ethanol to provide the novel yellow solid 2-methyl-1-[(3-nitro-4-quinolinyl)amino]-2-propanol, m.p. 244°-246° C. (dec.). Analysis: Calculated for C13 H15 N3 O3: %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N 16.1.
189.A Step A
Step A Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxy-2-methylpropylamine to provide 4-(2-hydroxy-2-methylpropylamino)3-nitroquinoline, m.p. 234°-244° C. (dec.). Analysis: Calculated for C13 H15 N3 O3; % C, 59.8; % H, 5.8; % N, 16.0; Found: % C, 59.8 % H, 5.9; % N 16.1.
189.A Part A
Part A Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxy-2-methylpropylamine to provide 4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline, m.p. 234°-244° C.(dec.). Analysis: Calculated for C13 H15 N3 O3: %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N, 16.1.
1.01 g
With triethylamine In dichloromethane Reflux;
115 2-Methyl-1-(3-nitroquinolin-4-yl)propan-2-ol
A mixture of 4-chloro-3-nitroquinoline (2.3 g, 11 mmol), l-amino-2-methylpropan-2-ol (1.0 g, 11 mmol), TEA (9.3 mL), and 100 mL of DCM was heated at reflux until the starting material was consumed. The mixture was allowed to cool, washed with saturated NaHC03 and H20, dried over anhydrous Na2S04, and concentrated to give 1.01 g of product. 1H NMR (DMSO-d6) δ 9.9 (br s, 1H, NH), 9.2 (s, 1H), 8.5 (d, 1H), 7.9- 7.8 (m, 2H), 7.6 (m, 1H), 5.1 (s, 1H, OH), 3.8 (m, 2H, ABX), 1.2 (s, 6H).
With triethylamine In N,N-dimethyl-formamide at 20℃;
84.A
Triethylamine (50.0 mL, 360 mmol) was added to a suspension of 4-chloro-3- nitroquinoline (50.0 g, 240 mmol) in DMF (200 mL), followed by dropwise addition of a solution of1-amino-2-methyl-propan-2-ol (23.5 g, 264 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at room temperature, then water (500 mL) was added and stirring was continued for 30 minutes. A solid was isolated by filtration, washed with water, and dried to yield 60.9 gof 2-methyl-1- [ (3-nitroquinolin-4- yl) amino] propan-2-ol, which was used without further purification.
With triethylamine In N,N-dimethyl-formamide at 20℃;
100.A
Part A Triethylamine (50.0 mL, 360 mmol) was added to a suspension of 4-chloro-3- nitroquinoline (50.0 g, 240 mmol) in DMF (200 mL), followed by dropwise addition of a solution ofl-amino-2-methyl-propan-2-ol (23.5 g, 264 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at room temperature, then water (500 mL) was added and stirring was continued for 30 minutes. A solid was isolated by filtration, washed with water, and dried to yield 60.9 g of 2-methyl-1- [ (3-nitroquinolin-4- yl) amino] propan-2-ol, which was used without further purification.
With N-ethyl-N,N-diisopropylamine In isopropanol; toluene at 70℃; for 0.5h;
7.E.E-4 Step E-4.
To a solution of 25 (1.0 eq) and N,N-diisopropylethylamine (DIPEA) (2.5 eq) in toluene and isopropanol (iPrOH) (4: 1) is added 9 (2.0 eq) and the mixture heated to 70°C for 0.5 h at which time a precipitate forms. The reaction is cooled and the solid collected by filtration, which is then washed sequentially with toluenedPrOH (7:3), diethyl ether and cold H2O. The residue is dried at 80°C to obtain 32 of sufficient purity to be used in the next reaction.
With N-ethyl-N,N-diisopropylamine In isopropanol; toluene at 70℃; for 0.5h;
1.E-4 Step E-4.
To a solution of 25 (1.0 eq) and N,N-diisopropylethylamine (DIPEA) (2.5 eq) in toluene and isopropanol (iPrOH) (4:1) is added 9 (2.0 eq) and the mixture heated to 70°C for 0.5 h at which time a precipitate forms. The reaction is cooled and the solid collected by filtration, which is then washed sequentially with toluene :iPrOIT (7:3), diethyl ether and cold EhO. The residue is dried at 80°C to obtain 32 of sufficient purity to be used in the next reaction.
Part E A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2*300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.
With triethylamine; In dichloromethane;
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.
7.C
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
With triethylamine In dichloromethane
7.C Part C
Part C A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2*300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
With triethylamine In dichloromethane
3.C Part C
Part C A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2*300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
With triethylamine In dichloromethane
3.C
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tert-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tert-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate as a yellow solid.
With triethylamine; In 1,4-dioxane; DMF (N,N-dimethyl-formamide); at 20℃;
Part B Under a nitrogen atmosphere, triethylamine (72 g, 710 mmol) was added to a solution of 4-chloro-3-nitroquinoline (98.9 g, 474 mmol) in N, N-dimethylformamide (DMF) (1 L). A solution oftert-butyl 3-amino-2-hydroxypropylcarbamate (108. 19 g, 569 mmol) in dioxane (800 mL) was slowly added, and the reaction was stirred overnight at ambient temperature and then poured into water (3 L) with continuous stirring. A precipitate formed and was isolated by filtration, washed with water, and dried for three days in a vacuum oven at 65 C to provide 167.54 g of tert-butyl 2-liydroxy-3- [ (3- nitroquinolin-4-yl) amino] propylcarbamate as a bright yellow powder.
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
PartB; A solution of 4-chloro-3-nitroquinoline (45.7 g, 0.219 mol), tert-buiyl 3-amino-2-hydroxypropylcarbamate (50 g, 0.26 mol), and triethylamine (46 mL, 0.33 mol) in DMF(800 mL) was stirred for 2 hours at room temperature. Some of the DMF was removed byevaporation under reduced pressure. The reaction mixture was poured onto water (3 L)and the mixture was stirred for 10 minutes. A bright yellow solid was collected byfiltration, washed with water (800 mL x 3), and dried under vacuum to provide tert-butyl2-hydroxy-3-[(3-nitroquinolin-4-yl)amino]propylcarbamate(76.4g).
With triethylamine In DMF (N,N-dimethyl-formamide) for 1h;
2.C
Part C; 4-Chloro-3-nitroquinoline (2. 34 g, 11.2 mmol, 1.0 eq. ) was added in a single portion to a stirred solution of the material from Part B (12.3 mmol, 1.10 eq. ) in DMF (45 mL). Triethylamine (3.3 mL, 2.1 eq. ) was added dropwise. After 1 hour analysis by TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between chloroform (200 mL) and water (50 mL). The aqueous layer was back extracted with chloroform (75 mL). The combined organics were dried over magnesium sulfate and then concentrated under reduced pressure to provide 2.72 g of N, N-dimethyl 3-[(3-nikoquinolin-4-yl) amino] propane-1-sulfonamide as a red solid.
With triethylamine; In N,N-dimethyl-formamide; at 20℃;
Example 24; 12-Methyl-9-(methylsulfonyl)-9, 10,11,12-tetrahydro-8No.- [l,4]diazepino[r,2':l,2]imidazo[4,5-c]quinolin-6-amine formic acid salt; Part A; Triethylamine (12.8 mL, 91.8 mmol) was added to a solution of 4-chloro-3- nitroquinoline (8.0 g, 38 mmol) in DMF (100 mL). The resulting solution was stirred for five minutes at room temperature, and then <strong>[5303-65-1]ethyl 3-aminobutyrate</strong> (6.2 mL, 42 mmol) was added. The reaction was stirred overnight at room temperature and poured into deionized water (320 mL). The mixture was extracted with ethyl acetate (1 x 125 mL and 2 x 100 mL). The combined extracts were washed with brine (3 x 120 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide 11.5 g of ethyl 3-[(3- nitroquinolin-4-yl)amino]butanoate as a yellow solid.
ethyl 2-[4-(3-nitroquinolin-4-yloxy)phenoxy]propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 11 Ethyl 2-[4-(3-nitroquinolin-4-yloxy)phenoxy]propionate (41) was prepared from 4-chloro-3-nitroquinoline and <strong>[65343-67-1]ethyl 2-(4-hydroxyphenoxy)propionate</strong> following essentially the same procedure as that described in Example 1. The compound was isolated as a yellow oil. Proton magnetic resonance spectrum (CDCl3; delta in ppm): 9.3 (1H, s); 8.3-7.4 (4H, m, quinoline protons); 6.8 (4H, s, phenoxy protons); 4.7 (1H, q, CH--CH3); 4.2 (2H, q, OCH2 --CH3); 1.6 (3H, d, CH--CH3); 1.2 (3H, t, OCH2 --CH3).
With triethylamine; In dichloromethane; for 2h;Heating / reflux;
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidme-l -carboxylate (78.4 mmol, prepared as described above) in dichloromethane (300 mL) was added triethylamine (11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). The mixture was stirred at rt for 1 h, then heated at reflux for 1 h. The solution was transferred to a separatory funnel and extracted with water (100 mL). The organic layer was isolated and upon standing a precipitate formed. The solid was isolated by filtration and washed with dichloromethane and water and dried. Additional solid precipitated from the mother liquor and was isolated. The two yellow solids were combined and dried to yield tert- butyl 4-hydroxy-4-[(3-nitroqumolin-4-yl)amino]methyl}piperidine4 ^ (20.23 g, 82%).
3.C
To a solution of l-(aminomethyl)cyclopentanol (approximately 55.2 mmol, prepared as described above) in dichloromethane (280 mL) was added triethylamine (7.76 mL, 55.7 mmol) and 4-cliloro-3-nitroquinoline (9.22 g, 44.3 mmol). The mixture was allowed to stand at rt over the weekend. A solid formed that was isolated by filtration. Two more crops of solid were isolated from the mother liquor. The yellow solid was stirred in water and filtered. The solid was washed with water multiple times and was dried under vacuum with heat to give l-[(3-nitroquinolin-4- yl)amino]methyl}cyclopentanol as yellow crystals (8.29 g, 52%).
With triethylamine In dichloromethane at 20℃;
23.C
Part C To a solution of 1-(aminomethyl)cyclopentanol (approximately 55.2 mmol, prepared as described above) in dichloromethane (280 mL) was added triethylamine (7.76 mL, 55.7 mmol) and 4-chloro-3-nitroquinoline (9.22 g, 44.3 mmol). The mixture was allowed to stand at room temperature over the weekend. A solid formed that was isolated by filtration. Two more crops of solid were isolated from the mother liquor. The yellow solid was stirred in water and filtered. The solid was washed with water multiple times and was dried under vacuum with heat to give 8.29 g of 1-[(3-nitroquinolin-4-yl)amino]methyl}cyclopentanol as yellow crystals.
With triethylamine; In dichloromethane; at 0 - 20℃;
Under a nitrogen atmosphere, triethylamine (2.51 mL, 18.0 mmol) was added to a suspension of 4-chloro-3-nitroquinoline (1.87 g, 8.99 mmol) in dichloromethane (30 mL). The resulting solution was chilled in an ice bath and then (S)-(+)-tetxahydrofurfurylamine (1.02 mL, 9.89 mmol) was added. The reaction was allowed to slowly warm to ambient temperature overnight. The reaction mixture was partitioned between chloroform (30 mL) and water (20 mL). The organic layer was washed sequentially with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 2.36 g of 3-nitro-iV-[(25}-tetrahydrofuran-2-ylmethyl]quinolin-4-amine as a yellow/orange solid.
92.C
Triethylamine (41 mL, 294 mmol) was added to a suspension of 4-chloro-3- nitroquinoline (24.5 g, 118 mmol) in dichloromethane (250 mL). The mixture was cooled to 5 °C. A solution of the material from Part B in dichloromethane (200 mL) was added over a period of 15 minutes. The reaction mixture was stirred at 5 °C for 1 hour and then at ambient temperature overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate (250 mL). The aqueous layer was back extracted with dichloromethane (2 x 50 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide an orange oil. This material was recrystallized from acetonitrile to provide 21.47 g of ethyl l-[(3- nitroquinolin-4-ylamino)methyl]cyclopropionate as a bright yellow solid.
With triethylamine In dichloromethane at 5 - 20℃; for 1.25h;
64.C
A suspension of 4-chloro-3-nitroquinoline (24.5 g, 118 mmol) and triethylamine (41 mL, 294 mmol) in dichloromethane (450 mL) was cooled to 5° C., and a solution of the material from Part B in dichloromethane (200 mL) was added over a period of 15 minutes. The reaction was stirred at 5° C. for one hour, allowed to warm to ambient temperature, stirred overnight, and washed with saturated aqueous sodium bicarbonate (250 mL). The aqueous layer was extracted with dichloromethane (2*50 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting orange oil was recrystallized from acetonitrile to provide 21.47 g of ethyl 1-[(3-nitroquinolin-4-yl)amino]methyl}cyclopropanecarboxylate as a bright yellow solid.
3-{2-[(3-nitroquinolinyl)amino]ethoxy}propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane for 1h;
13.E
Part E Triethylamine (188 mL, 1.37 mole) was added to a slurry of the material from Part D in dichloromethane (1.3 L). Under a nitrogen atmosphere 4-chloro-3-nitroquinoline (81.6 g, 391 mmol) was added to the reaction mixture. After 1 hour analysis by high performance liquid chromatography (HPLC) indicated that the starting quinoline had been consumed. The reaction mixture was washed sequentially with aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a sticky yellow solid. This material was purified by column chromatography (1.5 Kg of silica gel eluding with 98/2 dichloromethane/methanol) to provide 98.1 g of 3-{2-[(3-nitroquinolinyl)amino]ethoxy}propan-1-ol as a yellow solid.
With triethylamine; In dichloromethane; at 20℃; for 240h;
To a solution of l-(aminomethyl)cyclobutanol (62.5 mmol) in dichloromethane (312 mL) was added triethylamine (8.71 mL, 62.5 mmol) and 4-chloro-3-nitroquinoline (13.04 g, 62.5 mmol). More triethylamine (3 mL) was added almost immediately. The reaction was stirred under N2 for 10 d at rt, then was diluted with dichloromethane and washed with 1 M aqueous NaOH. A solid formed and was isolated by filtration. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to a solid that was crystallized from isopropanol. The resulting crystals were combined with the solid that was isolated from the extraction and the mixture was triturated with hot isopropanol. The solid was isolated by filtration, washed with diethyl ether, and air dried to yield l-[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as yellow crystals. (12.83 g, 75%).
With triethylamine; In dichloromethane; at 0 - 20℃;
A solution of 4-chloro-3-nitroquinoline (30.0 g, 144 mmol) in dichloromethane (350 mL) was cooled to 0 C under a nitrogen atmosphere, and triethylamine (22.1 mL, 158 mmol) was added. A solution of <strong>[180205-28-1]1-(aminomethyl)cyclobutanol</strong> (16.0 g, 158 mmol) in dichloromethane (130 mL) was then added over a period of one hour, followed by a rinse of dichloromethane (100 mL). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was triturated in water (500 mL) and saturated aqueous sodium bicarbonate (200 mL) for two hours. A solid was present and was isolated by filtration, washed with a large amount of water, and dried in a vacuum oven at 55 C to provide 38.7 g of 1-[(3-nitroquinolin-4- yl) amino]methyl}cyclobutanol as a yellow solid.
With triethylamine; In dichloromethane; at 20℃; for 240h;
Part C To a solution of <strong>[180205-28-1]1-(aminomethyl)cyclobutanol</strong> (62.5 mmol) in dichloromethane (312 mL) was added triethylamine (8.71 mL, 62.5 mmol) and 4-chloro-3-nitroquinoline (13.04 g, 62.5 mmol). More triethylamine (3 mL) was added almost immediately. The reaction was stirred under N2 for 10 days at room temperature, then was diluted with dichloromethane and washed with 1 M aqueous NaOH. A solid formed and was isolated by filtration. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a solid that was crystallized from 2-propanol. The resulting crystals were combined with the solid that was isolated from the extraction and the mixture was triturated with hot 2-propanol. The solid was isolated by filtration, washed with diethyl ether, and air dried to yield 12.83 g of 1-[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanol as yellow crystals.
ethyl 2,2-dimethyl-3-[(3-nitroquinolin-4-yl)amino]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-chloro-3-nitroquinoline; 3-amino-2,2-dimethylpropionic acid ethyl ester With triethylamine In dichloromethane at 0 - 20℃; for 4.5h;
Stage #2: 3-amino-2,2-dimethylpropionic acid ethyl ester In dichloromethane Heating / reflux;
Stage #3: With potassium carbonate In dichloromethane at 20℃; Heating / reflux;
26.C
A suspension of 4-chloro-3-nitroquinoline (35.0 g, 168 mmol) and triethylamine (84 mL, 0.60 mol) in dichloromethane (400 mL) was cooled to 0° C.; a solution of ethyl 3-amino-2,2-dimethylpropanoate (40.0 g, 0.220 mol) in dichloromethane (50 mL) was added dropwise. The reaction was stirred at 0° C. for 30 minutes and then at ambient temperature for four hours. The reaction was incomplete as determined by a TLC analysis, and additional ethyl 3-amino-2,2-dimethylpropionate (10.0 g, 55.0 mmol) was added. The reaction was stirred overnight; another analysis by TLC indicated the reaction was incomplete. Additional ethyl 3-amino-2,2-dimethylpropionate (5.0 g, 28 mmol) was added, and the reaction was heated at reflux for three hours. Potassium carbonate (10 g) was added, and the reaction was heated at reflux for two hours and stirred overnight at ambient temperature. Saturated aqueous sodium bicarbonate (50 mL) was added, and the reaction was stirred for three days. The organic layer was separated, washed with water (3*100 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide ethyl 2,2-dimethyl-3-[(3-nitroquinolin-4-yl)amino]propanoate as an orange oil, which was mixed with material from another run and used without purification.
With potassium carbonate; triethylamine; In chloroform; at 20℃; for 4h;
Potassium carbonate (66.23 g, 0.479 mol), triethylamine (167 mL, 1.20 mol), and <strong>[29840-57-1]ethyl 5-aminovalerate hydrochloride</strong> (104 g, 0.575 mol) were added to a mixture of 4-chloro-3-nitroquinoline (100 g, 0.470 mol) in chloroform (1 L). The reaction mixture was stirred at room temperature for 4 hours, then water (200 mL) was added. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 151 g of ethyl 5- [ (3-nitroquinolin- 4-yl) amino] pentanoate.
With N,N-diethyl-N-isopropylamine In isopropyl alcohol; toluene at 70℃; for 0.5h;
With triethylamine In isopropyl alcohol; toluene at 70℃; for 0.5h;
A.2 Step 2: Synthesis of 2-methyl-l-(3-nitroquinolin-4-ylamino)propan-2-ol (compound 2)
The trifluoroacetate salt of l-amino-2-methylpropan-2-ol (compound ) (450 mg, 2.4 mmol) was added to the solution of 4-chloro-3-nitroquinoline (compound 1) (250 mg, 1.2 mmol) and Et3N (0.5 ml, 3 mmol) in 4: 1 mixture of toluene and 2-propanol. The mixture was heated to 70 °C for half an hour until a solid started precipitating. The reaction mixture was then cooled, filtered, washed with toluene/2-propanol (7:3), ether and cold water. The residue was dried at 80 °C to obtain 2-methyl-l-(3-nitroquinolin-4-ylamino)propan-2-ol (compound 2). Liquid chromatography-mass spectrometry (LCMS) analysis: [M+H]+m/z = 261.
methyl 4-((3-nitroquinolin-4-ylamino)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With triethylamine; In dichloromethane; at 0 - 20℃;Reflux;
Methyl 4-((3-nitroquinolin-4-ylamino)methyl)benzoate: To a solution of intermediate 71 (5.94 g, 28.48 mmol) in dry DCM (50 mL) was added a solution of <strong>[18469-52-8]methyl 4-(aminomethyl)benzoate</strong> (5.05 g, 29.91 mmol), and triethylamine (19.9 mL, 142 mmol) in dichloromethane (50 mL) at 0C. During the addition the temperature of the reaction mixture rose to 20C. The resulting solution was heated at reflux overnight. Then the reaction mixture was cooled to RT and the solvent was removed at reduced pressure to afford a yellow solid product. The product was slurried in water, filtered, washed with water, and dried partially. The partially dried product was then slurried in ethanol (75 mL), filtered, washed successively with a small amount of ethanol and a small amount of diethyl ether, and dried at reduced pressure to afford the subject compound (8.31 g, yield 86%). Intermediate 72 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) delta (ppm) 9.51 (t, 1H), 9.01 (s, 1H), 8.47 (d, 1H), 7.92 (m, 3H), 7.85 (m, 1H), 7.56 (m, 1H), 7.49 (d, 2H), 4.96 (s, 2H), 3.84 (s, 3H).
1-amino-2-methylpropan-2-ol trifluoroacetate[ No CAS ]
[ 129655-57-8 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In isopropyl alcohol; toluene at 70℃; for 0.5h;
1.2 Step 2: Synthesis of 2-methyl-1-(3-nitroquinolin-4-ylamino )propan-2-ol (compound 2)
The trifluoroacetate salt of 1-amino-2-methylpropan-2-ol (compound 1') (450mg, 2.4 mmol) was added to the solution of 4-chloro-3-nitroquinoline (compound 1) (250 mg,1.2 mmol) and Et3N (0.5 ml, 3 mmol) in 4:1 mixture of toluene and 2-propanol. The mixturewas heated to 70°C for half an hour until a solid started precipitating. The reaction mixture was5 then cooled, filtered, washed with toluene/2-propanol (7:3), ether and cold water. The residuewas dried at 80°C to obtain 2-methyl-1-(3-nitroquinolin-4-ylamino)propan-2-ol (compound 2).LCMS: [M+Ht m/z=261.
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