* 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] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 4963 - 4966
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 3, p. 311 - 317
[3] Synthetic Communications, 1986, vol. 16, # 5, p. 543 - 546
[4] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7708 - 7713
[5] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 7, p. 763 - 770[6] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 7, p. 951 - 958
[7] Journal of Medicinal Chemistry, 1987, vol. 30, # 2, p. 239 - 249
[8] Patent: US4293554, 1981, A,
[9] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 663 - 673
[10] European Journal of Medicinal Chemistry, 2016, vol. 112, p. 48 - 59
2
[ 2166-31-6 ]
[ 10025-87-3 ]
[ 20375-65-9 ]
Reference：
[1] Chemische Berichte, 1899, vol. 32, p. 398
3
[ 98-86-2 ]
[ 298-12-4 ]
[ 2166-31-6 ]
Yield
Reaction Conditions
Operation in experiment
15%
Stage #1: at 100℃; for 2 h; Stage #2: With ammonia In water Stage #3: With hydrazine hydrate In water at 100℃; for 2 h;
19.6 g (162.95 mmol) of 1-phenylethanone and 5 g (54.32 mmol) of oxoacetate monohydrate were stirred at 100° C. for 2 hours. The reaction solution was then cooled to 40° C., and 20 ml of water and 4 ml of ammonia were added. The mixture was then twice extracted with 50 ml of dichloromethane. 2.64 ml (53.32 mmol) of hydrazine monohydrate were then added to the aqueous phase obtained, and the mixture was stirred at 100° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature. The precipitated crystals were filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. overnight. This gave 4.3 g (24.97 mmol, 15percent of theory) of the title compound as colorless crystals.LC-MS (method 7): Rt=1.39 min; m/z=173 (M+H)+.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 13.2 (s, 1H), 8.04 (d, 1H), 7.86 (d, 2H), 7.53-7.41 (m, 3H), 7.00 (d, 1H).
15%
Stage #1: at 100℃; for 2 h; Stage #2: With ammonia In water at 40℃;
Example 41A6-Phenylpyridazin-3 (2H)-one 19.6 g (162.95 mmol) of 1-phenylethanone and 5 g (54.32 mmol) of oxoacetic acid monohydrate were stirred at 100° C. for 2 hours. The reaction solution was then cooled to 40° C., and 20 ml of water and 4 ml of ammonia were added. The mixture was then extracted twice with 50 ml of dichloromethane. 2.64 ml (53.32 mmol) of hydrazine monohydrate were then added to the aqueous phase, and the mixture was stirred at 100° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature. The precipitated crystals were filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. overnight. This gave 4.3 g (24.97 mmol, 15percent of theory) of the title compound as colorless crystals.LC-MS (Method 4): Rt=1.39 min; m/z=173 (M+H)+.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 13.2 (s, 1H), 8.04 (d, 1H), 7.86 (d, 2H), 7.53-7.41 (m, 3H), 7.00 (d, 1H).
Reference：
[1] Patent: US2011/34450, 2011, A1, . Location in patent: Page/Page column 103
[2] Patent: US2012/28971, 2012, A1, . Location in patent: Page/Page column 24-25
[3] Synthesis, 1993, # 3, p. 334 - 342
[4] Medicinal Chemistry Research, 2013, vol. 22, # 6, p. 2553 - 2560
[5] Letters in Drug Design and Discovery, 2013, vol. 10, # 6, p. 507 - 514
[6] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 663 - 673
[7] European Journal of Medicinal Chemistry, 2016, vol. 112, p. 48 - 59
4
[ 1011-46-7 ]
[ 2166-31-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 9, p. 2873 - 2882
[2] European Journal of Organic Chemistry, 2013, # 27, p. 6130 - 6136
[3] Synthetic Communications, 2000, vol. 30, # 1, p. 1 - 7
[4] Synthesis, 1995, # 10, p. 1240 - 1242
[5] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1435 - 1438
[6] Synthetic Communications, 2001, vol. 31, # 5, p. 645 - 651
[7] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 1627 - 1636
[8] Journal of Chemical Research, Miniprint, 1995, # 8, p. 1840 - 1852
[9] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 7, p. 763 - 770[10] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 7, p. 951 - 958
[11] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 4, p. 371 - 372
[12] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 6, p. 1473 - 1476
5
[ 79-14-1 ]
[ 98-86-2 ]
[ 2166-31-6 ]
Yield
Reaction Conditions
Operation in experiment
17.9%
Stage #1: at 110℃; for 2 h; Stage #2: With ammonia In water at 40℃; Stage #3: With hydrazine hydrate In water at 100℃; for 2 h;
Preparation of 6-Phenylpyridazin-3(2H)-one 5-3: (1197) (1198) A mixture of Cpd-5-1(1 g, 13.5 mmol) and 5-2 (4.88 g, 40.5 mmol) was heated at 110°C for 2h, cooled down to 40°C followed by addition of water (4.5 ml) and concentrated aqueous ammonia (1 ml). The reaction mixture was thereafter extracted with DCM, organic part was separated and the ammoniacal aqueous layer was treated with hydrazine hydrate (676 mg, 13.5mmol) followed by heating at 100°C for 2h, reaction mass cooled down to room temperature, precipitate formed was collected by filtration, residue dried under vaccum to afford 6-phenylpyridazin-3(2H)-one 5-3 (417 mg, 2.42 mmol, 17.9 percent) as an off-white solid. LC MS: ES+ 173.3
Reference：
[1] Synthetic Communications, 2001, vol. 31, # 5, p. 645 - 651
[2] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 7, p. 763 - 770[3] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 7, p. 951 - 958
[4] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 6, p. 1473 - 1476
[5] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1435 - 1438
7
[ 89868-14-4 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 6, p. 1473 - 1476
8
[ 70529-47-4 ]
[ 2166-31-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1985, # 5, p. 865 - 870
[2] Bulletin de la Societe Chimique de France, 1985, # 5, p. 865 - 870
9
[ 64942-62-7 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 6, p. 1473 - 1476
10
[ 87769-64-0 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 6, p. 1473 - 1476
11
[ 98-86-2 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9865 - 9870,6
12
[ 1316302-41-6 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9865 - 9870,6
13
[ 1422963-93-6 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9865 - 9870,6
14
[ 1316302-44-9 ]
[ 2166-31-6 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9865 - 9870,6
15
[ 65245-10-5 ]
[ 2166-31-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1985, # 5, p. 865 - 870
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5774 - 5777
16
[ 81819-88-7 ]
[ 2166-31-6 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. 20, # 12, p. 1084 - 1086
17
[ 20375-65-9 ]
[ 2166-31-6 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. 20, # 12, p. 1084 - 1086
A mixture of 147.5 g. of 6-phenyl-3(2H)-pyridazinone and 800 ml. of phosphorus oxychloride is heated on a steam bath for 5 hours and then concentrated free of excess phosphorus oxychloride. The concentrate is diluted with cold water and the resulting solid is filtered, washed with water and air dried, giving 158 g. of 3-chloro-6-phenylpyridazine as a pinkish solid.
Stage #1: acetophenone; Glyoxilic acid at 100℃; for 2h;
Stage #2: With ammonia In water
5.1.88. 6-Phenyl-2,3-dihydropyridazin-3-one (42)
A mixture of acetophenone (19.0 mL, 163.0 mmol, 3.0 equiv.)and glyoxylic acid hydrate (5.0 g, 54.3 mmol,1.0 equiv.) were heatedat 100 °C for 2 h. After it was cooled at 40 °C, water (20 mL) andammonia (4 mL) were added. The aqueous phase was extracted 3times with DCM. Hydrazine hydrate (2.6 mL, 54.3 mmol, 1.0 equiv.)was added in the aqueous phase and the resulting solution washeated at reflux four 4 h. After cooling, the solid was filtered andwashed with water, to afford 42 as white solid (6.5 g, 37.5 mmol,70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (d, 1H, J 9.6 Hz),7.45-7.52 (m, 3H), 7.87 (d, 2H, J 7.2 Hz), 8.04 (d, 1H, J 9.6 Hz),13.2 (s, 1H).
15%
Stage #1: acetophenone; Glyoxilic acid at 100℃; for 2h;
Stage #2: With ammonia In water
Stage #3: With hydrazine hydrate In water at 100℃; for 2h;
262A
19.6 g (162.95 mmol) of 1-phenylethanone and 5 g (54.32 mmol) of oxoacetate monohydrate were stirred at 100° C. for 2 hours. The reaction solution was then cooled to 40° C., and 20 ml of water and 4 ml of ammonia were added. The mixture was then twice extracted with 50 ml of dichloromethane. 2.64 ml (53.32 mmol) of hydrazine monohydrate were then added to the aqueous phase obtained, and the mixture was stirred at 100° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature. The precipitated crystals were filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. overnight. This gave 4.3 g (24.97 mmol, 15% of theory) of the title compound as colorless crystals.LC-MS (method 7): Rt=1.39 min; m/z=173 (M+H)+.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 13.2 (s, 1H), 8.04 (d, 1H), 7.86 (d, 2H), 7.53-7.41 (m, 3H), 7.00 (d, 1H).
15%
Stage #1: acetophenone; Glyoxilic acid at 100℃; for 2h;
Stage #2: With ammonia In water at 40℃;
41A
Example 41A6-Phenylpyridazin-3 (2H)-one 19.6 g (162.95 mmol) of 1-phenylethanone and 5 g (54.32 mmol) of oxoacetic acid monohydrate were stirred at 100° C. for 2 hours. The reaction solution was then cooled to 40° C., and 20 ml of water and 4 ml of ammonia were added. The mixture was then extracted twice with 50 ml of dichloromethane. 2.64 ml (53.32 mmol) of hydrazine monohydrate were then added to the aqueous phase, and the mixture was stirred at 100° C. for 2 hours. After the reaction, the reaction solution was cooled to room temperature. The precipitated crystals were filtered off with suction, washed with water and dried in a vacuum drying cabinet at 50° C. overnight. This gave 4.3 g (24.97 mmol, 15% of theory) of the title compound as colorless crystals.LC-MS (Method 4): Rt=1.39 min; m/z=173 (M+H)+.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 13.2 (s, 1H), 8.04 (d, 1H), 7.86 (d, 2H), 7.53-7.41 (m, 3H), 7.00 (d, 1H).
Stage #1: acetophenone; Glyoxilic acid at 100 - 105℃; for 2h;
Stage #2: With hydrazine hydrate In water for 2h; Reflux;
Stage #1: acetophenone; Glyoxilic acid at 100 - 105℃; for 2h;
Stage #2: With hydrazine hydrate In water for 2h; Reflux;
Synthesis of 6-(4-nonsubstituted/methoxy/chlorophenyl)-3(2H)-pyridazinones (1, 2, 3)
General procedure: Glyoxylic acid (0.05 mol) and (0.15 mol) acetophenone derivative (nonsubstituted/4-methoxy/ 4-chloroacetophenone derivatives) were heated at 100-105 °C for 2h. At the end of this period, the reaction mixture was cooled to room temperature and then, 20 ml water and 5 ml ammonium hydroxide solution (25%) were added to the reaction mixture until the medium pH became 8. Then, reaction mixture was extracted with dichloromethane (4 x 25 ml), then hydrazine hydrate (0.05 mol) was added to the separated aqueous layer and the reaction mixture was refluxed for 2h. After completion of the reaction, reaction mixture was cooled to room temperature. The resulting precipitate was filtered to give compounds 1 (mp 201-202 °C; lit [19]:202-203 °C), 2 (mp 190-191 °C; lit [19]:188-191 °C), 3 (mp 270-271 °C; lit[19]:271-272 °C), respectively.
3-(6-oxo-3-phenylpyridazin-1(6H)-yl)piperidine-2,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21.1%
Preparation of 3-(6-Oxo-3-phenylpyridazin-1(6H)-yl)piperidine-2,6-dione (Compound 149): (1199) To a stirred solution of 6-phenylpyridazin-3(2H)-one 3 (200 mg, 1.16 mmol) in THF(5 mL ) at -30C was added LiHMDS (1.74 mL, 1.74 mmol), stirred for 1h followed by addition of 3- bromopiperidine-2,6-dione 4 (266 mg, 1.39 mmol). The reaction mixture was thereafter gradually warmed up to room temperature followed by heating under reflux overnight. After complete consumption of Cpd-3 as evident from TLC, the reaction mixture was quenched with ice water, volatiles stripped off, residue partitioned between ethyl acetate and water, combined organic extracts dried over sodium sulphate, concentrated, the residual crude purified by preparative TLC to afford 3-(6-oxo-3-phenylpyridazin-1(6H)-yl)piperidine-2,6-dione (Compound 149) (69.4 mg, 245 mumol, 21.1 %) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 11.08 (s, 1H), 8.10 (d, J = 9.72 Hz, 1H), 7.87- 7.88 (m, 2H), 7.48- 7.50 (m, 3H), 7.13 (d, J = 9.96 Hz), 5.80- 5.83 (m, 1H), 2.89- 2.92 (m, 1H), 2.61- 2.64 (m, 2H), 2.17 (m, 1H). LC MS: ES+ 284.3
With phosphorus pentachloride; trichlorophosphate at 90 - 110℃; for 4.5h; Molecular sieve;
4 Example 4
Addition of 68.9 g of 6-phenyl-3-pyridazinone g (0.4 mol) in a 500 ml four-neck flask, prepared in Example 1Modified ZSM-5 molecular sieve 7 g, 413.4 g of phosphorus oxychloride and 166.5 g of phosphorus pentachloride (0.8 mol), and then heated to 90°C, and kept warmAfter half an hour of reaction, the temperature was raised to 110°C and the reaction was refluxed for 4 hours. The reaction was completed. HPLC was used to determine the area normalized to give 3-phenyl-4-one.The ratio of chloropyridazine, 3-phenyl-4-6-dichloropyridazine, 3-phenyl-4-5-dichloropyridazine was 0.5:98.4:1.1;The reaction solution was distilled under reduced pressure to remove phosphorus oxychloride, and the temperature under vacuum distillation was 120°C. The degree of vacuum was -0.098 MPa;After being bundled, it is cooled to room temperature, then 137.8g of toluene is added, stirred and heated to recrystallize, the Buchner funnel is filtered, and the wet product is blownThe box was dried at 80°C for 8 hours to obtain 86.5 g of a white solid-like 3-phenyl-4-6-dichloropyridazine product (HPLC: 99.7%; Yield:95.3%).
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