* 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.
The 1,3-cyclohexanedione (0 · 03mol) and ammonium acetate (0 · 039mol) added to 100ml three-necked flask, stir hook, the reaction conditions in an oil bath at 110 °C 15min, Remove the oil bath and then naturally cool,During which the reaction liquid is solidified. After cooling to room temperature, ethyl acetate (10 ml) is added, heated to dissolve and cooled to 0 °C., filtered and the filter cake is dried to obtain yellow crystals of 3-amino-2-cyclohexenone (Yield 93.6percent)
90%
With AcONH4 In toluene
Example 5 3-Amino-cyclohex-2-enone A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90percent), which was used directly in the next step without further purification.
90%
With ammonium acetate In toluene for 5 h; Dean-Stark; Reflux
A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90percent), which was used directly in the next step without further purification.
86%
With ammonia In benzene for 4 h; Heating / reflux
To a 1 L two-necked flask charged 200 g (1.78 moL) of 1,3-cyclohexanedione and 600 mL benzene, attached a Dean-Stark apparatus with a condenser and an ammonia inlet. The mixture was heated to reflux and ammonia gas was bubbling into the reaction. The water generated from the reaction was trapped in the Dean-Stark apparatus. The mixture formed two layers and the bottom layer was solidified after refluxing for 4 h. The reaction was then stopped and cooled down to room temperature. The benzene was decanted and the remaining solid was triturated with 300 mL chloroform and filtered to give the desired product as a yellow solid (167.1 g, 1.51 moL, 86percent).1HNMR (400 MHz, CDCl3): 5.23 (s, 1 H), 3.20 (bs, 1 H), 2.37 (m, 2 H), 2.28 (m, 2 H), 1.97 (m, 2 H).
80%
With ammonium acetate In ethanol at 25 - 80℃; for 3 h; Inert atmosphere
S1. At room temperature (25 ° C - 30 ° C), weigh 112g into 2240mL of absolute ethanol, 84.8g of anhydrous ammonium acetate, heated to 80 ° C, reflux for 3h, nitrogen protection.When no raw materials were monitored by S2.TLC, the temperature was lowered to room temperature, and 212 g of anhydrous sodium carbonate was added to react overnight.S3. The reaction mixture was filtered through Celite, and then filtered and evaporated to dryness to give a yellow solid, and the yellow solid was beaten with 100 mL of EA until the impurities were washed.S4. After beating, filter, the filtrate is dissolved in 2240 mL of absolute ethanol, and the solvent is removed by using a 200-300 mesh silica gel column which has been saturated with ethanol.The filtrate by rotary evaporation to give a yellow solid 89g, molar yield 80percent, TLC purity 96percent.
78%
With ammonium acetate In toluene for 2 h; Reflux
Example 1A 3-Aminocyclohex-2-en-1-one A solution of 250 g (2.2 mol) of cyclohexane-1,3-dione and 180.45 g (2.3 mol) of ammonium acetate in 1.3 litres of toluene was heated under reflux for 2 hours using a water separator with reflux condenser. The reaction was then concentrated to dryness. The residue was taken up in 1.3 litres of ethyl acetate and 100 ml of methanol and heated to 110° C. The solution was then filtered while hot and slowly cooled to room temperature. The solution was then stored overnight at about 4° C. in the fridge. The resulting crystalline precipitate was filtered off and dried under reduced pressure. This gave 66.59 g (0.60 mol) as a first batch of the target product. Under reduced pressure, the recovered filtrate was concentrated to a volume of about 800 ml, seeded with a little crystalline product and then stored at about 4° C. for 12 days. The resulting crystalline precipitate was filtered off and dried under reduced pressure. This gave a further 13.28 g (0.12 mol) of the target product. Under reduced pressure, the recovered filtrate was concentrated to dryness. The residue was dissolved in 100 ml of a mixture of ethyl acetate and methanol (10:1), applied to silica gel and purified chromatographically on silica gel (mobile phase: ethyl acetate/methanol 10:1). This gave a further 113.79 g (1.02 mol) of the desired product as a yellow solid. In this manner, a total of 193.66 g (1.74 mol, 78percent of theory) of the target product were obtained. 1H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.71-1.84 (m, 2H), 2.01 (t, 2H), 2.25 (t, 2H), 4.91 (s, 1H), 6.39-6.99 (br. s, 2H).
70%
With ammonium acetate In toluene for 4 h; Reflux; Dean-Stark
Cyclohexane-1,3-dione (22.42 g, 200 mmol, 1 eq) was dissolved in 250 ml dry toluene and ammonium acetate (14.42 g, 200 mmol, 1 eq) was added. After refluxing under Dean-Stark conditions for 4 hours, the reaction mixture was evaporated. After recrystallization in ethyl acetate, 7.78 g of pure end product was obtained as a yellow-orange powder.
54%
With ammonium acetate; acetic acid In benzene for 7 h; Reflux
Preparation 1 3-Bromo-7,8-dihydroquinolin-5(6H)-one A mixture of cyclohexane-1,3-dione (30.00 g, 267.6 mmol), ammonium acetate (44.49 g, 535.1 mmol), glacial acetic acid (one drop), and benzene (150 mL) is stirred at reflux under Dean-Stark conditions for 7 h, cooled down to rt, and concentrated at reduced pressure. To the obtained residue EtOH and NaHC03 (2 eq.) are added. The formed precipitate is collected by filtration. The filtrate is concentrated, treated with dioxane and filtered. The solid on filter is washed with dioxane, and the combined filtrates are diluted with EtOAc. The formed solid is collected by filtration and dried to yield 3-aminocyclohex-2-enone (16.04 g, 54percent) as a white solid.
23%
Stage #1: With ammonium acetate In acetic acid; benzene for 7 h; Reflux Stage #2: With sodium hydrogencarbonate In ethanol
Example 983-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one[00286] A mixture of cyclohexane-1 ,3-dione (30.0 g, 0.27 mol), ammonium acetate (44.49 g, 0.54 mol), and acetic acid (1 mL) in benzene (300 mL) is stirred at reflux for 7 h using a Dean-Stark trap, cooled down to r.t., concentrated at reduced pressure, and diluted with EtOH. The mixture is neutralized by means of NaHC03. The formed solid is collected by filtration, and the filtrate is concentrated in vacuo. The obtained residue is dissolved in dioxane, and the residual solids are filtered. A precipitate is formed, which is collected by filtration and dried at 50 °C to give 3-aminocyclohex-2-enone (intermediate I) (6.77 g, 23percent) as yellow solid.[00287]A mixture of 2-bromomalonaldehyde (7.51 g, 49.75 mmol) and thionyl chloride (3.65 mL, 49.75 mmol) in anhydrous DCM (35 mL) is stirred at reflux for 9 h, cooled down to r.t. and concentrated at reduced pressure to give 2-bromo-3- chloroacrylaldehyde (intermediate II) (6.55 g, 88percent) as red oil, which is used in the next step without additional purification.[00288] Intermediate I (3.90 g, 35.10 mmol) is added to a solution of LiCI (2.60 g, 61 .45 mmol) in DMF (60 mL) at 40 °C, and the resulting solution is stirred at 50 °C for 5 min. Intermediate II (6.550 g, 43.91 mmol) is added, and the reaction mixture is stirred at 90 °C for 1.5 h, cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give a mixture of 3-bromo-7,8- dihydroquinolin-5(6/-/)-one and 3-chloro-7,8-dihydroquinolin-5(6/-/)-one (4.940 g) as yellowish oil (ratio approx. 1 : 1 according to LCMS). [00289]According to General Procedure 1 , the 1 : 1 mixture of halogenated 7,8- dihydroquinolin-5(6/-/)-ones (500 mg, approx. 2.45 mmol) is reacted with 6- ethynylpyridin-2-amine (292 mg, 2.45 mmol) in the presence of PdCI2[PPh3]2 (52 mg, 0.07 mmol), P(f-Bu)3 (0.061 mL, 0.25 mmol), and TEA (4 mL) in acetonitrile (4 mL) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (90 mg, 14percent).1H NMR (De-DMSO), δΗ, 2.05-2.15 (m, 2H), 2.67 (t, 2H), 3.09 (t, 2H), 6.1 1 (br s, 2H), 6.48 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H).LC/MS (M+H)+ = 264
99%
With ammonia In ethyl acetate; benzene
EXAMPLE 1 1-Amino cyclohexene-3-one 1,3-Cyclohexane dione (44.5 grams, 0.4 mol) was suspended in benzene (500 ml) in a 1 L flask equipped with mechanical stirrer, gas inlet tube, and Dean-Stark trap with reflux condenser. The mixture was heated to reflux to give a solution and ammonia gas was bubbled through the reaction until the theoretical amount of water had collected in the Dean Stark trap. The reaction mixture was cooled to room temperature and the solid was filtered. The yield was 44 g (99percent) of a tan solid; mp 120°-125° C. The reaction can be monitored by thin layer chromatography on silica gel plates with CHCl3: methanol: acetic acid 90:5:5. If the initial product is not a uniform solid, it can be slurried in hot ethyl acetate, cooled and collected.
Reference：
[1] New Journal of Chemistry, 2005, vol. 29, # 6, p. 769 - 772
[2] Patent: CN107337639, 2017, A, . Location in patent: Paragraph 0120; 0123; 0135; 0144-0146; 0157; 0168; 0179
[3] Synlett, 2009, # 5, p. 818 - 822
[4] Synthetic Communications, 1998, vol. 28, # 7, p. 1197 - 1200
[5] Tetrahedron, 2003, vol. 59, # 43, p. 8589 - 8595
[6] Advanced Synthesis and Catalysis, 2010, vol. 352, # 6, p. 1055 - 1062
[7] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3464 - 3471
[8] Patent: US2011/98311, 2011, A1,
[9] Patent: US2012/309758, 2012, A1,
[10] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 0371
[11] Patent: US2008/176308, 2008, A1, . Location in patent: Page/Page column 11
[12] Tetrahedron Letters, 2004, vol. 45, # 25, p. 4911 - 4915
[13] Patent: CN108218770, 2018, A, . Location in patent: Paragraph 0056-0065
[14] Patent: US2014/31391, 2014, A1, . Location in patent: Paragraph 0362; 0363; 0364
[15] Synlett, 2010, # 2, p. 231 - 234
[16] Synlett, 2014, vol. 25, # 10, p. 1443 - 1447
[17] Patent: EP2650284, 2013, A1, . Location in patent: Paragraph 0189
[18] Archives of Pharmacal Research, 2013, vol. 36, # 4, p. 436 - 447
[19] Patent: WO2012/52451, 2012, A1, . Location in patent: Page/Page column 102-103
[20] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2415 - 2425
[21] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 3, p. 685 - 690
[22] Patent: US5206367, 1993, A,
[23] Patent: US4952694, 1990, A,
[24] Patent: WO2009/55437, 2009, A2, . Location in patent: Page/Page column 60; 61
[25] Synthesis, 2009, # 6, p. 985 - 999
[26] Patent: US2012/309758, 2012, A1, . Location in patent: Page/Page column 63
[27] Advanced Synthesis and Catalysis, 2013, vol. 355, # 13, p. 2550 - 2557
[28] Tetrahedron Letters, 2014, vol. 55, # 10, p. 1686 - 1688
[29] Organic and Biomolecular Chemistry, 2014, vol. 12, # 26, p. 4571 - 4575
[30] Heterocycles, 2014, vol. 89, # 6, p. 1427 - 1440
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[32] Tetrahedron Letters, 2018, vol. 59, # 32, p. 3069 - 3076
2
[ 41609-04-5 ]
[ 762-42-5 ]
[ 108-44-1 ]
[ 5220-49-5 ]
Yield
Reaction Conditions
Operation in experiment
55%
With tert.-butylhydroperoxide; copper diacetate In water at 30℃; for 12 h;
General procedure: A mixture of N-benzyl enaminoketone (1.0 mmol), di-alkylacetylenedicarboxylate (1.0 mmol), aryl or alkyl amine (1.0 mmol), Cu(OAc)2 (8 molpercent) and TBHP (4.0 mmol, 0.56 mL of a 70percent aqueous solution) in water (0.5 mL) was stirred at 30 °C for 12 h under air. The reaction progress was monitored by TLC. After completion of the reaction, the solid was filtrated out and washed with hot ethyl acetate. Finally the solvent of the filtrate was removed under vacuum and the resulting crude product was purified by column chromatography over 60-120 mesh silica gel [ethyl acetate/ petroleum ether (60-80 °C)].
Reference：
[1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 219 - 220
4
[ 30182-67-3 ]
[ 5220-49-5 ]
Yield
Reaction Conditions
Operation in experiment
31%
With ammonium acetate In benzene for 5 h; Reflux
Into a 500 mL round bottom flask fitted with a Dean-Stark trap and a magnetic stirrer was added 150 mL of anhydrous benzene, 1,3-cyclohexanedione (5.6 g, 0.05 mol), and ammonium acetate (7.7 g, 0.1 mol). The mixture was stirred continuously, and refluxed for 5 h. The reaction was allowed to reach room temperature. The precipitate was recrystallized with ethyl acetate to afford yellow crystals (1.73 g, 31percent yield). Mp-128-131 °C [lit. 128-131 °C (35)]. 1H NMR Acetonitrile-d3) δ -1.8-2.4 (6H, m, cyclohexene ring), 5.1 (1H, s, CH). 5.3-5.5 (2H, s, br, NH2).
Reference：
[1] Synthesis, 1983, # 11, p. 902 - 903
[2] European Journal of Medicinal Chemistry, 2012, vol. 51, p. 42 - 51
5
[ 108-45-2 ]
[ 5220-49-5 ]
Reference：
[1] Patent: US5149874, 1992, A,
[2] Patent: US5149874, 1992, A,
6
[ 108-45-2 ]
[ 5220-49-5 ]
Reference：
[1] Patent: US5149874, 1992, A,
7
[ 108-45-2 ]
[ 5220-49-5 ]
Reference：
[1] Patent: US5149874, 1992, A,
[2] Patent: US5149874, 1992, A,
8
[ 591-27-5 ]
[ 75-05-8 ]
[ 621-31-8 ]
[ 23076-01-9 ]
[ 5220-49-5 ]
Reference：
[1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 219 - 220
9
[ 1609011-32-6 ]
[ 5220-49-5 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 1, p. 1 - 10
10
[ 84478-75-1 ]
[ 62257-16-3 ]
[ 5220-49-5 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 122 - 134
11
[ 84478-75-1 ]
[ 62257-16-3 ]
[ 5220-49-5 ]
[ 84478-72-8 ]
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 122 - 134
A mixture of 3-aminocyclohex-2-enone (100 mmol), 1 ,1 , 3,3- tetraethoxypropane (1 10 mmol), and 4-methylbenzenesulfonic acid (2.91 mmol) is diluted with λ/,λ/-dimethylformamide (40 ml_) and the reaction mixture is heated at reflux for 16 h. The reaction mixture is allowed to cool to rt, neutralized with sodium bicarbonate, diluted with water (400 ml_), and is extracted with ethyl acetate (3 x 100 ml_). The combined organic layers are dried (sodium sulfate) and concentrated. The residue is purified by chromatography (10/1 petroleum ether/ethyl acetate) to provide 5,6,7,8-tetrahydroquinolin-5-one in 7percent yield as a colorless oil.
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2736 - 2746
[2] Journal of Organic Chemistry, 1985, vol. 50, # 20, p. 3938 - 3940
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 213 - 220
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 12, p. 2146 - 2163
15
[ 5220-49-5 ]
[ 53400-41-2 ]
Reference：
[1] Patent: US4762843, 1988, A,
16
[ 5220-49-5 ]
[ 927-63-9 ]
[ 53400-41-2 ]
[ 56798-21-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 1, p. 41 - 46
17
[ 5220-49-5 ]
[ 79-10-7 ]
[ 5057-12-5 ]
Yield
Reaction Conditions
Operation in experiment
90.2%
for 6 h; Reflux
-amino-2-cyclohexenone (0.02mol) and acrylic acid (0.024mol) was added to a 100ml three-necked flask, heated to reflux with stirring 6h, cooled to room temperature, the reaction solution was solidified to give a reddish brown solid , Adding absolute ethanol (5ml), heating and dissolving, cooling to room temperature, filtering and drying the filter cake to obtain light yellow crystal which is 3,4,7,8-tetrahydro-2,5 (1H, 6H) Ketone (yield 90.2percent),
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 18, p. 3719
[2] Patent: CN107337639, 2017, A, . Location in patent: Paragraph 0120; 0125; 0137; 0148; 0159; 0169; 0170; 0181
[3] Patent: US5068334, 1991, A,
K 3-Methyl-3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione
EXAMPLE K 3-Methyl-3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione Prepared analogously to Example G from 1-amino- cyclohexen-3-one and methacrylic acid in an autoclave for a period of one hour at 180° C. Recrystallisation is from methanol and subsequently from a mixture of ethyl acetate/ethanol (3:1). Melting point: 210°-212° C., Yield: 28.8% of theory.
-amino-2-cyclohexenone (0.02mol) and acrylic acid (0.024mol) was added to a 100ml three-necked flask, heated to reflux with stirring 6h, cooled to room temperature, the reaction solution was solidified to give a reddish brown solid , Adding absolute ethanol (5ml), heating and dissolving, cooling to room temperature, filtering and drying the filter cake to obtain light yellow crystal which is 3,4,7,8-tetrahydro-2,5 (1H, 6H) Ketone (yield 90.2%),
45.1%
In methanol;
EXAMPLE G 3,4,7,8-Tetrahydro-2,5(1H,6H)-quinolinedione 5.00 g (0.675 mol) of 1-amino-cyclohexen-3-one and 65.65 g (1.35*0.675 mol) of acrylic acid are stirred for 3 hours under nitrogen in an oil bath heated to 180 C. The mixture is cooled and recrystallized from 1000 ml of methanol. Melting point: 192-194.5 C., Yield: 45.1% of theory,
With ammonium acetate; acetic acid In benzene for 0.3h; Heating;
31%
With ammonium acetate In benzene for 5h; Reflux;
3.2.6. 3-Aminocyclohex-2-enone (14a)
Into a 500 mL round bottom flask fitted with a Dean-Stark trap and a magnetic stirrer was added 150 mL of anhydrous benzene, 1,3-cyclohexanedione (5.6 g, 0.05 mol), and ammonium acetate (7.7 g, 0.1 mol). The mixture was stirred continuously, and refluxed for 5 h. The reaction was allowed to reach room temperature. The precipitate was recrystallized with ethyl acetate to afford yellow crystals (1.73 g, 31% yield). Mp-128-131 °C [lit. 128-131 °C (35)]. 1H NMR Acetonitrile-d3) δ -1.8-2.4 (6H, m, cyclohexene ring), 5.1 (1H, s, CH). 5.3-5.5 (2H, s, br, NH2).
Methyl propiolate (2.69 g, 32 mmol) and 3-AMINO-2-CYCLOHEXEN-1-ONE (3.5 g, 32 mmol) were dissolved in DMF (20 mL) and heated to reflux. After 3 hrs the mixture was cooled on an ice bath, and the crystalline material was collected and washed with a small amount of DMF cooled in dry ice. The filtrate was heated again for 16 hr after addition of methyl propiolate (2.69 g, 32 mmol) and the solid precipitate was collected and washed with a small amount of DMF. This procedure is repeated once again. The crude solid was recrystallized from methanol and to yield 1.93 g (37 %) of the desired 7, 8-DIHYDRO-LH, 6H-quinoline-2, 5-DIONE.'H NMR (270 MHz, CDCl3) 8 8.04 (d, 1H, J = 9. 5HZ), 6.45 (d, 1H, J=9.5 Hz), 2.94 (t, 2H, J = 6. 2 HZ), 2.57 (t, 2H, J = 6. 2 HZ) and 2.12-2. 21 (M, 2H); 13C NMR (67 MHz, CDC13) & 193.8, 165.9, 156.1, 139.1, 118.1, 115.0, 37.2, 27.3 and 21.4 ; ES-MS m/z 164 ((M+H) +).
29%
at 105 - 170℃; for 1.91667h;
Example 2A 7,8-Dihydroquinoline-2,5(1H,6H)-dione With stirring, 113.79 g (1.02 mol) of 3-aminocyclohex-2-en-1-one and 114.37 ml (1.19 mol) of methyl propionate were heated at 105 C. for 1 hour. The dark homogeneous solution formed was then slowly heated further to 170 C. After 20 min (temperature: 135 C.), a viscous material formed, and there was a marked evolution of gas. After a further 15 min (temperature: 160 C.), the reaction material became even more viscous while the evolution of gas subsided. After a total of 42 min, a temperature of 170 C. had been reached. After a further 13 min at this temperature, the reaction material was cooled to room temperature. 200 ml of dichloromethane were then added, the mixture was heated briefly and placed into an ultrasonic bath and the crystalline residue formed was filtered off. This procedure was repeated once more with a further 200 ml of dichloromethane. The crystalline residues obtained in this manner were combined, taken up in 1.6 litres of methanol and then heated with stirring until the solid had dissolved completely. This solution was then slowly cooled to room temperature and then stored in a fridge at about 4 C. for 2 days. The crystalline precipitate was filtered off and dried under reduced pressure. This gave 47.65 g (0.29 mol, 29% of theory) of the target product. 1H-NMR (400 MHz, DMSO-d6, delta/ppm): 1.90-2.07 (m, 2H), 2.42 (t, 2H), 2.78 (t, 2H), 6.23 (d, 1H), 7.76 (d, 1H), 12.06 (br. s, 1H).
28%
at 105℃; for 1.0h;
Example 32-Hydroxy-3-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile3.1 7,8-Dihydroquinoline-2,5(1H,6H)-dioneMethyl propiolate (5.03 ml, 56.2 mmol) was added to finely ground 3-aminocyclohex-2-enone (5 g, 45.0 mmol). The resulting mixture was heated to 105 C. resulting in a dark brown solution and stirred under reflux for 60 min. Then the reflux condenser was removed and the excess methyl propiolate was distilled off by raising the temperature to 170 C. The reaction mixture was cooled to RT and the resulting solid was triturated with dichloromethane (10 mL) and heated to 40 C. for 25 min. The hot mixture was filtered and the yellow residue was washed with dichloromethane (10 mL). The solid was dried under reduced pressure. Amount 2.07 g. Yield 28%.1H-NMR (DMSO-d6, 400 MHz) delta 2.03 (m, 2H), 2.45 (m, 2H), 2.81 (t, 2H), 6.25 (d, 1H), 7.78 (d, 1H), 12.05 (bs, 1H)MS (ES-API) m/z 164.1 (M+H+, 100%).
20%
at 100 - 105℃; for 2.0h;
Example 54A: 7,8-Dihydroquinoline-2,5(lH,6H)-dione [00395] A mixture of 3-aminocyclohex-2-enone (5.00 g, 45.0 mmol) and methyl propiolate (5.00 mL, 59.8 mmol) was heated without stirring at 100-105 C for 2 h. The reflux condenser was removed, and the brown, homogeneous reaction mixture was heated to 170 C to remove any excess methyl propiolate. At -165 C, the product started to crystallize. The resulting dark brown solidified reaction mixture was triturated quickly with dichloromethane (2 x 5 mL)). The solid was then suspended in methanol and sonicated for 60 min., collected by vacuum filtration, washed with methanol, and dried to give 7,8-dihydroquinoline-2,5(lH,6H)-dione (1.49 g, 9.13 mmol, 20% yield) as a yellow solid. The compound had an HPLC ret. time = 0.638 min. (condition A); LC/MS M+1 = 163.9. XH NMR (500 MHz, DMSO-d6) delta ppm 1.99 (quin, J=6.38 Hz, 2H), 2.39-2.44 (m, 2H), 2.78 (t, J=6.24 Hz, 2H), 6.23 (d, J=9.43 Hz, IH), 7.76 (d, J=9.43 Hz, IH), and 12.07 (br. s., IH).
720 mg
In N,N-dimethyl-formamide; for 11.0h;Reflux;
Step 1 : 7,8-Dihydro-1 H,6H-quinoline-2,5-dione. 3-Amino-cyclohex-2-enone (3.5 g, 31 .5 mmol) and methyl propiolate (2.8 ml, 31 .5 mmol) are dissolved in N,N-dimethylformamide (20 ml), the mixture is stirred under reflux for 3 hours. The mixture is cooled with an ice bath and the precipitate is collected, methyl propiolate (2.8 ml, 31 .5 mmol) is added to the filtrate and the mixture is heated again under reflux for 8 hours, then is cooled with an ice bath and the solid is collected. The combined precipitates are recrystallized from methanol and washed with diethyl ether to give the title compound. (Yield 720 mg) LC (Method 2): tR = 0.32-0.63 min; Mass spectrum (ES+): m/z = 164 [M+H]+.
With ammonium acetate; tetraethoxy orthosilicate In ethanol Heating;
93.6%
With ammonium acetate at 110℃; for 0.25h;
3.a Step a: Preparation of 3-amino-2-cyclohexenone
The 1,3-cyclohexanedione (0 · 03mol) and ammonium acetate (0 · 039mol) added to 100ml three-necked flask, stir hook, the reaction conditions in an oil bath at 110 °C 15min, Remove the oil bath and then naturally cool,During which the reaction liquid is solidified. After cooling to room temperature, ethyl acetate (10 ml) is added, heated to dissolve and cooled to 0 °C., filtered and the filter cake is dried to obtain yellow crystals of 3-amino-2-cyclohexenone (Yield 93.6%)
92%
With potassium hydrogensulfate; ammonium acetate; silica gel at 20℃; for 0.5h;
91%
With ammonium acetate In toluene for 5h; Heating;
90%
With ammonium acetate In toluene for 5h; Heating;
90%
With ammonium acetate In toluene Reflux;
90%
With ammonium acetate In toluene Reflux; Inert atmosphere;
90%
With AcONH4 In toluene
5 3-Amino-cyclohex-2-enone
Example 5 3-Amino-cyclohex-2-enone A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90%), which was used directly in the next step without further purification.
90%
With ammonium acetate In toluene for 5h; Dean-Stark; Reflux;
5 3-Amino-cyclohex-2-enone
A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90%), which was used directly in the next step without further purification.
86%
With ammonia In benzene for 4h; Heating / reflux;
6
To a 1 L two-necked flask charged 200 g (1.78 moL) of 1,3-cyclohexanedione and 600 mL benzene, attached a Dean-Stark apparatus with a condenser and an ammonia inlet. The mixture was heated to reflux and ammonia gas was bubbling into the reaction. The water generated from the reaction was trapped in the Dean-Stark apparatus. The mixture formed two layers and the bottom layer was solidified after refluxing for 4 h. The reaction was then stopped and cooled down to room temperature. The benzene was decanted and the remaining solid was triturated with 300 mL chloroform and filtered to give the desired product as a yellow solid (167.1 g, 1.51 moL, 86%).1HNMR (400 MHz, CDCl3): 5.23 (s, 1 H), 3.20 (bs, 1 H), 2.37 (m, 2 H), 2.28 (m, 2 H), 1.97 (m, 2 H).
80%
With ammonium acetate In toluene for 5h; Heating;
80%
With ammonium acetate In ethanol at 25 - 80℃; for 3h; Inert atmosphere;
1.1
S1. At room temperature (25 ° C - 30 ° C), weigh 112g into 2240mL of absolute ethanol, 84.8g of anhydrous ammonium acetate, heated to 80 ° C, reflux for 3h, nitrogen protection.When no raw materials were monitored by S2.TLC, the temperature was lowered to room temperature, and 212 g of anhydrous sodium carbonate was added to react overnight.S3. The reaction mixture was filtered through Celite, and then filtered and evaporated to dryness to give a yellow solid, and the yellow solid was beaten with 100 mL of EA until the impurities were washed.S4. After beating, filter, the filtrate is dissolved in 2240 mL of absolute ethanol, and the solvent is removed by using a 200-300 mesh silica gel column which has been saturated with ethanol.The filtrate by rotary evaporation to give a yellow solid 89g, molar yield 80%, TLC purity 96%.
80%
With ammonium acetate In ethanol at 70℃; for 8h;
78%
With ammonium acetate In toluene for 2h; Reflux;
1A 3-Aminocyclohex-2-en-1-one
Example 1A 3-Aminocyclohex-2-en-1-one A solution of 250 g (2.2 mol) of cyclohexane-1,3-dione and 180.45 g (2.3 mol) of ammonium acetate in 1.3 litres of toluene was heated under reflux for 2 hours using a water separator with reflux condenser. The reaction was then concentrated to dryness. The residue was taken up in 1.3 litres of ethyl acetate and 100 ml of methanol and heated to 110° C. The solution was then filtered while hot and slowly cooled to room temperature. The solution was then stored overnight at about 4° C. in the fridge. The resulting crystalline precipitate was filtered off and dried under reduced pressure. This gave 66.59 g (0.60 mol) as a first batch of the target product. Under reduced pressure, the recovered filtrate was concentrated to a volume of about 800 ml, seeded with a little crystalline product and then stored at about 4° C. for 12 days. The resulting crystalline precipitate was filtered off and dried under reduced pressure. This gave a further 13.28 g (0.12 mol) of the target product. Under reduced pressure, the recovered filtrate was concentrated to dryness. The residue was dissolved in 100 ml of a mixture of ethyl acetate and methanol (10:1), applied to silica gel and purified chromatographically on silica gel (mobile phase: ethyl acetate/methanol 10:1). This gave a further 113.79 g (1.02 mol) of the desired product as a yellow solid. In this manner, a total of 193.66 g (1.74 mol, 78% of theory) of the target product were obtained. 1H-NMR (400 MHz, DMSO-d6, δ/ppm): 1.71-1.84 (m, 2H), 2.01 (t, 2H), 2.25 (t, 2H), 4.91 (s, 1H), 6.39-6.99 (br. s, 2H).
73%
With ammonia In toluene at 80℃; Inert atmosphere;
70%
With ammonium acetate In toluene for 4h; Reflux; Dean-Stark;
GENERAL PROCEDURE 1: synthesis of 3-aminocyclohex-2-en-1-one 2
Cyclohexane-1,3-dione (22.42 g, 200 mmol, 1 eq) was dissolved in 250 ml dry toluene and ammonium acetate (14.42 g, 200 mmol, 1 eq) was added. After refluxing under Dean-Stark conditions for 4 hours, the reaction mixture was evaporated. After recrystallization in ethyl acetate, 7.78 g of pure end product was obtained as a yellow-orange powder.
54%
With ammonium acetate; acetic acid In benzene for 7h; Reflux;
1
Preparation 1 3-Bromo-7,8-dihydroquinolin-5(6H)-one A mixture of cyclohexane-1,3-dione (30.00 g, 267.6 mmol), ammonium acetate (44.49 g, 535.1 mmol), glacial acetic acid (one drop), and benzene (150 mL) is stirred at reflux under Dean-Stark conditions for 7 h, cooled down to rt, and concentrated at reduced pressure. To the obtained residue EtOH and NaHC03 (2 eq.) are added. The formed precipitate is collected by filtration. The filtrate is concentrated, treated with dioxane and filtered. The solid on filter is washed with dioxane, and the combined filtrates are diluted with EtOAc. The formed solid is collected by filtration and dried to yield 3-aminocyclohex-2-enone (16.04 g, 54%) as a white solid.
44%
With ammonium acetate In benzene Dean-Stark; Reflux;
23%
Stage #1: 1,3-cylohexanedione With ammonium acetate In acetic acid; benzene for 7h; Reflux;
Stage #2: With sodium hydrogencarbonate In ethanol
98
Example 983-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one[00286] A mixture of cyclohexane-1 ,3-dione (30.0 g, 0.27 mol), ammonium acetate (44.49 g, 0.54 mol), and acetic acid (1 mL) in benzene (300 mL) is stirred at reflux for 7 h using a Dean-Stark trap, cooled down to r.t., concentrated at reduced pressure, and diluted with EtOH. The mixture is neutralized by means of NaHC03. The formed solid is collected by filtration, and the filtrate is concentrated in vacuo. The obtained residue is dissolved in dioxane, and the residual solids are filtered. A precipitate is formed, which is collected by filtration and dried at 50 °C to give 3-aminocyclohex-2-enone (intermediate I) (6.77 g, 23%) as yellow solid.[00287]A mixture of 2-bromomalonaldehyde (7.51 g, 49.75 mmol) and thionyl chloride (3.65 mL, 49.75 mmol) in anhydrous DCM (35 mL) is stirred at reflux for 9 h, cooled down to r.t. and concentrated at reduced pressure to give 2-bromo-3- chloroacrylaldehyde (intermediate II) (6.55 g, 88%) as red oil, which is used in the next step without additional purification.[00288] Intermediate I (3.90 g, 35.10 mmol) is added to a solution of LiCI (2.60 g, 61 .45 mmol) in DMF (60 mL) at 40 °C, and the resulting solution is stirred at 50 °C for 5 min. Intermediate II (6.550 g, 43.91 mmol) is added, and the reaction mixture is stirred at 90 °C for 1.5 h, cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give a mixture of 3-bromo-7,8- dihydroquinolin-5(6/-/)-one and 3-chloro-7,8-dihydroquinolin-5(6/-/)-one (4.940 g) as yellowish oil (ratio approx. 1 : 1 according to LCMS). [00289]According to General Procedure 1 , the 1 : 1 mixture of halogenated 7,8- dihydroquinolin-5(6/-/)-ones (500 mg, approx. 2.45 mmol) is reacted with 6- ethynylpyridin-2-amine (292 mg, 2.45 mmol) in the presence of PdCI2[PPh3]2 (52 mg, 0.07 mmol), P(f-Bu)3 (0.061 mL, 0.25 mmol), and TEA (4 mL) in acetonitrile (4 mL) at 100 °C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (90 mg, 14%).1H NMR (De-DMSO), δΗ, 2.05-2.15 (m, 2H), 2.67 (t, 2H), 3.09 (t, 2H), 6.1 1 (br s, 2H), 6.48 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H).LC/MS (M+H)+ = 264
With ammonia In benzene for 1h; Heating;
With ammonium acetate In toluene
44 g (99%)
With ammonia In ethyl acetate; benzene
1 1-Amino cyclohexene-3-one
EXAMPLE 1 1-Amino cyclohexene-3-one 1,3-Cyclohexane dione (44.5 grams, 0.4 mol) was suspended in benzene (500 ml) in a 1 L flask equipped with mechanical stirrer, gas inlet tube, and Dean-Stark trap with reflux condenser. The mixture was heated to reflux to give a solution and ammonia gas was bubbled through the reaction until the theoretical amount of water had collected in the Dean Stark trap. The reaction mixture was cooled to room temperature and the solid was filtered. The yield was 44 g (99%) of a tan solid; mp 120°-125° C. The reaction can be monitored by thin layer chromatography on silica gel plates with CHCl3: methanol: acetic acid 90:5:5. If the initial product is not a uniform solid, it can be slurried in hot ethyl acetate, cooled and collected.
With ammonia In water; benzene
C PREPARATION C
PREPARATION C In a three-liter reaction flask equipped with a Dean-Stark trap, there were placed 900 ml. of benzene under a dry nitrogen atmosphere. After heating the latter solvent to 70° C., 100 g. (0.89 mole) of 1,3-cyclohexanedione were added and the resulting solution was then treated with ammonia gas for a period of 1.75 hours. At this point, 14 ml. of water had collected in the trap (this was water of condensation from the reaction). The resulting reaction mixture was then allowed to cool down to 25° C. by standing overnight (ca. 16 hours), and the yellow solid material which formed was subsequently collected by means of suction filtration to ultimately afford 102.9 g. of crude 3-amino-2-cyclohexen-1-one. The yield of crude product was nearly quantitative. The latter material was used as such in the next reaction step without any further purification being necessary.
With ammonium acetate In toluene for 4h; Heating / reflux; Dean-Stark trap;
2; 4
Ammonium acetate (151 mmol) and cyclohexane-1 ,3-dione (150.00 mmol) are combined and diluted with toluene (300 ml_) in a round bottom flask with a Dean-Stark condenser. The reaction mixture is heated at reflux for 4 h and is concentrated. The solid residue is recrystallized (ethyl acetate) to provide 3-amino-2- cyclohexen-1 -one as a yellow solid. The material is of sufficient purity to use in the subsequent transformation.
With ammonia for 3h; Reflux;
With ammonium acetate for 5h; Dean-stark; Reflux;
5
A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH4 (38.5 g, 0.5 mol) in toluene was heated at reflux for 5 h with a Dean-stark apparatus. The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90%), which was used directly in the next step without further purification.
With ammonium acetate In toluene at 120℃; for 4h;
With ammonium acetate In toluene for 3h; Reflux; Dean-Stark;
General procedure: 10 mmol cyclic 1,3-diketone wasadded to a mixture of 10 mmol ammonium acetate in dry toluene (20 mL). Themixture was heated for 3 h under reux using a Dean-Stark water separator. Theresulting oily product was separated and recrystallized with ethylacetate to give the corresponding enaminone as crystals. The enaminone productwas dissolved in 50ml THF and 2 equiv. of pyridine were added. To the mixedsolution, acetyl chloride (2 equiv.) in 5ml THF was added dropwise at 0 °C. Thereaction mixture was warmed up to ambient temperature and stirred additional 5h at 60oC. The solvent was removed undervacuum and the crude product purified by flash chromatography
With ammonium acetate In ethanol Reflux;
With ammonium acetate In toluene
With ammonia
Multi-step reaction with 2 steps
1: air / ethanol / 2 h / 78 °C
2: copper diacetate; tert.-butylhydroperoxide / water / 12 h / 30 °C
With ammonium acetate In neat (no solvent) at 100℃;
Synthesis of cyclic β-enaminones under solvent-free conditions
General procedure: A mixture of dimedone or cyclohexane-1,3-dione (1 mmol), ammonium acetate(1.5 mmol) was heated at 100 °C for appropriate time. After completion of the reactionindicated by TLC (1-2 h), the reaction mixture was cooled to room temperature.By addition of a few drops of chloroform, the yellow precipitate was obtained, whichwas purified by recrystallization from n-hexane/ethyl acetate, m. p. = 157-159 °Cand m. p. = 132-134 °C, respectively
toluene-4-sulfonic acid; In N,N-dimethyl-formamide; for 16h;Heating / reflux;
A mixture of 3-aminocyclohex-2-enone (100 mmol), 1 ,1 , 3,3- tetraethoxypropane (1 10 mmol), and 4-methylbenzenesulfonic acid (2.91 mmol) is diluted with lambda/,lambda/-dimethylformamide (40 ml_) and the reaction mixture is heated at reflux for 16 h. The reaction mixture is allowed to cool to rt, neutralized with sodium bicarbonate, diluted with water (400 ml_), and is extracted with ethyl acetate (3 x 100 ml_). The combined organic layers are dried (sodium sulfate) and concentrated. The residue is purified by chromatography (10/1 petroleum ether/ethyl acetate) to provide 5,6,7,8-tetrahydroquinolin-5-one in 7% yield as a colorless oil.
toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 140℃; for 18h;
To a solution of 10.12 g (0.14 mmol) 3-aminocyclohex-2-en-l-one and 22 mL 1,1,3,3- tetraethoxypropane in 40 mL dry DMF under nitrogen atmosphere was added 0.5 g (cat.) p- toluenesulfonic acid. The reaction mixture was heated at 140 0C for 18 hr. The volatiles were removed under vacuum and the residue distilled under vacuum to give an oil. This material was further purified by column chromatography on silica gel eluting with hexanes/EtOAc (3/1) then EtOAc (100%) afford 1.75 g of the title compound. LC-MS: (MH)+: 148.2.
5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-thiopyrano[3,4-b]quinoline-4,6(3H,7H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 50 5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-thiopyrano[3,4-b]quinoline-4,6(3H,7H)-dione A mixture of <strong>[6881-49-8]thiopyran-3,5-dione</strong> (Fehnel, E. A., J. Amer. Chem. Soc., (1955), 77, 4241-4244) (0.12 g, 1.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.20 g, 1.0 mmol), 3-amino-2-cyclohexene-1-one (0.11 g, 1.0 mmol) and ethanol (5 mL) was heated to 80 C. in a sealed tube for 60 hours and cooled to ambient temperature. The resulting solid was collected by filtration, washed with ethanol and dried for 16 hours under high vacuum to provide the title compound (0.13 g). MS (APCI(+)) m/z 408 (M+H)+; MS (APCI(-)) m/z 406 (M-H)-; 1H NMR (DMSO-d6) delta 1.77-1.88 (m, 1H), 1.89-1.98 (m, 1H), 2.25 (dd, 2H), 2.46-2.62 (m, 2H), 3.10 (dd, 1H), 3.48 (ddd, 2H), 3.82 (d, 1H), 4.96 (s, 1H), 7.15-7.24 (m, 2H), 7.41 (dd, 1H), 9.71 (s, 1H); Anal. Calcd for C18H15BrFNO2S: C, 52.95; H, 3.70; N, 3.43. Found: C, 52.81; H, 3.79; N, 3.17.
In ethanol;
EXAMPLE 50 5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-thiopyrano[3,4-b]quinoline-4,6(3H,7H)-dione A mixture of <strong>[6881-49-8]thiopyran-3,5-dione</strong> (Fehnel, E. A., J. Amer. Chem. Soc., (1955), 77, 4241-4244) (0.12 g, 1.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.20 g, 1.0 mmol), 3-amino-2-cyclohexene-1-one (0.11 g, 1.0 mmol) and ethanol (5 mL) was heated to 80 C. in a sealed tube for 60 hours and cooled to ambient temperature. The resulting solid was collected by filtration, washed with ethanol and fried for 16 hours under high vacuum to provide the title compound (0.13 g). MS (APCI(+)) m/z 408 (M+H)+; MS (APCI(-)) m/z 406 (M-H)-; 1H NMR (DMSO-d6) delta 1.77-1.88 (m, 1H), 1.89-1.98 (m 1H), 2.25 (dd, 2H), 2.46-2.62 (m, 2H), 3.10 (dd, 1H), 3.48 (ddd, 2H), 3.82 (d, 1H), 4.96 (s, 1H), 7.15-7.24 (m, 2H), 7.41 (dd, 1H), 9.71 (s, 1H); Anal. Calcd for C18H15BrFNO2S: C,52.95; H, 3.70; N, 3.43. Found: C, 52.81; H, 3.79; N, 3.17.
2.A 2-benzyl-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H, 7H)-dione Hydrochloride
EXAMPLE 2A 2-benzyl-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H, 7H)-dione Hydrochloride A solution of 3-amino-2-cyclohexen-1-one (0.55 g, 5.0 mmol), 3-bromo-4-fluorobenzaldehyde (1.01 g, 5.0 mmol) and N-benzylpiperidine-3,5-dione (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464) (1.01 g, 5.0 mmol) was heated for 3 days in ethyl alcohol (10 mL) in a sealed tube and then allowed to cool to ambient temperature. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (5% ethanol/methylene chloride) to provide the title compound (0.84 g) which was converted to the HCl salt. mp 240-241° C.; MS (DCI/NH3) m/z 481 (M+H)+; 1H NMR (CDCl3)(free base) δ 2.0 (m, 2H), 2.67 (m, 2H), 2.48 (m, 2H), 3.05-3.48 (m, 4H), 3.7 (m, 2H), 5.1 (s, 1H), 6.05 (bs, 1H), 6.99 (t, 1H), 7.32 (m, 6H), 7.41 (dd, 1H); Anal. Calcd for C25H22BrFN2O2.HCl: C, 57.99; H, 4.48; N, 5.41. Found: C, 57.87; H, 4.46; N, 5.35.
In ethanol
2.A 2-benzyl-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione hydrochloride
EXAMPLE 2A 2-benzyl-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione hydrochloride A solution of 3-amino-2-cyclohexen-1-one (0.55 g, 5.0 mmol), 3-bromo-4-fluorobenzaldehyde (1.01 g, 5.0 mmol) and N-benzylpiperidine-3,5-dione (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464) (1.01 g, 5.0 mmol) was heated for 3 days in ethyl alcohol (10 mL) in a sealed tube and then allowed to cool to ambient temperature. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (5% ethanol/methylene chloride) to provide the title compound (0.84 g) which was converted to the HCl salt. mp 240-241° C.; MS (DCI/NH3)m/z481(M+H)+; 1H NMR (CDCl3)(free base) δ2.0(m, 2H), 2.67 (m, 2H), 2.48 (m,2H), 3.05-3.48 (m, 4H), 3.7 (M, 2H), 5.1 (s, 1H), 6.05 (bs, 1H), 6.99 (t, 1H), 7.32 (m, 6H), 7.41 (dd, 1H); Anal. Calcd for C25H22BrFN2O2HCl:C, 57.99; H, 4.48; N, 5.41. Found: C, 57.87; H, 4.46;
EXAMPLE 26 The following example illustrates the conversion of 3-amino-2-cyclohexene-1-one to 3,4'-oxydianiline. 3-Amino-2-cyclohexene-1-one (1.5 mole, 166.7 g), potassium acetate (6 mmol, 0.6 g), and 5% palladium on carbon (4.7 g, 65.5% water) were added to N,N-dimethylacetamide (475 g) solvent in a one liter creased round bottom flask equipped with a nitrogen purge, thermometer, condenser, distillation head, overhead stirrer, and heating mantle. The solution was then heated to reflux for two hours at 173 C. with a continuous nitrogen purge. The palladium catalyst was filtered from the solution. Gas chromatography analysis indicated 130.9 g 3-aminophenol (1.2 mole, 80% yield based on 3-amino-2-cyclohexene-1-one). The crude solution was then added to 4-chloronitrobenzene (204.8 g, 1.3 mole) and potassium carbonate (124.4 g, 0.9 mole) in a one liter round bottom flask equipped as above and refluxed at 167 C. for 2.5 hour. Water was removed during the first 0.5 hour as the temperature approached reflux. The solution was cooled to 120 C. before filtering through a course filter. The salts were washed with 50 g N,N-dimethylacetamide. The solution together with 0.4 g 5% palladium on carbon (65.5% in water) were then charged into a one liter autoclave. The autoclave was purged with nitrogen for fifteen minutes followed by a constant 100 psig hydrogen pressure at 125 C. for 3.0 hour. The palladium catalyst was filtered at room temperature. After the solvent was distilled, a forecut was removed at 200 C. and 1.5 mm Hg vacuum before distillation at 210 C. and 1.5 mm Hg vacuum isolated 185.6 g pure 3,4,-oxydianiline (0.9 mole, 60% yield based on 3-amino-2-cyclohexene-1-one.
PREPARATION D To a mechanically-stirred slurry consisting of 60 g. of lithium chloride in 350 ml. of anhydrous dimethylformamide at 40 C., there were added 88.9 g. (0.80 mole) of 3-amino-2-cyclohexene-1-one (the product of Preparation C). When all this material had dissolved, the temperature was increased to 60 C. and all of the 1,2-dichloro-1-propen-3-al obtained in Preparation B (i.e., the product of Preparation B) was added in one portion. This resulted in a mild exotherm accompanied by vigorous bubbling. After allowing the reaction mixture to stand at 90 C. for a period of one hour, the reaction flask and its contents were cooled to 25 C. and the contents were poured over 400 ml. of water. The resulting slurry was then extracted with twelve-500 ml. portions of hexanes, which were subsequently combined and then dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were eventually obtained 51.62 g. (28%) of pure 3-chloro-5,6,7,8-tetrahydro-5-quinolone in the form of a yellow solid melting at 88-94 C.; 1 H-NMR (300 MHz, DMSO-d6)delta2.10 (m, 2H), 2.65 (t, 2H), 3.05 (t, 2H), 8.08 (s, 1H), 8.70 (s, 1H).
EXAMPLE 1 7,8-Dihydro-5(6H)-quinolinone The procedure of Rimek and Zymalkowski (Arch. Pharm. 1961, 294, 759-765) was followed. Over a period of 1 hour, 40.9 g (0.757 mol) of freshly-distilled propiolaldehyde was added dropwise to a solution of 42.1 g (0.379 mol) of 3-amino-2-cyclohexenone in 1.5 1 of N,N-dimethylformamide (DMF). The solution was stirred at room temperature for 12 hours. The DMF was evaporated at reduced pressure. Vacuum distillation (bp 60-65 C. at 0.025-0.050 mmHg) of the resultant black tars gave 30.2 g (54.2%) of 7,8-dihydro-5(6H)-quinolinone as a colorless liquid.
To a 500 mL flask, added 3-amino-cyclohex-2-enone (110 g, 0.99 moL) and ethyl propiolate (100 mL, 0.99 moL) and attached a condenser. The mixture was heated to 100 degree Celsius. The reaction started slowly at beginning and accelerated as the reaction progress. After the reaction was refluxed at 120 degree Celsius for 4 h, the mixture was heated up to 150 degree Celsius to remove any liquid. Finally, the mixture was heated up to 190 degree Celsius and remained for 1 h. The reaction was cooled to room temperature and 300 mL methylene chloride was added. The mixture was trituated and filtered to give the desired product (34 g, 21%).
Stage #1: malonic acid bis-(2,4,6-trichloro-phenyl) ester; 3-amino-cyclohex-2-enone In bromobenzene at 155℃; for 0.5h;
Stage #2: With trichlorophosphate at 95℃; for 4h;
1 (+-)-[2-(2,6-Diethyl-phenyl)-4-methoxy-5,6,7,8-tetrahydro-quinolin-5-yl]-ethyl-naphthlen-1-yl-amine (Compound #12)
Example 1 (+-)-[2-(2,6-Diethyl-phenyl)-4-methoxy-5,6,7,8-tetrahydro-quinolin-5-yl]-ethyl-naphthlen-1-yl-amine (Compound #12) A mixture of 3-amino-cyclohex-2-enone (12.5 g, 113 mmol, 1 equiv) and malonic acid bis-(2,4,6-trichlorophenyl) ester (52.1 g, 113 mmol, 1 equiv) in bromobenzene (120 mL) was heated in a 155° C. oil bath for 30 minutes. The reaction mixture was allowed to cool and was poured into a mixture of EtOAc (240 mL) and Et2O (240 mL). The precipitate was collected by vacuum filtration and the collected solids were washed with EtOAc and were air-dried. The solid was treated with phosphorus oxychloride (86 mL, 939 mmol) and the resultant mixture was heated in a 95° C. oil bath for 4 hours. The reaction mixture was allowed to cool and was then concentrated. The residue was poured into ice (100 mL) and the mixture was neutralized to pH 7 by addition of solid Na2CO3 (gas evolution). The mixture was extracted with CH2Cl2 (3*100 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (SiO2, 0-15% EtOAc in hexanes), to yield 2,4-dichloro-7,8-dihydro-6H-quinolin-5-one (4.81 g, 30%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 3.16 (t, 2H), 2.72 (t, 2H), 2.16 (t, 2H); MS m/z (MH+) 216.0.
Stage #1: malonic acid bis-(2,4,6-trichloro-phenyl) ester; 3-amino-cyclohex-2-enone With bromobenzene Heating;
Stage #2: With trichlorophosphate Heating; Further stages.;
Example 983-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one[00286] A mixture of cyclohexane-1 ,3-dione (30.0 g, 0.27 mol), ammonium acetate (44.49 g, 0.54 mol), and acetic acid (1 mL) in benzene (300 mL) is stirred at reflux for 7 h using a Dean-Stark trap, cooled down to r.t., concentrated at reduced pressure, and diluted with EtOH. The mixture is neutralized by means of NaHC03. The formed solid is collected by filtration, and the filtrate is concentrated in vacuo. The obtained residue is dissolved in dioxane, and the residual solids are filtered. A precipitate is formed, which is collected by filtration and dried at 50 C to give 3-aminocyclohex-2-enone (intermediate I) (6.77 g, 23%) as yellow solid.[00287]A mixture of 2-bromomalonaldehyde (7.51 g, 49.75 mmol) and thionyl chloride (3.65 mL, 49.75 mmol) in anhydrous DCM (35 mL) is stirred at reflux for 9 h, cooled down to r.t. and concentrated at reduced pressure to give 2-bromo-3- chloroacrylaldehyde (intermediate II) (6.55 g, 88%) as red oil, which is used in the next step without additional purification.[00288] Intermediate I (3.90 g, 35.10 mmol) is added to a solution of LiCI (2.60 g, 61 .45 mmol) in DMF (60 mL) at 40 C, and the resulting solution is stirred at 50 C for 5 min. Intermediate II (6.550 g, 43.91 mmol) is added, and the reaction mixture is stirred at 90 C for 1.5 h, cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give a mixture of 3-bromo-7,8- dihydroquinolin-5(6/-/)-one and 3-chloro-7,8-dihydroquinolin-5(6/-/)-one (4.940 g) as yellowish oil (ratio approx. 1 : 1 according to LCMS). [00289]According to General Procedure 1 , the 1 : 1 mixture of halogenated 7,8- dihydroquinolin-5(6/-/)-ones (500 mg, approx. 2.45 mmol) is reacted with 6- ethynylpyridin-2-amine (292 mg, 2.45 mmol) in the presence of PdCI2[PPh3]2 (52 mg, 0.07 mmol), P(f-Bu)3 (0.061 mL, 0.25 mmol), and TEA (4 mL) in acetonitrile (4 mL) at 100 C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (90 mg, 14%).1H NMR (De-DMSO), deltaEta, 2.05-2.15 (m, 2H), 2.67 (t, 2H), 3.09 (t, 2H), 6.1 1 (br s, 2H), 6.48 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H).LC/MS (M+H)+ = 264
General procedure; To a 250 mL single neck flask equipped with a ST "Y" tube, condenser and a pressure equalizing dropping funnel containing 85 mL of anhydrous THF, was cautiously added NaH (0.84 g, 35.0 mmol) with constant stirring, maintaining the temperature below 20 C with external cooling. After the reaction, 14b (1.9 g, 15.0 mmol) was added over 30 min through the "Y" tube, and after the addition, a further 10 mL of THF washed the "Y" tube. The reaction mixture was heated to reflux for 20 min, cooled to room temperature and 5-methylisoxazolyl carbonylchloride [7] (2.30 g, 16.0 mmol) in anhydrous THF (25 mL) was added dropwise over 5 min. After stirring at room temperature for a further 10 min, the mixture was quenched with water and transferred to a 250 mL Erlenmeyer flask, neutralized with concentrated HCl (∼10 mL), diluted with dichloromethane (55 mL) and transferred to a separatory funnel. The aqueous layer was discarded and the organic layer was washed successively with water (55 mL), 10% NaHCO3 (2 × 55 mL), and water (55 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and the residue triturated with anhydrous Et2O (110 mL). The crude solid was recrystallized from EtOAc, to give 15b (0.75 g 21%) as cream colored crystals.
General procedure for synthesis of tetrahydroquinolinones
General procedure: A vial was added 3-oxobutanamide(1 equiv), carbaldehyde (1 equiv), 3-aminocyclohex-2-enone (1 equiv) and IPA (5 mL/mmol) and heated to80°C for two-four days. The reaction mixture was concentrated under vacuum and purified by flashchromatography.
4-([1,1'-biphenyl]-3-yl)-2-methyl-5-oxo-N-(o-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
In isopropyl alcohol at 80℃;
General procedure for synthesis of tetrahydroquinolinones
General procedure: A vial was added 3-oxobutanamide(1 equiv), carbaldehyde (1 equiv), 3-aminocyclohex-2-enone (1 equiv) and IPA (5 mL/mmol) and heated to80°C for two-four days. The reaction mixture was concentrated under vacuum and purified by flashchromatography.
General procedure: 3-aminocyclohex-2-en-1-one (5 g, 1 eq) was dissolved in 200 ml acetic acid and an appropriate 1-substituted-4,4,4-trifluoro-1,3-dione (1.5 eq) was added. After refluxing for 7 hours, the reaction mixture was evaporated, toluene was added and the mixture was evaporated again. The end products were purified using column chromatography (petroleum ether/ethylacetate) and/or recrystallization in isopropanol.
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