* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With palladium on activated charcoal; hydrogen In toluene at 25 - 35℃; Autoclave
Taken 200.Og of 3,4-difluoro nitro benzene, 600.Oml of Toluene and 12.Og of pd/C into autoclave at 25°C-35°C. Apply the Hydrogen gas 2.0-6.0Kg/Cm2 and maintained the reaction for 3-4 hrs at 25°C-35°C Check the reaction mass TLC to conform reactioncompletion. After reaction complies unload the reaction mass and filter through hyflow bed and wash with toluene (200.OmI). Take the filtrate and distilled under vacuum at below 50°C. the obtained 3,4-Difluoro aniline crude weight 152.Og,.Yield:93.8percent,purity by HPLC:95 .85percent.
77%
With iron; ammonium chloride In methanol; water at 90℃; for 12 h;
To a stirred solution of 1, 2-difluoro-4-nitrobenzene (4 g, 1 mmol) in methanol and water (25 mL: 5 mL) at RT, iron powder (2.5 g) and ammonium chloride (2 g) were added. The reaction mixture was refluxed for 12 h and the progress of reaction was monitored by TLC. After 12 h reaction time, the reaction mixture was filtered using celite pad. Then the solvent was evaporated under reduced pressure, water was added and the product was extracted with ethyl acetate and dried over anhydrous sodium sulphate. The crude product was purified by using column chromatography by eluting with ethyl acetate: hexane (30:70 v/v) which afforded the title compound in 77percent yield (2.5 g, brown liquid). 1H NMR (300 MHz, CDCl3): δ 6.88-6.94 (m, 1H, Ar-H), 6.43-6.47 (m, 1H, Ar-H), 6.31-6.34 (m, 1H, Ar-H), 3.60 (s, 2H, NH2). 13C NMR (75 MHz, CDCl3): δ 150.83, 147.60, 143.39, 140.02, 115.80, 108.57, 101.89. IR (CHCl3, νmax cm-1): 3383, 2360, 1617, 1521, 1266, 1213. MS (ESI, m/z) [M+H]+ 130.
43%
With iron; ammonium chloride In methanol; water at 60℃; for 5 h; Heating / reflux
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1, 2-difluor nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ML) and heated to 60 °C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture REFLUXED for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1, 2-difluoro-4- aminobenzene (7 g, 43percent). [00147] BC13 (6.2 ML, 1M in DCM) was added drop wise to 1,2- DIFLUORO-4AMINOBENZENE (0.5 g, 0.004 mol) in trichloroethylene (6.5 ML) at 0°C and this mixture stirred for 15 min. 4-Cyanopyridine (0.48 g, 0.005 mol) was added and the solution was warmed to RT and stirred for 30 min. The solution was then heated at 80-90 °C for 1 h. The resulting solution was REFLUXED at 160°C for 4 hr and stirred at RT over night. 3N HCI was added to the reaction mixture and refluxed at 110 °C for 1.5 h. The reaction mixture was cooled to RT and made basic (pH = 12) with 6N NaOH. The reaction mixture was diluted with water and DCM. The resulting two layers were separated and the aqueous layer was extracted with DCM, dried over sodium sulphate and concentrated. The compound was purified by column chromatography using silica gel to yield title compound (0.25 g, 27percent).
Reference：
[1] Patent: WO2015/68171, 2015, A1, . Location in patent: Page/Page column 9; 16
[2] Tetrahedron Letters, 2010, vol. 51, # 5, p. 786 - 789
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 613 - 617
[4] ChemPlusChem, 2018, vol. 83, # 5, p. 375 - 382
[5] Synthesis, 2001, # 1, p. 81 - 84
[6] Patent: WO2004/46092, 2004, A2, . Location in patent: Page 48
[7] Journal of the American Chemical Society, 1951, vol. 73, p. 5884
[8] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[9] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[10] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 165 - 180
[11] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6492 - 6499
2
[ 369-34-6 ]
[ 7439-89-6 ]
[ 3863-11-4 ]
Yield
Reaction Conditions
Operation in experiment
86%
With hydrogenchloride In methanol
COMPARATIVE EXAMPLE 1 (Process wherein reduction and a diazochlorination method are used in combination) 10 g of 3,4-difluoronitrobenzene was dissolved in 20 and 2 g of methanol and 10 g of concentrated hydrochloric acid and 2 g of iron powder were added thereto. The mixture was stirred at 60° C. for two hours, and then distilled to obtain 3,4-difluoroaniline. The reduction yield was 86percent.
Reference：
[1] Patent: US5208394, 1993, A,
3
[ 369-34-6 ]
[ 403-19-0 ]
Reference：
[1] Patent: US4224335, 1980, A,
4
[ 99-54-7 ]
[ 369-34-6 ]
[ 350-30-1 ]
Reference：
[1] Russian Journal of Organic Chemistry, 1994, vol. 30, # 12, p. 1925 - 1929[2] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 12, p. 1829 - 1832
[3] Chemistry Letters, 1990, # 5, p. 769 - 772
[4] Russian Journal of Organic Chemistry, 1994, vol. 30, # 12, p. 1925 - 1929[5] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 12, p. 1829 - 1832
5
[ 369-34-6 ]
[ 2713-33-9 ]
Reference：
[1] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 165 - 180
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
6
[ 67-56-1 ]
[ 369-34-6 ]
[ 455-93-6 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 10 - 20℃; for 2 - 3 h;
Step 4: Preparation of 3-fluoro-4-methoxyaniline (8) Metallic sodium (1.45 grams, 63 mmol) was added slowly and portion wise to pre cooled (10° C.) methanol (100 mL) with stirring under nitrogen atmosphere. The mixture was stirred at room temperature until all the sodium metal gets dissolved. To this was added 3,4-difluoro nitrobenzene (6) (10 grams, 63 mmol) at room temperature and stirring continued at the same temperature for 2-3 hours. The mixture was then concentrated under vacuum and poured into ice-water (100 mL). The pH of the mixture was adjusted to ~7 by adding 2N HCl with stirring. The solid separated was filtered off, washed with water and dried under vacuum to afford the product 2-fluoro-4-nitroanisol (7) (9.75 grams). Yield: 91percent; Melting point: 102-104° C.
64%
With potassium hydroxide In dimethyl sulfoxide at 20℃; for 16 h;
General procedure: A mixture of 2-fluorobenzamide (1a, 69.5 mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16 h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture was extracted with ethyl acetate three times (3 * 10 mL). The combined organic phases were dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05 in volume) to afford 2aa as a white solid in 80percent yield (60.7 mg).
57%
With sodium hydroxide In dimethyl sulfoxide at 20℃; for 12 h;
3,4-difluoronitrobenzene (31.88, 0.2111001), high purity NaOH (168,0.4111001), methanol (88,0.25mo 1), DMSO (200 mL) was added to the reactor and the reaction was stirred at 20 ° C for 12 hours. After completion of the reaction, 800 mL of ethyl acetate was added to the system and diluted 5 times with 200 mL of saturated brine. The organic phase was separated and dried over anhydrous sodium sulfateAfter which it was filtered, evaporated to dryness, and then it was loaded onto a silica gel column to separate petroleum ether: ethyl acetate = 4: 1 (volume) Was eluted as an eluent until the product appeared, the solution containing the product was collected and evaporated to dryness. After drying with a vacuum chestnut, 3-fluoro-4-methoxy nitrobenzene pure product, the yield of 57percent.
Reference：
[1] Patent: US2006/128729, 2006, A1, . Location in patent: Page/Page column 77
[2] Tetrahedron, 2018, vol. 74, # 2, p. 303 - 307
[3] Patent: CN106565522, 2017, A, . Location in patent: Paragraph 0037; 0038
[4] Russian Chemical Bulletin, 2006, vol. 55, # 7, p. 1243 - 1247
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 11, p. 3203 - 3207[2] Angew. Chem., 2013, vol. 125, # 11, p. 3285 - 3289,5
9
[ 97-00-7 ]
[ 369-34-6 ]
[ 364-74-9 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
[2] Chemistry Letters, 1989, p. 2213 - 2216
10
[ 98-95-3 ]
[ 402-67-5 ]
[ 369-34-6 ]
[ 364-74-9 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Yield
Reaction Conditions
Operation in experiment
0.05 mmol
at 0 - 25℃; Cooling with ice
General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).
Reference：
[1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8
11
[ 369-34-6 ]
[ 1427-07-2 ]
Reference：
[1] Synthesis, 2000, # 12, p. 1659 - 1661
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 6, p. 857 - 859
[2] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 4, p. 353 - 360
[3] J. Med. Chem., 1996, vol. 39, # 3, p. 673 - 679
[4] Patent: WO2011/77310, 2011, A1,
[5] Patent: WO2011/114210, 2011, A2,
[6] Patent: WO2011/137222, 2011, A1,
[7] Patent: US2011/275805, 2011, A1,
[8] Patent: EP2388251, 2011, A1,
[9] Patent: US2011/306606, 2011, A1,
[10] Turkish Journal of Chemistry, 2012, vol. 36, # 1, p. 37 - 53
[11] Patent: WO2012/114355, 2012, A1,
[12] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 5, p. 1143 - 1146,4
[13] Patent: WO2013/72923, 2013, A1,
[14] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 779 - 785
[15] Patent: US2013/324719, 2013, A1,
[16] Patent: WO2014/12360, 2014, A1,
[17] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 4, p. 874 - 880
[18] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7614 - 7620
[19] Patent: US2015/87639, 2015, A1,
[20] Patent: TWI607995, 2017, B,
[21] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 120 - 131
[22] Patent: WO2015/162622, 2015, A1,
[23] Patent: CN103420933, 2016, B,
[24] Patent: CN102617500, 2016, B,
[25] ChemMedChem, 2017, vol. 12, # 18, p. 1525 - 1533
[26] Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4052 - 4066
[27] Patent: WO2005/103042, 2005, A1,
[28] Patent: WO2005/103000, 2005, A1,
[29] Patent: EP2394993, 2011, A2,
[30] Patent: WO2008/122787, 2008, A1,
17
[ 369-34-6 ]
[ 168828-82-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 6, p. 857 - 859
[2] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 4, p. 353 - 360
[3] J. Med. Chem., 1996, vol. 39, # 3, p. 673 - 679
[4] Patent: WO2011/77310, 2011, A1,
[5] Patent: WO2011/114210, 2011, A2,
[6] Patent: WO2011/114210, 2011, A2,
[7] Patent: WO2012/114355, 2012, A1,
[8] Patent: WO2013/72923, 2013, A1,
[9] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 779 - 785
[10] Patent: US2013/324719, 2013, A1,
[11] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7614 - 7620
[12] Patent: WO2015/68121, 2015, A1,
[13] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 120 - 131
[14] Patent: CN102617500, 2016, B,
18
[ 369-34-6 ]
[ 154590-66-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4261 - 4267
[2] Patent: WO2011/37731, 2011, A1,
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 16, p. 4490 - 4498
[4] Patent: CN107033095, 2017, A,
19
[ 369-34-6 ]
[ 174649-09-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 4, p. 353 - 360
[2] J. Med. Chem., 1996, vol. 39, # 3, p. 673 - 679
[3] Patent: WO2011/77310, 2011, A1,
[4] Patent: WO2011/114210, 2011, A2,
[5] Patent: WO2011/114210, 2011, A2,
[6] Patent: WO2012/114355, 2012, A1,
[7] Patent: WO2013/72923, 2013, A1,
[8] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 779 - 785
[9] Patent: US2013/324719, 2013, A1,
[10] Patent: WO2015/68121, 2015, A1,
[11] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 120 - 131
20
[ 369-34-6 ]
[ 154590-35-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4261 - 4267
[2] Patent: US2011/306606, 2011, A1,
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[4] Patent: US2014/121200, 2014, A1,
[5] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 120 - 131
[6] Patent: CN107033095, 2017, A,
[7] Chemical Papers, 2018, vol. 72, # 2, p. 457 - 468
[8] Patent: EP2394993, 2011, A2,
21
[ 369-34-6 ]
[ 57260-71-6 ]
[ 154590-35-9 ]
Reference：
[1] Patent: WO2011/37731, 2011, A1,
22
[ 369-34-6 ]
[ 57260-71-6 ]
[ 154590-34-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate In N,N-dimethyl-formamide at 90 - 95℃; for 18 h;
Step A. 4-(2-Fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. A mixture of piperazine-1 -carboxylic acid tert-butyl ester (10.0 g, 53.7 mmol), 3,4-difluoronitrobenzene (6.0 ml_, 54.2 mmol) and K2CO3 (22.0 g, 159 mmol) in DMF (60.00 mL) was heated to about 90-950C for 18 h. The resulting mixture was cooled to room temperature and diluted with ethyl acetate (700.0 mL) and water (200.0 mL). The organic phase was separated and washed with water (3x300 mL), dried (Na2SO4), filtered and concentrated to yield a yellow solid (17.0O g, 97 percent). 1H NMR (CDCI3): 8.01 -7.96 (m, 1 H), 7.95-7.88 (m, 1 H), 6.90 (t, J = 8.8, 1 H), 3.65-3.55 (m, 4H), 3.28-3.20 (m, 4H), 1.48 (s, 9H).
91%
With potassium carbonate In N,N-dimethyl-formamide at 5℃;
To an ice cold (5 °C) solution of piperazine-l -carboxylic acid tert-butyl ester (17.56 g, 94.28 mmol) in dry DMF (50 mL) was added K2CO3 (12.8 g, 94.28 mmol) and the slurry stirred for 15 minutes. 1 ,2-Difluoro-4-nitro-benzene (15.0 g, 94.28 mmol) was added to the slurry and the reaction mixture stirred vigorously for 2 h. The mixture was filtered and the insoluble material washed with DMF (25 mL). The combined filtrate was evaporated to dryness under reduced pressure, and the yellow solid that formed was re-crystallized from DCM to affording 30.1 g (91percent) of the title compound. 1H NMR (400 MHz, DMSO-i/6) δ (ppm): 8.04 - 7.99 (m, 2H), 7.17 (t, J= 9.0 Hz, 1H), 3.48 (t, J = 4.8 Hz, 4H), 3.25 (t, J= 5.2 Hz, 4H), 1.42 (s, 9H); l 9F NMR (376 MHz, DMSO-4 δ (ppm): - 1 19.79 (dd, J = 13.8, 9.0 Hz).
91%
With triethylamine In methanol at 50 - 60℃; for 17 h;
3-4-1: Preparation of [3-fluoro-4-BOC-piperazino)]nitrobenzene To 100 ml of methanol were sequentially added 5 g (31.4 mmol) of 3,4-difluoronitrobenzene, 5.3 ml (37.7 mmol) of triethylamine and 6.4 g (34.5 mmol) of Boc-piperazine, followed by reaction at a temperature of 50 to 60° for 17 hours. After the reaction was complete, the reaction liquid was cooled to room temperature and 20 ml of water was slowly added dropwise thereto, followed by stirring for 4 hours. The resulting solid was filtered, washed with a 1:1 (v/v) solution of water and methanol and then dried under vacuum at about 40° to afford 9.3 g (yield: 91percent) of the desired compound. 1H-NMR (DMSO-d6): 1.42(s, 9H), 3.25(m, 4H), 3.48(m, 4H), 7.18(3, 1H), 8.03(m, 2H).
91%
With triethylamine In methanol at 50 - 60℃; for 17 h;
Example 3-4-1 Preparation of [3-fluoro-4-(BOC-piperazino)]nitrobenzene To 100ml of methanol were sequentially added 5g (31.4mmol) of 3,4-difluoronitrobenzene, 5.3ml (37.7mmol) of triethylamine and 6.4g (34.5mmol) of BOC-piperazine, followed by reaction at a temperature of 50 to 60°C for 17 hours. After the reaction was complete, the reaction liquid was cooled to room temperature and 20ml of water was slowly added dropwise thereto, followed by stirring for 4 hours. The resulting solid was filtered, washed with a 1:1 (v/v) solution of water and methanol and then dried under vacuum at about 40°C to afford 9.3g (yield: 91percent) of the desired compound. 1H-NMR (DMSO-d6): 1.42(s, 9H), 3.25(m, 4H), 3.48(m, 4H), 7.18(3,1H), 8.03(m, 2H).
72%
for 16 h; Heating / reflux
Preparation 57; 4-(2-Fluoro-4-nitro-phenyl)-piperazine- 1 -carboxylic acid tert-bvXyl ester; Dissolve 3,4-difluoronitrobenzene (2.0 g, 12.6 mmol) in acetonitrile (35 mL) and add piperazine-1 -carboxylic acid tert-bvAyl ester (4.7 g, 25.2 mmol). Heat the mixture at reflux for 16 h. Cool the mixture to room temperature and concentrate in vacuo. Partition the residue between dichloromethane (75 mL) and water (75 mL), separate the organic portion and extract the aqueous portion with dichloromethane (2 x 25 mL).Combine the organics and dry (Na2SO4), filter, and concentrate in vacuo to give 2.83 g (72percent) of the title compound. MS/ES m/z 270.2 [M-tertBu+H]+.
Reference：
[1] Patent: WO2009/79597, 2009, A1, . Location in patent: Page/Page column 58-59
[2] Patent: WO2011/37731, 2011, A1, . Location in patent: Page/Page column 113-114
[3] Patent: US2011/306606, 2011, A1, . Location in patent: Page/Page column 15
[4] Patent: EP2394993, 2011, A2, . Location in patent: Page/Page column 23
[5] Patent: WO2007/146758, 2007, A2, . Location in patent: Page/Page column 53
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1302 - 1305
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5552 - 5556
[8] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[9] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0251; 0252
[10] Chemical Papers, 2018, vol. 72, # 2, p. 457 - 468
23
[ 369-34-6 ]
[ 154590-34-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4261 - 4267
[2] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 120 - 131
[3] Patent: CN107033095, 2017, A,
24
[ 369-34-6 ]
[ 337529-74-5 ]
Reference：
[1] Patent: WO2013/68461, 2013, A1,
25
[ 369-34-6 ]
[ 168268-00-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3353 - 3358
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6674 - 6679
[3] Patent: CN108069919, 2018, A,
[4] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 814 - 831
26
[ 369-34-6 ]
[ 221198-99-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 16, p. 4981 - 4991
[2] Patent: WO2014/12360, 2014, A1,
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 43 - 56
[4] Patent: WO2014/151871, 2014, A2,
[5] Patent: US2015/87639, 2015, A1,
[6] Patent: TWI607995, 2017, B,
Reference：
[1] Organic Process Research and Development, 2014, vol. 18, # 4, p. 501 - 510
[2] Organic Process Research and Development, 2018, vol. 22, # 3, p. 409 - 419
Step A Synthesis of 2-fluoro-4-nitroaniline as an intermediate A mixture of 10.0 grams (0.063 mole) of 3,4-difluoronitrobenzene and 40 mL of aqueous 29% ammonium hydroxide was placed in a pressure bottle and sealed. The mixture was stirred and heated at 135 C. for about 18 hours. The bottle and contents were then cooled and the bottle opened. A solid was collected by filtration and washed, first with water and then with petroleum ether. The solid was dried, yielding 9.4 grams of 2-fluoro-4-nitroaniline.
Step 4: Preparation of 3-fluoro-4-methoxyaniline (8) Metallic sodium (1.45 grams, 63 mmol) was added slowly and portion wise to pre cooled (10 C.) methanol (100 mL) with stirring under nitrogen atmosphere. The mixture was stirred at room temperature until all the sodium metal gets dissolved. To this was added 3,4-difluoro nitrobenzene (6) (10 grams, 63 mmol) at room temperature and stirring continued at the same temperature for 2-3 hours. The mixture was then concentrated under vacuum and poured into ice-water (100 mL). The pH of the mixture was adjusted to ~7 by adding 2N HCl with stirring. The solid separated was filtered off, washed with water and dried under vacuum to afford the product 2-fluoro-4-nitroanisol (7) (9.75 grams). Yield: 91%; Melting point: 102-104 C.
64%
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; for 16h;
General procedure: A mixture of 2-fluorobenzamide (1a, 69.5 mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16 h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture was extracted with ethyl acetate three times (3 * 10 mL). The combined organic phases were dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05 in volume) to afford 2aa as a white solid in 80% yield (60.7 mg).
57%
With sodium hydroxide; In dimethyl sulfoxide; at 20℃; for 12h;
3,4-difluoronitrobenzene (31.88, 0.2111001), high purity NaOH (168,0.4111001), methanol (88,0.25mo 1), DMSO (200 mL) was added to the reactor and the reaction was stirred at 20 C for 12 hours. After completion of the reaction, 800 mL of ethyl acetate was added to the system and diluted 5 times with 200 mL of saturated brine. The organic phase was separated and dried over anhydrous sodium sulfateAfter which it was filtered, evaporated to dryness, and then it was loaded onto a silica gel column to separate petroleum ether: ethyl acetate = 4: 1 (volume) Was eluted as an eluent until the product appeared, the solution containing the product was collected and evaporated to dryness. After drying with a vacuum chestnut, 3-fluoro-4-methoxy nitrobenzene pure product, the yield of 57%.
I. N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline Ethyl acetate (400.0ml), 3,4-difluoronitrobenzene (lOO.Ogm) and morpholine (115.0gm) at 25-30 C were charged into RBF, raised temperature to reflux (82-85 C), stirred for 2 hours under reflux and then cooled to 25-30 C. Ethyl acetate (600.0 ml) and aqueous HC1 solution 400ml (-6%) at 25-30 C were charged to the reaction mixture and then layers were separated. To the organic layer, methanol (200.0 ml) and ammonium formate (156.24 gm) were charged at 25-30C (N2blanketing). 10% Pd/C (11.0 gm) was charged to the reaction mixture at 25-30C (Temperature raise to 40-50C due to exothermic reaction) and Stirred at 45-50C for 2hrs. The reaction mixture was cooled to 25-30C, charged water (200.0 ml) and filtered over highflow bed to remove Pd/C and washed the highflow bed with water (200.0 ml). The separated organic layer was concentrated under vacuum at 35-40 C to get thick slurry (NLT 650 mmHg). Acetone (200.0 ml) was charged to the reaction mass and concentrated at 35-40C to get thick slurry (NLT 650 mmHg). Acetone (1700.0ml) water (900.0 ml) and sodium bicarbonate (103. Ogm) were charged at 25-30C to the reaction mixture and then cooled to 0-5 C. Benzyl chloroformate (115. Ogm) was added at 0-8C within 5 mins and stirred at 0-5C for lhour. Water (3000.0ml) was charged into reaction mass under agitation at 0-5C, agitate for 30 mins at 20-25C, filtered the solid and washed with water (2x600.0ml) followed by hexane (2x300.0ml). The solid was dried in air oven at 25-30C for 30mins followed by at 45-50C to obtain titled compound.Dry Wight: 180-190 gm
With triethylamine; In acetonitrile; at 20℃; for 72.0833h;
To rac-2-methylpiperazine (2.64 g, 23.1 mmol) in acetonitrile (50 mL) was added triethylamine (1.95 g, 2.7 mL, 19.2 mmol) followed by 3,4-difluoronitrobenzene (1 g, 7.7 mmol) dropwise over 5 min under a nitrogen atmosphere. The resulting yellow solution was allowed to stir at room temperature for 3 days. Excess acetonitrile was removed by evaporation under reduced pressure and the residue reconstituted in DCM (SOML), washed with water (2X50ML), dried (MGS04) and concentrated to afford the title compound as a yellow solid. LC-MS (UV 215nm) : 100%; m/z 240. 19; 0.91 MIN. 1HNMR (CDC13) : 1.13 (3H, d, J6.4), 2.56 (1H, dd, J 10.2 11.7), 2.91-2. 99 (1H, m), 3.00-3. 13 (3H, m), 3.52-3. 59 (2H, m), 6.91 (1H, T, J 8. 8), 7. 85-8. 01 (2H, m).
With triethylamine; In acetonitrile; at 20℃; for 72.0833h;
4- (4-Amino-2-fluorophenyl)-1, 2-dimethylpiperazine; 4- (2-Fluoro-4-nitrophenyl)-2-methylpiperazine; To rac-2-methylpiperazine (2.64 g, 23.1 mmol) in acetonitrile (50 mL) was added triethylamine (1.95 g, 2.7 mL, 19.2 mmol) followed by 3,4-difluoronitrobenzene (1 g, 7.7 mmol) dropwise over 5 min under a nitrogen atmosphere. The resulting yellow solution was allowed to stir at room temperature for 3 days. Excess acetonitrile was removed by evaporation under reduced pressure and the residue reconstituted in DCM (50mL), washed with water (2x50mL), dried (MgS04) and concentrated to afford the title compound as a yellow solid. LC-MS (UV 215nm) : 100%; m/z 240. 19; 0.91 min. IH NMR (CDC13) : 1.13 (3H, d, J6. 4), 2.56 (1H, dd, J 10.2 11.7), 2.91-2. 99 (1H, m), 3.00-3. 13 (3H, m), 3.52-3. 59 (2H, m), 6.91 (1H, t, J 8.8), 7.85-8. 01 (2H, m).
With dipotassium hydrogenphosphate; In DMF (N,N-dimethyl-formamide); at 85℃; for 60h;
Intermediate 22: 1- (2-Fluoro-4-nitro-phenyl)-4-methvl-1, 2, 31-triazole; A mixture of 4-methyl- [1, 2,3]-triazole (60 g, 0.72 mol), K2HP04 (250 g, 1.44 mol) and 3,4- difluoronitrobenzene (80 ml, 0.723 mol) in DMF (3.4 litres) was stirred at 85C under N2 for 2.5 days. After removal of DMF in vacuo, the residue was chromatographed on silica gel with 0-5% ethyl acetate in dichloromethane to give the title compound as a light yellow solid (38.3 g, 24%). The other two isomers were also isolated. 1H-NMR (CDCl3) No. _5 : 8 8.35 (m, 1H) ; 8.23 (m, 2H); 7.98 (dd, 1H); 2.48 (d, 3H)
3-Fluoro-4-(3-cyano-1-pyrrolyl)nitrobenzene <strong>[7126-38-7]3-Cyanopyrrole</strong> (3.6 g, 39.1 mmol, CE Loader et al, Can. J. Chem., 1981, 59, 2673) and 3,4-difluoronitrobenzene (6.5 g, 40.9 mmol) were dissolved in DMF (50 ml) and cooled in an ice-bath. The mixture was stirred and sodium hydride (60percent in oil, 1.6 g, 40 mmol) added over 20 minutes. After allowing the mixture to come to ambient temperature, it was heated to 65° for 1 hour. Solvent was evaporated, the residue triturated with water, and filtered. The crude solide was purified by flash chromatography on silica, eluding with dichloromethane. Relevant fractions were combined to give the title product (3.75 g), mp 117-119°. MS (ESP): 230 (MH-) for C11H6FN3O2 NMR (CDCl3) delta: 6.68 (s, 1H); 7.09 (m, 1H); 7.61 (overlapping m, 2H); 8.20 (overlapping m, 2H).
N-carbomethoxy-3-fluoro-4-morpholinylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
palladium; In tetrahydrofuran; methanol; n-heptane; water; toluene;
Step B N-Carbomethoxy-3-fluoro-4-morpholinylaniline (Compound I, R1=3-Fluoro-4-morpholinylphenyl) 3,4-Difluoronitrobenzene (24.967 g, 156.94 mmol) was added to a mixture of morpholine (60.0 ml, 688 mmol, 4.38 eq) in THF (30 ml) at -6 C. The mixture was permitted to warm to 10 over 2 hrs, then maintained at 10 C. for 1/2 hr. A mixture of <strong>[5949-29-1]<strong>[5949-29-1]citric acid</strong> monohydrate</strong> (75 g, 357 mmol, 2.27 eq) in water (365 ml) was added with concomitant exotherm to 280. The phases were separated, and the aqueous washed with toluene (95 ml). The organic phases were washed with water (315 ml), the aqueous back wash extracted with toluene (95 ml), and concentrated under reduced pressure. Toluene (76 ml) and methanol (60 ml) were added, followed by palladium on carbon (5%, 50% water wet, 3.1370 g, 0.7371 mmol, 0.00470 eq), and the mixture sealed in a Parr shaker. Hydrogen pressure (40 PSI) was applied and maintained while agitating for 4.5 hrs. The catalyst then was removed by filtration under reduced pressure, and washed with toluene (100 ml). The mixture was cooled to 2 C., and a mixture of aqueous potassium carbonate (47%, 17.1 ml, 85 mmol, 0.54 eq) and water (150 ml) was added. Methyl chloroformate (16.4 ml, 212 mmol, 1.35 eq) then was added while maintaining the temperature at about 3-3.5. The resultant slurry was permitted to warm to 20-25 C., then stirred 17 hrs. The mixture is warmed to 75 to give a solution, then cooled to 46, heptane (333 ml) added, then the mixture cooled to 0 C., the precipitate collected by filtration with reduced pressure, washed with heptane (100 ml cooled to 5 C.) then water (230 ml cooled to 5 C.), and dried to give Compound I, wherein R1=3-fluoro-4-morpholinylphenyl, TLC (silica gel; methanol/methylene chloride, 5/95) Rf=0.74 (one spot); 1H-NMR (CDCl3) delta: 3.03, 3.76, 3.86, 6.75, 6.87, 6.98, 7.27; CMR (CDC13) 51.18, 52.42, 67.03, 107.81, 114.56, 119.00, 133.25, 135.77, 154.07, 155.70.
palladium; In tetrahydrofuran; methanol; n-heptane; water; toluene;
Step A 3-Fluoro-4-morpholinylaniline 3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) was added to a mixture of morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at 14 C. The mixture was permitted to warm to 10 C., then maintained at 10-13 C. for 1 hr. A mixture of <strong>[5949-29-1]<strong>[5949-29-1]citric acid</strong> monohydrate</strong> (75 g, 357 mmol, 2.25 eq) in water (365 ml) was added with a concomitant exotherm to 28 C. The phases were separated, and the aqueous phase was washed with toluene (95 ml). The organic phase was washed with water (315 ml), then concentrated under reduced pressure. Toluene (46 ml) and methanol (60 ml) were added, followed by palladium on carbon (5%, 50% water wet, 3.1603 g, 0.7426 mmol, 0.00469 eq), and the mixture was sealed in a Parr shaker. Hydrogen pressure (40 psi) was applied and maintained while agitating for 42 min. The catalyst then was removed by filtration under reduced pressure, and washed with toluene (60 ml). Heptane (150 ml) added to the filtrate and the resultant slurry concentrated under reduced pressure. Heptane (300 ml) was added, and the precipitate collected by filtration under reduced pressure, washed with heptane, and dried to give the title compound, HPLC (stationary phase is 4.6*250 mm Zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 um) RT=1.08 min, >99.3 area); 1H-NMR (Pyridine-d5) delta: 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90; CMR (Pyridine-d5) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and 157.72.
3-fluoro-4-(4-methyl-3-oxopiperazin-1-yl)nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 2-Methylpentane; ethyl acetate; acetonitrile;
N,N-Diisopropylethylamine (11.5 ml) and 1-methyl-2-oxopiperazine (4.12 g) were added to a solution of 3,4-difluoronitrobenzene (1.82 ml) in acetonitrile (100 ml), and the mixture heated to reflux for 16 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 100percent ethyl acetate in iso-hexane. Relevant fractions were combined and evaporated to give 3-fluoro-4-(4-methyl-3-oxopiperazin-1-yl)nitrobenzene (3.37 g). MS (CI): 254 (MH+). NMR (DMSO-D6) delta: 3.06 (s,3H); 3.53 (t,2H); 3.67 (t,2H); 3.97 (s,2H): 6.90 (t,1H); 7.95 (dd,1H); 8.02 (m,1H).
With sodium hydroxide; N-ethyl-N,N-diisopropylamine; In water; acetonitrile;
Reference example 7 3-Fluoro-4-(4-methoxypiperidin-1-yl)nitrobenzene To a solution of 15.0 g of 3,4-difluoronitrobenzene and 41 ml of N,N-diisopropylethylamine in 150 ml of dried acetonitrile, 15.8 g of <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> was added, and the mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure, the residue was added with water and 10% aqueous sodium hydroxide, and the resulting alkaline mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 24.1 g of a yellowish brown liquid. NMR spectrum (DMSO-d6) delta ppm: 1.54-1.62(2H,m),1.92-2.00(2H,m),3.08-3.16(2H,m),3.28(3H,s),3.38-3.46(1H,m),3.49-3.5 7(2H,m),7.16(1H,t,J=8.5Hz),7.95(1H,dd,J=14,3Hz),7.97(1H,dd,J=8.5,3Hz) IR spectrum nu (liq.) cm-1: 1336,1518 Mass spectrum (m/z): 254(M+)
With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 60℃; for 3h;
A solution of <strong>[64051-79-2]3-hydroxypiperidine hydrochloride</strong> (1.0 g, 7.267 mmol), 3, 4- difluoronitrobenzene (1.15 g, 7.267 mmol) and K2CO3 (1.205 g, 8.72 mmol) in anhydrous DMF was stirred at 50-60 0C for 3 h. At the end of this period TLC showed complete reaction. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated solution of NaCl (50 mL), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure to afford desired product in quantitative yield. The product was used without further purification. GC-MS m/z 240 [M+].
With N-ethyl-N,N-diisopropylamine; In ethanol; at 0 - 20℃; for 12h;
2 g (12.6 mmol) 3,4-difluoronitrobenzene is dissolved in 1.6 ml of ethanol, 2.4 mL (15.1 mmol, 1.2 eq) Huenig base is added and then 1.44 g (12.6 mmol, 1 eq) hexahydro-1-methyl-1H-1.4-diazepine is added dropwise while cooling with ice. After about 12 h stirring at RT the reaction is complete. Then methanol and 50 mL silica gel are added, the volatile constituents are eliminated in vacuo and the mixture is purified by column chromatography (DCM/MeOH 97/3 to 85/15 in 35 min). 3 g (11.9 mmol, 94%) of the nitro compound is obtained. Rf=0.39 (silica gel, DCM:MeOH:NH3 9:1:0.1) MS-ESI+: 253 (M+H)+
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 13h;
To a stirred solution of <strong>[475058-41-4](3S)-piperidin-3-ol hydrochloride</strong> (2.000 g, 0.01453 mol) in N,N- dimethylformamide (17.46 mL, 0.2256 mol) were added l,2-difluoro-4-nitrobenzene (2.43 g, 0.0153 mol) and potassium carbonate (5.02 g, 0.0363 mol). The stirring continued at 90 C for 13 h. After the reaction mixture was cooled, the mixture was diluted with EtOAc and washed with water and brine. The organic layers were dried and concentrated in vacuo. The resultant residue was used in the next step (3.35 g, 95%). An analytically pure sample was purified on RP-HPLC. LCMS (M+H): 241.2.
Step A: 1 '-(2-Fluoro-4-nitrophenyl)-1 ,4'-bipiperidine; <n="236"/>To a solution containing 2.0 ml_ (18.1 mmol) of 1 ,2-difluoro-4-nitrobenzene and 20 ml. of THF was added 3.3 g (19.9 mmol) of 1 ,4'-bipiperidine and 5.8 mL (41.6 mmol) of TEA. The reaction mixture was allowed to stir at rt overnight and partitioned between EtOAc and H2O. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to silica gel chromatography to give 3.9 g (68percent) of 1'-(2-fluoro-4-nitrophenyl)-1 ,4'-bipiperidine as a bright yellow solid: 1H-NMR (400 MHz, DMSO-d6) delta 7.98 (d, J = 11.4 Hz, 2 H), 7.15 (t, J = 9.1 Hz, 1 H), 3.72 (d, J = 12.1 Hz, 2 H), 2.90 (t, J = 12.2 Hz, 2 H), 2.40 - 2.48 (m, 5 H), 1.81 (d, J = 14.1 Hz, 2 H), 1.55 (dd, J = 12.1 and 3.3 Hz, 2 H), 1.45 - 1.51 (m, 4 H), and 1.37 (dt, J = 10.7 and 5.3 Hz, 2 H); MS (ESI): 308.17 (M+H+).
1-(2-Fluoro-4-nitro-phenyl)-3-methyl-1H-[1,2,4]triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium hydrogenphosphate trihydrate; In dimethyl sulfoxide; at 70℃; for 6h;
a) 1-(2-Fluoro-4-nitro-phenyl)-<strong>[7170-01-6]3-methyl-1H-[1,2,4]triazole</strong>; 3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in 1 dimethyl sulfoxide (5 mL) were stirred for 6 hours at 70 C. The mixture was concentrated in vacuo; the residue was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried over magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (261 mg, 36%) as white crystals MS ISP (m/e): 223.3[(M+H)+]. 1H NMR (CDCl3, 300 MHz): delta (ppm)=8.72 (d, 1H), 8.20 (m, 3H), 2.52 (s, 3H). Mp 105-107 C.
With potassium hydrogenphosphate trihydrate; In dimethyl sulfoxide; at 70℃; for 6h;
a) 1-(2-Fluoro-4-nitro-phenyl)-5-methyl-1H-[1,2,4]triazole; 3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in dimethyl sulfoxide (1.5 mL) were stirred for 6 hours at 70 C. The mixture was concentrated in vacuo; the residue was diluted in water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried with magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (160 mg, 22%) as white crystals MS ISP (m/e): 223.2[(M+H)+]. 1H NMR (CDCl3, 300 MHz): delta (ppm)=8.22 (m, 2H), 8.04 (s, 1H), 7.74 (dd, 1H), 2.48 (d, 3H). Mp 56-58 C.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 4.0h;
Preparation 7 6-Bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole A mixture of <strong>[1206800-18-1]6-bromo-5-hydroxy-1H-indazole</strong> (7.0 g, 33.0 mmol), 3,4-difluoronitrobenzene (4.98 mg, 31.0 mmol), NaHCO3 (2.5 g, 31.0 mmol) in DMF (100 mL) is stirred at 80 C. for 4 hours. Then LiCl (10% aqueous solution) is added and the solution is extracted with EtOAc. The organic phase is dried over anhydrous MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluding with PE:DCM (1:1) to give the desired product (5.5 g, 46.6% yield). MS (m/z): 354.0 (M+H).
1-(2-Fluoro-4-nitro-phenyl)-3-methyl-1H-[1,2,4]triazole[ No CAS ]
[ 1185019-89-9 ]
Yield
Reaction Conditions
Operation in experiment
17%; 15%
With sodium hydrogencarbonate; In dimethyl sulfoxide; at 80℃; for 48h;
A mixture of 3-methyl-lH-l,2,4-triazole (15.0 g, 181 mmol), 1,2- difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80 0C for 48 h . The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford l-(2-fluoro- 4-nitrophenyI)-3-methyl-lH-l,2>;4-triazole (7.2 g, 30.8 mmol, 17 % yield) as an off- white solid. Pure fractions of the more polar regioisomer were combined and concentrated to afford l-(2~fluoro-4-nitrophenyl)-5-methyl-lH-l52,4-triazoIe (6.23 g, 28.0 mmol, 15 % yield) as an off-white solid. Data for l-(2-fluoro-4-nitrophenyl)-5-methyHH-l,2,4-triazole: LC-MS(M+H)+ = 223.1. 1HNMR (500 MHz, chloroform-*/) delta ppm 8.18 - 8.24 (m, 2 H) 8.04 (s, 1 H) 7.69 - 7.78 (m, 1 H) 2.47-2.53 (m, 3 H).Data for 1 -(2-fluoro-4-nitrophenyl)-3 -methyl- 1 H- 1 ,2,4-triazole: LC-MS (M+H)+ = 223.1. 1H NMR (500 MHz, chloroform-tO delta ppm 8.73 (d, J-2.7 Hz5I H), 8.15 - 8.26 (m, 3 H), 2.53 (s, 3 H).
17%; 15%
With sodium hydrogencarbonate; In dimethyl sulfoxide; at 80℃; for 48h;
A mixture of 3 -methyl- IH-1, 2,4-triazole (15.0 g, 181 mmol), l,2-difluoro-4- nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80 0C for 48 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford l-(2-fluoro-4-nitrophenyl)-3-methyl-lH-l,2,4-triazole (7.2 g, 30.8 mmol, 17 % yield) as an off-white solid. Pure fractions of the more polar regioisomer were combined and concentrated to afford l-(2-fluoro-4-nitrophenyl)-5-methyl-lH-l,2,4-triazole (6.23 g, 28.0 mmol, 15 % yield) as an off-white solid. Data for l-(2-fluoro-4-nitrophenyl)-3- methyl-lH-l,2,4-triazole: LC-MS (M+H)+ = 223.1. 1H NMR (500 MHz, CDCl3) delta ppm 8.73 (d, J=2.7 Hz, 1 H), 8.15 - 8.26 (m, 3 H), 2.53 (s, 3 H).
17%; 15%
With sodium hydrogencarbonate; In dimethyl sulfoxide; at 80℃; for 48h;
A mixture of 3-methyl-lH-l,2,4-triazole (15.0 g, 181 mmol), l,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80 C for 48 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford l-(2-fluoro-4-nitrophenyl)-3-methyl-lH-l,2,4-triazole (7.2 g, 30.8 mmol, 17 % yield) as an off-white solid. Data for l-(2-fluoro-4-nitrophenyl)-3-methyl-lH-l,2,4- triazole [Bl]: LC-MS (M+H)+ = 223.1. XH NMR (500 MHz, CDC13) delta ppm 8.73 (d, J=2.7 Hz,l H), 8.15 - 8.26 (m, 3 H), 2.53 (s, 3 H). Pure fractions of the more polar regioisomer were combined and concentrated to afford l-(2-fluoro-4-nitrophenyl)-5- methyl-lH-l,2,4-triazole (6.23 g, 15 % yield) as an off-white solid. Data for l-(2-fluoro- 4-nitrophenyl)-5-methyl-lH-l,2,4-triazole [CI]: LC-MS (M+H)+ = 223.1. 'H NMR (500 MHz, CDC13) delta ppm 8.18 - 8.24 (m, 2 H), 8.04 (s, 1 H), 7.69 - 7.78 (m, 1 H), 2.47- 2.53 (m, 3 H).
With caesium carbonate; In dimethyl sulfoxide; at 50℃; for 12h;
To a mixture of Bll (1 g, 4.87 mmol, 1 eq) and 1 ,2-difluoro-4-nitro-benzene (1.55 g, 9.75 mmol, 1.08 mL, 2 eq) in DMSO (10 mL) was added Cs2C03 (3.18 g, 9.75 mmol, 2 eq). The reaction mixture was stirred at 50C for 12 hours to give a brown mixture. LCMS showed the reaction was completed. The mixture was allowed to 20C, diluted with EtOAc (100 mL), washed with water (50 mL x 3) and brine (80 mL), dried over anhydrous Na2S04, filtered and concentrated to give a crude compound. The crude compound was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 10%~50%~ 100% Ethyl acetate/Petroleum ethergradient 30 mL/min) to afford B12 (1 g, 59% yield, 98.9% purity) as a yellow solid.
51.2%
With caesium carbonate; In N,N-dimethyl-formamide; acetonitrile;
Step 3) 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline A solution of 6,7-dimethoxyquinolin-4-ol (50 g, 0.244 mol) and Cs2CO3 (159 g, 0.488 mol) in CH3CN (300 mL)/DMF (300 mL) was stirred at room temperature for 30 min. 1,2-Difluoro-4-nitrobenzene (42.7 g, 0.268 mol) was then added dropwise. After stirring at rt for 3.5 h, the reaction solution was concentrated in vacuo. Ice (500 mL) was added to the residual suspension and the mixture was stirred overnight for precipitation. The solid was collected by filtration and further purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow powder (43.1 g, 51.2%). MS (ESI, pos. ion) m/z: 345.1 (M+1); LC-MS Rt: 3.394 min. 1H NMR (400 MHz, CDCl3): delta 4.04 (s, 3H), 4.07 (s, 3H), 6.56 (d, J=5.2 Hz, 1H), 7.35 (t, 1H), 7.45 (d, J=8.0 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 8.20 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 8.59 (d, J=4.8 Hz, 1H).
51.2%
A solution of 6,7-dimethoxyquinolin-4-ol (50 g, 0.244 mol) and Cs2CO3 (159 g, 0.488 mol) in CH3CN (300 mL) / DMF (300 mL) was stirred at room temperature for 30 min. 1,2-Difluoro-4-nitrobenzene (42.7 g, 0.268 mol) was then added dropwise. After stirring at rt for 3.5 h, the reaction solution was concentrated in vacuo. Ice (500 mL) was added to the residual suspension and the mixture was stirred overnight for precipitation. The solid was collected by filtration and further purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow powder (43.1 g, 51.2%). MS (ESI, pos. ion) m/z: 345.1 (M+1); LC-MS Rt: 3.394 min. 1H NMR (400MHz, CDCl3): delta 4.04 (s, 3H), 4.07 (s, 3H), 6.56 (d, J=5.2Hz, 1H), 7.35 (t, 1H), 7.45 (d, J=8.0Hz, 1H), 8.14 (d, J=9.2Hz, 1H), 8.20 (dd, J=2.4Hz, J=9.6Hz, 1H), 8.59 (d, J=4.8Hz, 1H).
40.9%
With caesium carbonate; In N,N-dimethyl-formamide; at 25℃; for 16h;
To a mixture of compound A5 (12.0 g, 58.5 mmol) in DMF (150 mL) was added compound A4, 4-difluoronitrobenzene (9.77 g, 61.4 mmol) and Cs2C03 (22.9 g, 70.2 mmol), the reaction mixture was stirred at 25 C for 16 hours. TLC showed the reaction was completed. The mixture was quenched with water (250 mL), then filtered, the filter cake was combined with above batch, purified by silica gel column (EtOAc /DCM= 1/3 to 1/1) to give 9.60 g (yield: 40.9%) of compound A6 as a yellow solid.
38.8%
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h;Microwave irradiation;
Step 1 : 4-(2-fluoro-4-nitro-phenoxv)-6,7-dimethoxv-quinoline (A1 )A mixture of 6,7-dimethoxyquinolin-4-ol (1.4g, 6.8mmol, 1.0 eq.), 3,4-difluoro- nitrobenzene (1.44g, 8.84mmol, 1.3eq.) and cesium carbonate (3.6g, 10.9mmol, 1.6eq.) in dry DMF (10mL) was heated for 1 h at 50C in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH = 100:0 to 5:1 ) to yield the desired product A1 (909mg, 2.64mmol, 38.8%) as a yellow solid. 1H NMR (400MHz, CDCI3, 300K) delta 4.04 (s, 3H), 4.06 (s, 3H), 6.55 (d, J = 5.2 Hz, 1 H), 7.34 (dd, J = 7.8 Hz, J = 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.46 (s, 1 H), 8.13 (m, 1 H), 8.19 (dd, J = 9.8 Hz, J = 2.5 Hz, 1 H), 8.58 (d, J = 5.2 Hz, 1 H). MS (ES) C17H13FN2O5 requires: 344, found: 345 (M+H)+. Furthermore an isomer (941 mg, 2.74mmol, 40.2%) was isolated as a yellow solid. MS (ES) C17H13FN205 requires: 344, found: 345 (M+H)+.
21.4%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
Add 6,7-dimethoxyquinolin-4-ol (25.00g, 121.83mmol, 1.0eq), 1,2-difluoro-4-nitrobenzene (29.10g, 182.74mmol, 1.5eq) and K2CO3 (33.70 g, 243.65 mmol, 2.0 eq.) Was added to DMF (250 mL), and the reaction was stirred at 80 C. overnight under nitrogen protection.The reaction was monitored for completeness by TLC, filtered, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated under reduced pressure. Dichloromethane (100 mL) was added, washed with water (40 mL x 4) and saturated brine (40 mL), and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EA = 1: 4 to 1: 9) to obtain the product (9.00 g, yield: 21.4%).
2.3g
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
The <strong>[13425-93-9]6,7-dimethoxy-quinoline-4-ol</strong> (5.0g), cesium carbonate (1.3g) and 1,2-difluoro-4-nitrobenzene (3.5 ml) is added to DMF (20 ml) in, and the mixture in stirring the mixture at room temperature for 6 hours. The reaction solution is diluted with ethyl acetate, the organic layer is then washed with water. The aqueous layer is extracted with ethyl acetate twice, and the combined organic layer with saturated aqueous salt solution washing, and drying with anhydrous sodium sulfate. The organic layer is concentrated. The resulting residue with silica gel column chromatography (hexane: ethyl acetate = 1:1 ? 0:100) purification, to obtain the title compound (2.3g), which has the following physical property value.
With triethylamine; In methanol; at 50 - 60℃; for 24h;
3-11-1:Preparation of [3-fluoro-4-(3-carbamoylpiperidino)]nitrobenzeneTo 50 ml of methanol were sequentially added 5 g (31.4 mmol) of 3,4-difluoronitrobenzene, 5.26 ml (37.7 mmol) of triethylamine and 4.4 g (34.6 mmol) of <strong>[4138-26-5]nipecotamide</strong>, followed by reaction at a temperature of 50 to 60° for 24 hours.After the reaction was complete, the reaction liquid was cooled to room temperature.The resulting solid was filtered, washed with about 50 ml of methanol and then dried under vacuum at about 40° to afford 5.7 g (yield: 76percent) of the desired compound.Mass (M+): 268.11H-NMR (DMSO-d6): 1.56(t, 2H), 1.74(m, 1H), 1.89(m, 1H), 2.48(m, 1H), 2.88(m, 1H), 2.96(m, 1H), 3.64(m, 2H), 6.91(s, 1H), 7.15(m, 1H), 7.38(s, 1H), 7.95(m, 2H).
76%
With triethylamine; In methanol; at 50 - 60℃; for 24h;
Example 3-11-1 Preparation of [3-fluoro-4-(3-carbamoylpiperidino)]nitrobenzene To 50ml of methanol were sequentially added 5g (31.4mmol) of 3,4-difluoronitrobenzene, 5.26ml (37.7mmol) of triethylamine and 4.4g (34.6mmol) of <strong>[4138-26-5]nipecotamide</strong>, followed by reaction at a temperature of 50 to 60°C for 24 hours. After the reaction was complete, the reaction liquid was cooled to room temperature. The resulting solid was filtered, washed with about 50ml of methanol and then dried under vacuum at about 40°C to afford 5.7g (yield: 76percent) of the desired compound. Mass (M+): 268.1 1H-NMR (DMSO-d6): 1.56(t, 2H), 1.74(m, 1H), 1.89(m, 1H), 2.48(m, 1H), 2.88(m, 1H), 2.96(m, 1H), 3.64(m, 2H), 6.91(s, 1H), 7.15(m, 1H), 7.38(s, 1H), 7.95(m, 2H).
4-(2-fluoro-5-nitro-phenoxy)-6,7-dimethoxy-quinoline[ No CAS ]
[ 516526-44-6 ]
Yield
Reaction Conditions
Operation in experiment
40.2%; 38.8%
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h;Microwave irradiation;
Step 1: 4-(2-fluoro-4-nitro-phenoxy)-6,7-dimethoxy-quinoline (A1) A mixture of 6,7-dimethoxyquinolin-4-ol (1.4g, 6.8mmol, 1.0 eq.), 3,4-difluoronitrobenzene (1.44g, 8.84mmol, 1.3eq.) and cesium carbonate (3.6g, 10.9mmol, 1.6eq.) in dry DMF (10mL) was heated for 1 h at 50C in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH = 100:0 to 5:1) to yield the desired product A1 (909mg, 2.64mmol, 38.8%) as a yellow solid. 1H NMR (400MHz, CDCl3, 300K) delta 4.04 (s, 3H), 4.06 (s, 3H), 6.55 (d, J = 5.2 Hz, 1H), 7.34 (dd, J = 7.8 Hz, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.46 (s, 1H), 8.13 (m, 1H), 8.19 (dd, J = 9.8 Hz, J = 2.5 Hz, 1H), 8.58 (d, J = 5.2 Hz, 1H). MS (ES) C17H13FN2O5 requires: 344, found: 345 (M+H)+. Furthermore an isomer (941 mg, 2.74mmol, 40.2%) was isolated as a yellow solid. MS (ES) C17H13FN2O5 requires: 344, found: 345 (M+H)+.
To a solution of 4 (500 mg, 3.85 mmol) in ethylacetate, triethylamine (973 mg, 9.63 mmol) is added and stirred at 25 C for 10 min. The reaction mixture is cooled to 0 C and 3, 4- difluoronitrobenzene (612 mg, 3.85 mmol) is added dropwise and allowed to stir at 25 C for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc and the solvent is removed. The product is purified by column chromatography using hexanes-EtOAc mixtures to obtain the product as a crystalline yellow solid 9 (721 mg) in 70% isolated yield. 1H NMR (50 MHz, CDC13): delta 7.93-7.84 (m, 2 H), 6.86 (t, J = 4 Hz, 1 H), 3.70-3.67 (m, 4 H), 0.91- 0.85 (m, 4 H), 0.12 (s, 6 H). 13C NMR (100 MHz, CDC13): delta 151.12 (d, J = 246.71 Hz), 144.43 (d, J = 7.13 Hz), 137.84 (d, J = 8.59 Hz), 121.45, 1 15.90 (d, J = 4.61 Hz), 113.18 (7 = 27.78 Hz), 49.44, 13.79, -2.85.
70%
To a solution of 4 (500 mg, 3.85 mmol) in ethylacetate, triethylamine (973 mg, 9.63 mmol) is added and stirred at 25 C. for 10 min. The reaction mixture is cooled to 0 C. and 3,4-difluoronitrobenzene (612 mg, 3.85 mmol) is added dropwise and allowed to stir at 25 C. for 6 h. Water is then added and the organic layer is separated. The aqueous layer is extracted with EtOAc and the solvent is removed. The product is purified by column chromatography using hexanes-EtOAc mixtures to obtain the product as a crystalline yellow solid 9 (721 mg) in 70% isolated yield. 1H NMR (50 MHz, CDCl3): delta 7.93-7.84 (m, 2H), 6.86 (t, J=4 Hz, 1H), 3.70-3.67 (m, 4H), 0.91-0.85 (m, 4H), 0.12 (s, 6H). 13C NMR (100 MHz, CDCl3): delta 151.12 (d, J=246.71 Hz), 144.43 (d, J=7.13 Hz), 137.84 (d, J=8.59 Hz), 121.45, 115.90 (d, J=4.61 Hz), 113.18 (J=27.78 Hz), 49.44, 13.79, -2.85.
28.1 g
4,4-Dimethyl azasilinane hydrochloride (19.3 g, 105.8 mmol) and triethylamine (48.2 g, 349.1 mmol) were dispersed in N,N-dimethylformamide (200 mL). The resulting mixture was stirred at room temperature for 10 min, and then transferred to an ice water bath and stirred. 3,4-Difluoronitrobenzene (16.8 g, 105.8 mmol) was added dropwise. After the completion of the dropwise addition, the resulting mixture was stirred for 30 min in an ice water bath, and then stirred at room temperature overnight. The reaction mixture was poured into 1 L of water, stirred for 10 min, suction-filtered, and washed with a large amount of water. The resulting solid was collected and dried to give 1-(2-fluoro-4-nitrophenyl)-4,4-dimethyl-1,4-azasilinane (28.1 g). 1H NMR (300 MHz, DMSO-d6): delta7.91-7.95 (m, 2H), 7.10-7.14 (m, 1H), 3.71-3.73 (m, 4H), 0.85-0.88 (m, 4H), 0.11 (s, 6H).
A suspension of <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)imidazole</strong> (300 mg, 2 mmol) and potassium carbonate (828 mg, 6 mmol) in 2 mL DMSO was heated at 120C for 30 min before addition of 3,4-difluoronitrobenzene (318 mg, 2 mmol). The resulting reaction mixture was heated at 120C for 3 more hours. After cooling down to room temperature, the reaction mixture was worked up with EA/brine. The organic phase was dried over sodium sulfate, concentrated and subjected to silica gel column purification using hexane and 50% EA in hexane to afford 122 (301 mg, yield: 52%, purity >95%) as a yellow solid. (LC-MS: calculated: 289.19, found:290.03).
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
To a suspension of K2C03 (5.53 g, 40 mmol) and 1,1-dioxo-thio- morpholinehydrochioride (3.60 g, 21 mmol) in DMSO (50 mL) was added 3,4-difluoronitrobenzene (3.18 g, 20 mmol). The reaction was heated at 100C for 12 h. The mixture was diluted with water (150 mL) and extracted with CH2C17 (100 mL x 2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (6.04 g, 70%).
70%
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
To a suspension of K2CO3 (5.53 g, 40 mmol) and <strong>[59801-62-6]1,1-dioxo-thio-morpholinehydrochloride</strong> (3.60 g, 21 mmol) in DMSO (50 mL) was added 3,4-difluoronitrobenzene (3.18 g, 20 mmol). The reaction was heated at 100 C. for 12 h. The mixture was diluted with water (150 mL) and extracted with CH2Cl2 (100 mL*2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (6.04 g, 70%).
70%
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 12h;
3,4-Difluoronitrobenzene (3.18 g, 20 mmol) was added to contain potassium carbonate (5.53 g, 40 mmol)In a suspension of <strong>[59801-62-6]1,1-dioxothiomorpholine hydrochloride</strong> (3.60 g, 21 mmol) in DMSO (50 mL), the temperature was raised to 100 C. and reacted for 12 h.Add water (150 mL) and extract with dichloromethane (100 mL x 2).The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a yellow solid (6.04 g, 70%).
(2S,5R)-tert-butyl 4-(2-fluoro-4-nitrophenyl)-2,5-dimethylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 192h;Inert atmosphere;
A suspension of 1,2-difluoro-4-nitrobenzene (371 mg,2.333 mmol), (2S,5R)-tert-butyl 2,5-dimethylpiperazine-1- carboxylate (500 mg, 2.333 mmol) and potassium carbonate(484 mg, 3.50 mmol) in anhydrous acetonitrile (3 mL) was heated to 100 C under a nitrogen atmosphere for 8 days. The reaction mixture was allowed to cool to room temperature, diluted with water (20 mL) and extracted into ethyl acetate (3 x 10 mL) . The combined organicphases were dried over Na2504, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (silica lOOg cartridge, cyclohexane:ethyl acetate, gradient elution from 95:5 to 60:40) to give the title compound as ayellow oil (800 mg, 97%) . ?H NMR (400 MHz, CDC13) : 0 7.97 (dd, 1H), 7.90 (dd, 1H), 6.84 (t, 1H), 4.42 (br s, 1H),
(S)-tert-butyl 4-(2-fluoro-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 21.0h;
To a stirred suspension of 1,2-difluoro-4-nitrobenzene (0.464 mL, 4.20 mmol) and potassium carbonate (2.324 g, 16.81 mmol) in anhydrous DMF (5 mL) was added <strong>[1030377-21-9](S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate</strong> (1 g,4.62 mmol) and the mixture heated at 90 C for 21 hours. After cooling the mixture was partitioned between brine/water (100 mL) and ethyl acetate (50 mL) . The aqueous was separated and extracted with ethyl acetate (3x 50 mL) . The combined ethyl acetate fractions were washed with brine/water (1:1, 4 x 25 mL), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 20-100% Ethyl Acetate inCyclohexane) to afford the title compound (1.14 g, 76 %) ?H NMR (300 MHz, CDC13) : 5 8.00 (ddd, 1H), 7.92 (dd, 1H), 6.94 (t, 1H), 4.22-4.35 (m, 1H), 4.03 (d, 1H), 3.90 (d,2H), 3.74 (d, 1H), 3.50 (d, 1H), 3.30 (t, 1H), 3.05 (dd,1H), 2.97 (td, 1H), 1.97 (br s, 1H), 1.49 (s, 9H) . LCMS(Method C) : = 1.48 mi m/z = 356 [M+H].
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
To a stirred solution of <strong>[36953-41-0]3-bromo-4-hydroxypyridine</strong> (2) (17.0g, 98.0mmol) in DMF (80.0mL) was added 3, 4-difluoronitrobenzene (13.0mL, 0.12mol) and anhydrous K2CO3 (34.0g, 0.25mol). Upon the completion of addition, the reaction mixture was heated at 80C for 2h. The mixture was cooled and poured into ice-water. The mixture was filtrated and washed with water, and then dried to give 3 as a yellow solid (20.1g, 66.1%). MS (ESI) m/z: 312.9 [M+H]+.
4-chloro-1-(2-fluoro-4-nitrophenyl)-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 4h;
A magnetically stirred mixture of 4-chloro-1H- imidazole (15.0 g, 146 mmol), i,2-difluoro-4-nitrobenzene (30 g, 189 mmol), and K2C03 (20.22 g, 146 mmol) in DMSO (50 mE) was heated at 80 C. for 4 h. The resulting dark black solution was allowed to cool to RT. The reaction contents was poured into 800 mE water and vigorously stirred for 15 mi An orange preceipitate immediately crashed out and was collected to give 4-chloro-i-(2-fluoro- 4-nitro-phenyl)-1H-imidazole (34.6 g, 98%). ?H NMR (500 MHz, CHEOROFORM-d) oe 8.23-8.16 (m, 2H), 7.81-7.78 (m, 1H), 7.61-7.56 (m, 1H), 7.26-7.25 (m, 1H). ECMS M+H=242.07.
With potassium hydroxide; In dimethyl sulfoxide; at 30 - 60℃; for 8h;
Compound 2Sa (3.0 g, 18.8 mmol), compound 2Sb (3.0 g, 13.8 mmol, 100% ee) and potassium hydroxide (2.4 g, 42.8 mmol) were added sequentially to 30 mL DMSO while stirring. The reaction mixture was heated to 30C. for 3 hours and then warmed to 60C. for 5 hours. After completion of the reaction, the system was cooled to room temperature, 300 mL of water was added, precipitation formed, and stirring was continued at room temperature overnight. Solid was collected via filtering, and and was added to 25 mL of a mixed solvent consisting of 5:1 petroleum ether:ethyl acetate, and stirred at room temperature for half an hour. The solid was collected via filtering, and was dried to give compound 2Sc (3.0 g, yield 64%) as a yellow solid. MS 336.2 [M+H]+.
64%
With potassium hydroxide; In dimethyl sulfoxide; at 30℃; for 3h;
30 mL DMSO was stirred in room temperature and was added A1Sa (3.0 g, 18.8 mmol), compound A1Sb (3.0 g, 13.8 mmol, 100% ee) and KOH (2.4 g, 42.8 mmol) in turn. The reaction mixture was heated to 30 C. and stirred for 3 hours. The reaction was cooled to room temperature when it was finished, and was added 300 mL water, then the solid was precipitated from the solution, the mixture was stirred overnight at room temperature, and was filtrated. The filtrate were added to mixed solution (petroleum ether/EAOAc=5:1, 25 mL), and stirred for half hour at room temperature, and filtrated to afford yellow solid compound A1Sc (3.0 g, yield 64%). MS 336.2 [M+H]+.
With potassium carbonate; In acetonitrile; at 70℃; for 3h;Inert atmosphere;
Add compound 6a to a 50 mL single-mouth flask equipped with magnetic stirring(750 mg, 4.72 mmol) and acetonitrile(20 mL), stirred and dissolved, and added the dihydrochloride salt of compound 2a (1.1 g, 5.66 mmol)And potassium carbonate (2.2 g, 15.57 mmol), the reaction mixture was heated to 70 C under nitrogen atmosphereThe reaction was stirred for 3 hours with heat. Cool to room temperature and distill off the solvent under reduced pressure.Add water (60 mL), precipitate a large amount of yellow solid, and filter.Washed (10 mL) and dried to obtain the yellow solid955mg,The yield was 75.9%.
3-(2-fluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With trimethylamine; In ethyl acetate; at 20℃; for 16h;
To a solution of 3,4-difluoro nitrobenzene (0.5 g, 3.14 mmol) in ethyl acetate (10 ml_), was added trimethylamine 81.3 ml_, 9.42 mmol) followed by <strong>[54745-74-3]8-oxa-3-azabicyclo[3.2.1]octane hydrochloride</strong> (0.56 g, 3.77 mmol). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was filtered, concentrated under vacuum, and the solid obtained was washed with ether to afford the title compound as yellow solid (0.7 g, 88%).1H-NMR (400 MHz, DMSO-cfe) d = 7.99-8.02 (m, 2H), 7.10 (t, J = 8.88 Hz, 1 H), 4.41 (br-s, 2H), 3.40 (d, J = 1 1.80 Hz, 2H), 3.13 (d, J = 10.64 Hz, 2H), 1.89 (br-s, 4H).MS: 253.1 (M+H)+.
(S)-4-(2-fluoro-4-nitrophenyl)-3-methyl-morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 22.25h;Inert atmosphere; Sealed tube;
In a 5 mL Biotage microwave vial, a stir bar, K2CO3 (1.096 g, 7.93 mmol), 1,2-difluoro-4-nitrobenzene (420 mg, 2.64 mmol), and <strong>[1022094-03-6](S)-3-methylmorpholine hydrochloride</strong> (400 mg, 2.91 mmol), were added, the vial sealed, and purged with Ar for 15 min. DMF (2.643 mL) was injected into the vial and heated at 80 C. for 22 h. Upon cooling, the mixture is poured into 100 mL H2O, filtered, thoroughly washed with H2O, and then hexanes. Upon cooling, the mixture is transferred to a separatory funnel, H2O was added, and the aq layer was extracted with diethyl ether and the pooled organics were washed with saturated brine and dried with Na2SO4. The solvent was evaporated to afford the product, (S)-4-(2-fluoro-4-nitrophenyl)-3-methylmorpholine 171-A as a yellow oil (597 mg, 2.484 mmol, 94% yield). 1H NMR (CDCl3) delta: 7.84 (dd, J=9.1, 2.6 Hz, 1H), 7.73 (dd, J=13.4, 2.6 Hz, 1H), 6.84 (t, J=8.8 Hz, 1H), 3.93-3.75 (m, 3H), 3.70-3.55 (m, 2H), 3.45-3.34 (m, 1H), 3.03 (dt, J=12.4, 2.8 Hz, 1H), 1.11 (d, J=6.7 Hz, 3H).
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