* 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 ammonia In methanol at 70℃; for 1.5 h; Microwave irradiation
To a solution of 1,2,4-trifluoro-5-nitrobenzene (1) (5.00 g, 28.0 mmol, 1.00 equiv) in methanol (5 mL) was added methanolic ammonia (15 mL) and taken in microwave vial. The reaction mixture was heated in microwave at 70° C. for 90 min. The reaction mixture was cooled to RT and removed the solvent from the reaction under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to furnish compound 2 (0.600 g, 12.0percent) as yellow solid. TLC: 30percent EtOAc/Hexane (Rf: 0.35); 1H NMR (500 MHz, CDCl3): δ 8.00 (t, J=9.0 Hz, 1H), 6.65-6.58 (m, 1H), 6.08 (br s, 2H).
Reference：
[1] Patent: US2013/287686, 2013, A1, . Location in patent: Paragraph 0144; 0145
[2] Journal of Medicinal Chemistry, 1965, vol. 8, p. 737 - 740
[3] Patent: US2018/185362, 2018, A1, . Location in patent: Paragraph 0556; 0557; 0558; 0559
2
[ 458-11-7 ]
[ 78056-39-0 ]
Reference：
[1] Journal of Fluorine Chemistry, 2003, vol. 121, # 2, p. 171 - 175
[2] Russian Journal of Organic Chemistry, 1998, vol. 34, # 3, p. 369 - 374
[3] Heterocycles, 1995, vol. 41, # 10, p. 2203 - 2220
[4] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1786 - 1792
[5] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 6, p. 1517 - 1523
[6] Patent: US4855292, 1989, A,
[7] Patent: US4874764, 1989, A,
[8] Patent: US4880806, 1989, A,
4,5-Difluoro-2-nitro-aniline (10 g, 57 mmol) and 10percent palladium on carbon (2.0 g, 1.9 mmol) were placed in methanol (150 mL). The mixture was hydrogenated at 50 psi in a hydrogenator. After 3 hours the reaction mixture was filtered through diatomaceous earth and concentrated to a solid which was dried overnight (8.05 g, 98percent).
97%
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 12 h;
Step 1: A mixture of 4,5-difluoro-2-nitroaniline (1.73 g, 10 mmol), palladium on activated charcoal (200 mg),and MeOH (50 mL) was stirred under hydrogen (1 atm) at rt for 12 h. The mixture was filtered to remove the catalystand the filtrate was concentrated under reduced pressure to afford 4,5-difluorobenzene-1,2-diamine (1.42 g, 97percent) as abrown solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 6.50 (m, 2H), 2.75 - 3.48 (br s, 4H).
62%
With tin(ll) chloride In ethanol at 20℃; for 0.5 h; Heating / reflux
A mixture of 4,5-difluoro-2- nitro-phenylamine (10.00 g, 57.46 mmol) and tin(II) chloride dihydrate (64.83 g, 287.32 mmol) in ethanol (100 mL) was heated to reflux under nitrogen atmosphere for 30 min. After mixture was cooled down to room temperature, the pH of the solution was made basic (10 to 12) by addition of 5percent of sodium hydroxide solution. The solution was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate. Solvent was removed under reduced pressure and the residue was crystallized in hexane to give a white solid (6.05 g, 62percent). 1H NMR (300 MHz, CDC13): 6 6.53 (t, J= 8.5 Hz, 2H), 3.38 (br, 4H). HRMS: Calcd. For C6H6F2N2 144.0499, Found 144.0500.
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 3, p. 331 - 342
[2] Patent: US2005/43292, 2005, A1, . Location in patent: Page/Page column 14
[3] Patent: EP2766359, 2016, B1, . Location in patent: Paragraph 0755
[4] Journal of Medicinal Chemistry, 1997, vol. 40, # 5, p. 811 - 818
[5] Russian Journal of Organic Chemistry, 2001, vol. 37, # 4, p. 564 - 569
[6] Angewandte Chemie - International Edition, 2011, vol. 50, # 13, p. 2995 - 2998
[7] Chemistry of Materials, 2012, vol. 24, # 16, p. 3247 - 3254
[8] Journal of the American Chemical Society, 2013, vol. 135, # 45, p. 17060 - 17068
[9] Journal of Materials Chemistry A, 2013, vol. 1, # 48, p. 15535 - 15543
[10] Patent: WO2005/123737, 2005, A2, . Location in patent: Page/Page column 119
[11] Chemical and Pharmaceutical Bulletin, 1989, vol. 37, # 6, p. 1517 - 1523
[12] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
[13] Journal of Medicinal Chemistry, 1995, vol. 38, # 25, p. 4906 - 4916
[14] Farmaco, 1998, vol. 53, # 7, p. 455 - 461
[15] Patent: US2005/20606, 2005, A1, . Location in patent: Page 8
[16] Patent: WO2005/123737, 2005, A2, . Location in patent: Page/Page column 111
[17] Patent: EP1627875, 2006, A1, . Location in patent: Page/Page column 10-11
[18] Patent: US6413938, 2002, B1,
[19] Patent: US5631373, 1997, A,
[20] Patent: US6204249, 2001, B1,
[21] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 936 - 948
[22] Patent: WO2006/108103, 2006, A1, . Location in patent: Page/Page column 28-29
[23] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1156 - 1159
[24] Synthesis (Germany), 2013, vol. 45, # 2, p. 272 - 280
[25] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487
[26] Dalton Transactions, 2015, vol. 44, # 40, p. 17453 - 17461
[27] Patent: US2018/185362, 2018, A1, . Location in patent: Paragraph 0556; 0560; 0561; 0562
[28] Patent: US5514680, 1996, A,
[29] Patent: US2008/119496, 2008, A1, . Location in patent: Page/Page column 9
[30] Patent: WO2008/60301, 2008, A1, . Location in patent: Page/Page column 27-28
[31] Patent: WO2007/135527, 2007, A2, . Location in patent: Page/Page column 69-70
8
[ 78056-39-0 ]
[ 7439-89-6 ]
[ 76179-40-3 ]
Yield
Reaction Conditions
Operation in experiment
77%
With hydrogenchloride In methanol
4,5-Difluoro-1,2-phenylenediamine (10) To a solution of 5.55 g (31.876 mmole) of 4,5-difluoro-2-nitroaniline in 50 mL of MeOH, were added 100 mL of 2 N HCl and 8.90 g (159.380 mmole) of iron powder. The reaction mixture was stirred at room temperature for 2 hr and then filtered. The filtrate was neutralized with conc. NH4 OH to ~pH 8. The resulting suspension was filtered again and the filter cake was washed thoroughly with MeOH. The filtrate and washings were combined, concentrated to ~100 mL, and extracted with CHCl3 (100 mL*3). The CHCl3 solution was washed with a sat. NaCl solution (100 mL*2), dried (Na2 SO4), and evaporated. The residue was coevaporated with CHCl3 to give 3.515 g (77percent) of 10. This material was used in the next reaction without further purification. A brown crystalline sample of 10 was obtained by recrystallization from CCl4. 1 H NMR (DMSO-d6): d6.44 (t, 2,3-H and 6-H, JF-H =10.5 H), 4.59 (br. s, 4,2*NH2).
Reference：
[1] Patent: US5360795, 1994, A,
9
[ 78056-39-0 ]
[ 91895-29-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
[2] Patent: US5514680, 1996, A,
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 13, p. 2995 - 2998
[2] Journal of the American Chemical Society, 2013, vol. 135, # 45, p. 17060 - 17068
[3] Journal of Materials Chemistry A, 2013, vol. 1, # 48, p. 15535 - 15543
13
[ 78056-39-0 ]
[ 1295502-53-2 ]
Reference：
[1] Journal of Materials Chemistry A, 2013, vol. 1, # 48, p. 15535 - 15543
14
[ 78056-39-0 ]
[ 1450590-76-7 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 45, p. 17060 - 17068
With ammonia; In methanol; at 70℃; for 1.5h;Microwave irradiation;
To a solution of 1,2,4-trifluoro-5-nitrobenzene (1) (5.00 g, 28.0 mmol, 1.00 equiv) in methanol (5 mL) was added methanolic ammonia (15 mL) and taken in microwave vial. The reaction mixture was heated in microwave at 70 C. for 90 min. The reaction mixture was cooled to RT and removed the solvent from the reaction under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 1:4) to furnish compound 2 (0.600 g, 12.0%) as yellow solid. TLC: 30% EtOAc/Hexane (Rf: 0.35); 1H NMR (500 MHz, CDCl3): delta 8.00 (t, J=9.0 Hz, 1H), 6.65-6.58 (m, 1H), 6.08 (br s, 2H).
With ammonia; In methanol; at 90℃; for 2h;Inert atmosphere; Sealed tube;
To a stirred solution of 1 ,2,4-trifluoro-5-nitroben- zene (5 g, 28.24 mmol) in methanol (5 mE) under an inert atmosphere was added methanolic ammonia (15 mE) at 0 C. The reaction mixture was heated to 90 C. and stirred for 2 h in a sealed tube. After consumption of starting material (by TEC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% EtOAc/hexane) to afford 4,5-difluoro-2-nitroaniline (800 mg, 4.59 mmol, 16%) as pale yellow solid. ?H NMR (500 MHz, CDC13): oe 8.00 (dd, J=10.4,8.7 Hz, 1H), 6.60 (dd, J=11.0, 6.4 Hz, 1H), 6.09 (brs, 2H) EC-MS: m/z 172.8 [M-H] at 2.49 RT (88.25%purity)
To a suspension of commercially available <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> 24 (10 g, 57.44 mmol) in methanol (200 mL) was added KOH,2 M (60 mL, 120 mmol) and the mixture was stirred vigorously at room temperature for 20 h. The mixture was concentrated under reduced pressure, the residue was taken up in dichloromethane (500 mL) and washed with water (100 mL), dried over sodium sulfateand concentrated under reduced pressure to give the product as a yellow solid, 10.77 g (quant). MS (ESP) m/z 187 (MH+); 1H NMR(DMSO-d6) delta: 7.75 (d, 1H); 7.52 (br s, 2H); 6.63 (d, 1H); 3.87 (s, 3H).
EXAMPLE 72; Preparation of 4-fluoro-5-methoxy-2-nitroaniline; [0148] To an ice cooled 100 ml round bottom flask charged with 30 ml of methanol was added 0.40 g (17.4 mmol) of sodium. After the solution was homogeneous, Ig (5.71 mmol) of 4,5 difluoro, 2-nitro aniline was added. The solution turns a bright yellow and a precipitate slowly forms. After 1 hour the solution was concentrated and 2N HCl added to the residue. The mixture was extracted with ethyl acetate (3 X 30 ml) and the organic layers combined, dried (MgStheta4) and concentrated to yield a yellow solid.IH NMR (CDCl3): delta 7.83 (d,lH, ArH), 6.20 (d,lH,ArH), 6.18 (bs, 2H, NH2), 3.92(s,3H,CH3);MS (ESI) m/z 185 ([M-H]-);Anal, calcd for C7H7FN2O3: C:45.17 H:3.79 N:15.05 Found: C:45.77 H:3.92 N:14.05.
With hydrogen;palladium 10% on activated carbon; In methanol; under 2585.81 Torr; for 3h;
4,5-Difluoro-2-nitro-aniline (10 g, 57 mmol) and 10% palladium on carbon (2.0 g, 1.9 mmol) were placed in methanol (150 mL). The mixture was hydrogenated at 50 psi in a hydrogenator. After 3 hours the reaction mixture was filtered through diatomaceous earth and concentrated to a solid which was dried overnight (8.05 g, 98%).
97%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 760.051 Torr; for 12h;
Step 1: A mixture of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (1.73 g, 10 mmol), palladium on activated charcoal (200 mg),and MeOH (50 mL) was stirred under hydrogen (1 atm) at rt for 12 h. The mixture was filtered to remove the catalystand the filtrate was concentrated under reduced pressure to afford 4,5-difluorobenzene-1,2-diamine (1.42 g, 97%) as abrown solid, which was not purified further. 1H NMR (300 MHz, CDCl3) delta 6.50 (m, 2H), 2.75 - 3.48 (br s, 4H).
62%
With tin(ll) chloride; In ethanol; at 20℃; for 0.5h;Heating / reflux;
A mixture of 4,5-difluoro-2- nitro-phenylamine (10.00 g, 57.46 mmol) and tin(II) chloride dihydrate (64.83 g, 287.32 mmol) in ethanol (100 mL) was heated to reflux under nitrogen atmosphere for 30 min. After mixture was cooled down to room temperature, the pH of the solution was made basic (10 to 12) by addition of 5% of sodium hydroxide solution. The solution was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate. Solvent was removed under reduced pressure and the residue was crystallized in hexane to give a white solid (6.05 g, 62%). ¹H NMR (300 MHz, CDC13): 6 6.53 (t, J= 8.5 Hz, 2H), 3.38 (br, 4H). HRMS: Calcd. For C6H6F2N2 144.0499, Found 144.0500.
With hydrogenchloride; acetic acid; zinc; In water; at 0 - 20℃; for 3.08333h;
4,5-Difluoro-2-nitroaniline (5.75 g, 33.03 mmol) was dissolved in acetic acid (100 mL) and concentrated hydrochloric acid (2.3 mL), and while the mixture was vigorously stirred in an ice bath, zinc powder (6.91 g, 105.6 mmol) was added thereto over ten minutes. The resultant mixture was stirred for 20 minutes at the same temperature and then for 130 minutes at room temperature. Further, zinc powder (1.20 g, 18.35 mmol) was added thereto over five minutes at the same temperature, and the resultant mixture was stirred for 30 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with aqueous saturated bicarbonate, followed by filtration through use of Celite. The filtrate was extracted with chloroform, and the organic layer was washed with saturated brine. The product was dried over sodium sulfate anhydrate, and then concentrated under reduced pressure, to thereby yield a brown oil (4.73 g). The brown oil was dissolved in ethanol (200 mL), and potassium o-ethylxanthate (15.75 g, 98.25 mmol) was added thereto, followed by reflux for 14 hours. The reaction mixture was concentrated under reduced pressure, the residue was extracted with ethyl acetate-1-mol/L hydrochloric acid, and the organic layer was washed with saturated brine. The product was dried over sodium sulfate anhydrate and then concentrated under reduced pressure, and the residue was crystallized from chloroform-hexane, to thereby yield 5,6-difluoro-2-mercaptobenzimidazole (5.58 g, total yield 91%) as a pale brown powder.
With tin(ll) chloride; In ethanol;
4,5-Difluoro-2-nitro-phenylamine is a known compound.8 It was reduced with tin (II) chloride dihydrate in ethanol to give the 4,S-difluoro-benzene-1,2-diamine. The diamine was reacted with hexaketocyclohexane octahydrate to give [(HATNA)F6]. The product was purified by train purification (sublimation). The compound is yellow needle like crystal. It is slightly soluble in chloroform. It is very soluble in chloroform/TFA (3:1) mixture.
3,4-Difluoro-6-nitroaniline (5.75 g, 33.03 mmol) was dissolved in acetic acid (100 mL) and concentrated hydrochloric acid (2.3 mL). While the solution was vigorously stirred on an ice bath, zinc dust (6.91 g, 105.6 mmol) was added to the solution over a period of 10 minutes. The reaction mixture was stirred at the same temperature for 20 minutes and at room temperature for 130 minutes. On an ice bath, zinc dust (1.20 g, 18.35 mmol) was added to the reaction mixture over 5 minutes, followed by stirring for 30 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was neutralized with a saturated aqueous sodium bicarbonate solution, followed by filtration by use of Celite. The filtrate was extracted with chloroform, and the organic layer was washed with saturated brine. After washing, the organic layer was dried over sodium sulfate anhydrate, followed by concentration under reduced pressure, to thereby yield a brown oil (4.73 g). The brown oil was dissolved in ethanol (200 mL). Potassium xanthate (15.75 g, 98.25 mmol) was added to the solution, followed by refluxing for 14 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate-1 mol/L hydrochloric acid. The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The thus-obtained residue was recrystallized from chloroform and n-hexane, to thereby yield 5,6-difluoro-2-mercaptobenzimidazole as a pale brown powder (5.58 g, 2 steps 91%). Melting point: 296-298C
In methanol; water; ethyl acetate;
A. 4,5-Difluoro-1,2-phenylenediamine Into a Parr bottle were placed <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (5.00 g, 28.72 mmol), platinum (IV) oxide (0.31 g, 1.13 mmol) and methanol (60 mL). The bottle was flushed three times with hydrogen and was finally pressurized to 45 psig with hydrogen. The bottle was shaken for 5 h, after which time it was depressurized and the contents were poured into a separatory funnel containing ethyl acetate (300 mL) and water (300 mL). The organic layer was collected and washed with saturated aqueous brine solution (100 mL), dried over magnesium sulfate and the solvents were removed under reduced pressure using a rotary evaporator to leave 3.37 g (81%) of a brown solid. MS (Cl): m/z 145 (M+1).
With CaCl2; In ethanol; water;
Method 1. 4,5-Difluoro-1,2-diaminobenzene. 4,5-Difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Tsuji et al., (Tsuji, Y. et al., J. Org. Chem. 55:580 (1990)). Zn powder (942 mg, 14.4 mmol), CaCl2 (94.4 mg), H2 O (1.0 mL) and 4.0 mL EtOH were combined and brought to reflux as described for 4-fluoro-1,2-diaminobenzene (see Example 11) and to this mixture was added slowly dropwise a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (200 mg, 1.15 mmol) in 2 mL EtOH. Analysis and workup were as described for 4-fluoro-1,2-diaminobenzene (Example 11) except that the reaction was dissolved in 5 mL H2 O and the solution extracted with 3*10 mL Et2 O. The organic layers were combined and treated with activated charcoal, dried (MgSO4), and filtered through a pad of Celite. The solvent was evaporated at reduced pressure to yield 111.5 mg (67.3%) of a brown crystalline solid. 1 H NMR (CDCl3) delta3.34 (br s, 4H, NH2), 6.53 (t, 2H, ArH).
In methanol; water; ethyl acetate;
Example 43 4,5-Difluoro-1,2-phenylenediamine Into a Parr bottle were placed <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (5.00 g, 28.72 mmol), platinum (IV) oxide (0.31 g, 1.13 mmol) and methanol (60 mL). The bottle was flushed three times with hydrogen and was finally pressurized to 45 psig with hydrogen. The bottle was shaken for 5 h, after which time it was depressurized and the contents were poured into a separatory funnel containing ethyl acetate (300 mL) and water (300 mL). The organic layer was collected and washed with saturated aqueous brine solution (100 mL), dried over magnesium sulfate and the solvents were removed under reduced pressure using a rotary evaporator to leave 3.37 g (81%) of a brown solid. MS (Ca): m/z 145 (M+1).
With sodium dithionite; sodium hydrogencarbonate; In tetrahydrofuran; methanol; water; for 2h;
Example 4: Synthesis of 5,6-Difluoro-lH-benzo[d]imidazole EPO <DP n="31"/>EtOCH=C(CN)2 iPrOH [0088] A solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (6)(1.0 g) in 30 niL of THF was treated with a solution comprised of 6 g OfNa2S2O4 and 3 g NaHCO3 in 30 niL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-l,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6-difluoro-lH-benzo[d]imidazole (8).
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 3h;
To a stirred solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong>(800 mg, 4.59 mmol) in methanol (15 mE) under an inertatmosphere was added 10% Pd/C (50% wet, 200 mg) atroom temperature. The reaction mixture was stirred at roomtemperature under a hydrogen atmosphere (balloon pressure) for 3 h. Afier consumption of starting material (by TLC), the reaction mixture was filtered through a pad of celite and washed with methanol (15 mE) and CH2C12 (10 mE). The filtrate was concentrated under reduced pressure. The crude material was washed with n-hexane (15 mE) to afford 4,5-difluorobenzene- 1 ,2-diamine mt-i 2 (500 mg, 3.47 mmol, 80%) as a black solid. ?H NMR (500 MHz, DMSO-d5): oe 6.47-6.41 (m, 2H), 4.55 (brs, 4H) EC-MS: mlz 145 [M+H] at 1.59 RT (75.16% purity)
With CaCl2; In ethanol; water;
Method A 4,5-Difluoro-1,2-diaminobenzene 4,5-Difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Tsuji et al., (Tsuji, Y. et al., J. Org. Chem. 55:580 (1990)). Zn powder (942 mg, 14.4 mmol), CaCl2 (94.4 mg), H2 O (1.0 mL) and 4.0 mL EtOH were combined and brought to reflux as described for 4-fluoro-1,2-diaminobenzene (see Example 11) and to this mixture was added slowly dropwise a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (200 mg, 1.15 mmol) in 2 mL EtOH. Analysis and workup were as described for 4-fluoro-1,2-diaminobenzene (Example 11) except that the reaction was dissolved in 5 mL H2 O and the solution extracted with 3*10 mL Et2 O. The organic layers were combined and treated with activated charcoal, dried (MgSO4) and filtered through a pad of Celite. The solvent was evaporated at reduced pressure to yield 111.5 mg (67.3%) of a brown crystalline solid. 1 H NMR (CDCl3) delta3.34 (br s, 4H, NH2), 6.53 (t, 2H, ArH).
With sodium dithionite; water; sodium hydrogencarbonate; In tetrahydrofuran; for 2h;
Example 4 Synthesis of 5,6-Difluoro-1H-benzo[d]imidazole A solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (6)(1.0 g) in 30 mL of THF was treated with a solution comprised of 6 g of Na2S2O4 and 3 g NaHCO3 in 30 mL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-1,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6-difluoro-1H-benzo[d]imidazole (8).
With sodium dithionite; sodium hydrogencarbonate; In tetrahydrofuran; methanol; water; for 2h;
A solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (6)(1.0 g) in 30 mL of THF was treated with a solution comprised of 6 g OfNa2SaO4 and 3 g NaHCC>3 in 30 mL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of <n="29"/>ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-l,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6- difluoro-lH-benzo[d]imidazole (8).
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 3h;
Sodium methylate (54 g, 1 mol) was added to a solution of diethoxyacetonitrile (139 ml_, 1 mol) in methanol (500 ml_). The reaction mixture was kept at room temperature for 24 g, then the reaction mixture was evaporated, treated with water (500 mL), and the product was extracted with ether (2x300 mL). The combined organic extracts were dried over anhydrous K2CO3 and evaporated to give 114.62 g (60% purity) of methyl 2,2- diethoxyethanimidoate. The obtained crude product was used for the next stage without additional purification.10% Pd/C (2 g) was added to a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (40 g, 0.229 mol) in methanol (500 mL). The reaction mixture was hydrogenated at room temperature for 3 h and treated with the mixture of compound methyl 2,2-diethoxyethanimidoate (71 g, 0.23 mol) with acetic acid (60 g). After 16 h at room temperature, the reaction mixture was evaporated, washed with the 10% K2CO3 solution (1 L), and the product was extracted with ether (300 mL). The organic extract was evaporated, and the residue was purified on silica gel (ethyl acetate/hexane 1 :5) to give 48 g of 2-(diethoxymethyl)-5,6-difluoro-1H-benzimidazole. Cs2CO3 (67.21 g, 0.206 mol) and methyl iodide (27 g, 0.19 mol) were added to a solution of 2-(DiethoxymethyI)-5,6-difluoro-1H-benzimidazoIe (48 g, 0.1875 mol) in DMF (250 mL). The reaction mixture was stirred at room temperature for 16 h and evaporated. Ethyl acetate (300 mL) was added to the residue, and the reaction mixture was washed with water (1 L). The organic layer was separated, dried, and evaporated. The residue was purified on silica gel (ethyl acetate/hexane 1 :5) to give 40.8 g of 2-(diethoxymethyl)-5,6-difluoro-1-methyl- 1 /-/-benzimidazole. <n="71"/>2-(Diethoxymethyl)-5,6-difluoro-1-methyl-1W-benzimidazole was treated with 5 M HCI (300 ml_), and the reaction mixture was kept at 60 0C for 6 h. Then the reaction mixture was evaporated to a volume of 100 ml_ and treated with acetone (200 mL). Then the mixture was kept in a refrigerator, and white crystals precipitated. The crystals were separated by filtration and dried under a reduced pressure to give 5,6-Difluoro-1-methyl-1H-benzimidazole-2- carbaldehyde Hydrochloride Hydrate in 72% (26.77 g, 21.4 g of free base) yield. Satisfactory C, H, lambda/-analysis was obtained.
With hydrogenchloride; water for 3h; Inert atmosphere; Schlenk technique; Reflux;
70%
With hydrogenchloride In ethanol for 2h; Heating;
61%
With sulfuric acid for 2h; Reflux;
5.3 4,5-Difluoro-2-nitroaniline (4)
Intermediate 3 (1g, 4.6mmol) was dissolved in H2SO4 conc (10ml) under reflux (2h). Next, the reaction was quenched with ice. A precipitate was obtained, then filtered off and washed with water to reach pH. Yellow solid; C6H4F2N2O2, MW: 174.11; 61% yield (1.0g, 5.7mmol); m.p. 95.6-105.5°C; Rf 0.53.1H NMR (DMSO-d6): δ 7.99 (1H, dd, 1JH-F=11.0Hz, 2JH-F=8.4Hz, H-5), 7.56 (2H, s, NH2), 6.96 (1H, dd, 1JH-F=12.8Hz, 2JH-F=7.2Hz, H-2). 13C NMR (DMSO-d6): δ 154.67 (C, dd, 1JC-F=126Hz, 2JC-F=15Hz, C-F), 144.63 (C, d, JC-F=12Hz, C), 139.89 (C-F), 125.06 (C-NH2), 110.93 (CH-CF), 105.41 (C, d, JC-F=21Hz, CH-CF). ESI-MS m/z calcd for C6H4F2N2O2 175.03136, found 174.95352 [M+ H]+.
With sulfuric acid at 100℃; for 0.25h;
In hydrogenchloride; ethanol
R.2 4,5-Difluoro-2-nitroaniline
A solution of N-(4,5-difluoro-2-nitrophenyl)acetamide (70 g) in concentrated hydrochloric acid (110 ml) and ethanol (440 ml) was refluxed for 2 hours. The reaction mixture was poured into ice water (1.5 liter) and the resulting precipitate was collected by filtration and washed with chilled water sufficiently to give the title compound (53.2 g) as yellow prisms, mp 109°-109.5° C. Analysis (%) for C6 H4 F2 N2 O2, Calcd. (Found): C, 41.39 (41.29); H, 2.32 (2.31); N, 16.09 (15.96).
With hydrogenchloride
3 Ethyl 6,7-Difluoro-3,4-dihydro-3-oxo-2-quinoxaline Carboxylate.
A mixture of 6.51 g. of 4,5-difluoro-2-nitroacetanilide and 100 ml. of 6 N aqueous hydrochloric acid was heated to refluxing temperature for about 2 hours. The reaction mixture was then cooled. Crystals which formed were separated by filtration, and the separated crystals were washed with water, dried, and recrystallized from a hexane-dichloromethane solvent mixture. A yield of 5.0 g. of 4,5-difluoro-2-nitroaniline was obtained, melting at 106°-108° C. Analysis Calc.; C, 41.39; H, 7.32; N, 16.07. Found: C, 41.41; H, 7.35; N, 15.85.
With hydrogenchloride
3 Preparation of Ethyl 6,7-Difluoro-3,4-dihydro-3-oxo-2-quinoxaline Carboxylate
A mixture of 6.51 g. of 4,5-difluoro-2-nitroacetanilide and 100 ml. of 6 N aqueous hydrochloric acid was heated to refluxing temperature for about 2 hours. The reaction mixture was then cooled. Crystals which formed were separated by filtration, and the separated crystals were washed with water, dried, and recrystallized from a hexane-dichloromethane solvent mixture. A yield of 5.0 g. of 4,5-difluoro-2-nitroaniline was obtained, melting at 106°-108° C. Analysis Calc.: C, 41.39; H, 7.32; N, 16.07. Found: C, 41.41; H, 7.35; N, 15.85.
In hydrogenchloride; ethanol
6 Reference example 2 4,5-Difluoro-2-nitroaniline
A solution of N-(4,5-difluoro-2-nitrophenyl)acetamide (70 g) in concentrated hydrochloric acid (110 ml) and ethanol (440 ml) was refluxed for 2 hours. The reaction mixture was poured into ice water (1.5 liter) and the resulting precipitate was collected by filtration and washed with chilled water sufficiently to give the title compound (53.2 g) as yellow prisms, mp 109-109.5 °C. Analysis (%) for C6H4F2N2O2, Calcd. (Found): C, 41.39 (41.29); H, 2.32 (2.31); N, 16.09 (15.96).
With sodium hypochlorite solution; sodium hydroxide; In tetrahydrofuran; at 0℃; for 2h;
(1) Add 8.7g (0.05mol) of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> to a 500mL three-necked flask, add 75mL of tetrahydrofuran to fully dissolve it, and then add 0.6g (0.015mol) of sodium hydroxide as a catalyst. 240 mL of sodium hypochlorite was added dropwise in an ice bath (0 C), and the reaction was stirred for 2 hours.After the reaction was completed, the reaction solution was extracted twice with dichloromethane (400 mL × 2). The organic phase was collected and the solvent was distilled off under reduced pressure.7.0 g of a pale yellow solid was obtained, which is 5,6-difluoro-N-benzofurazine,The yield was 81.4%.
With sodium hypochlorite; sodium hydroxide; In tetrahydrofuran; water; at 0℃; for 2h;
[109] A mixture of compound 1 (17.4 g, 100 mmol), sodium hydroxide (1.20 g, 30.0 mmol) and tetrahydrofuran (200 mL) was cooled to 0C. Sodium hypochlorite solution (13% available chlorine, 90 mL) was added dropwise. Upon addition, the mixture was stirred at 0C for another 2 h. The mixture was diluted with water and extracted with dichloromethane for three times. The organic extract was combined and washed successively with water and a saturated solution of ammonium chloride. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product was offered as a brown solid which was used without further purification (15.4 g, 89%). An analytical sample was obtained by flash column chromatography (eluent: nhexane:dichloromethane = 3:1). ?H NMR (400 MHz, DMSO-d6) (57.98 (br, 2H). ?3C{?H} NMR (100 MHz, 353 K, DMSO-d6) (5152.7 (dd, J= 262, 21.1 Hz) 100.7 (d, J= 25.0 Hz). ?9F NMR (376 MHz, DMSO-d6) (5-122.06 (s, iF), -125.52 (s, 2F). HRMS (CI-) Calcd for C6H2F2N202 (M): 172.0084, Found: 172.0079.
Stage #1: 4,5-difluoro-2-nitroaniline With hydrogenchloride; sodium nitrite In water at 5℃; for 1h;
Stage #2: With sodium azide; sodium acetate In water at 20℃; for 3h;
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃;
Example 12N-{3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide Trifluoroacetate Stage I: 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitro-phenylamine 36.2 g of sodium bicarbonate and 28.7 mL of N-methylhomopiperazine are added to a solution of 15 g of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> in 120 mL of anhydrous DMF. The reaction medium is heated to 80 C. using an oil bath for 2H30. The reaction medium is cooled to ambient temperature, then poured into 500 mL of water. The mixture is cooled using an ice bath and stirred, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with water. The solid is dried in an oven at 40 C. 21.2 g of 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrophenylamine are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, delta in ppm): 2.22 (s, 3H); 2.45 (m, 4H); 3.17 (m, 4H); 6.42 (d, J=8.0 Hz, 1H); 7.34 (broad s, 2H); 7.63 (d, J=14.5 Hz, 1H). EI mass spectrum: m/z=254: M+. (base peak)-m/z=239: (M-CH3)+-m/z=234: (M-HF)+.-m/z=183:
With N-chloro-succinimide In N,N-dimethyl-formamide for 120h; Ambient temperature;
In acetic acid
R.3 2-Chloro-3,4-difluoro-6-nitroaniline
REFERENCE EXAMPLE 3 2-Chloro-3,4-difluoro-6-nitroaniline Into a solution of 4,5-difluoro-2-nitroaniline (20 g) in acetic acid (200 ml) was boubled chlorine gas at 13° to 15° C. during 45 minutes. The reaction mixture was poured into ice water (500 ml) and extracted with dichloromethane. The organic layer was washed with 6% aqueous sodium carbonate and with water successively, dried over anhydrous sodium sulfate and then concentrated. The residue was purified with silica gel chromatography eluding with dichloromethane-n-hexane (1:4) and further recrystallized from hexane to give the title compound (2.91 g) as yellow needles, mp 86°-88° C. Analysis (%) for C6 H3 ClF2 N2 O2, Calcd. (Found): C, 34.56 (34.58); H, 1.45 (1.37); N, 13.43 (13.41).
In acetic acid
R.3 2-Chloro-3,4-difluoro-6-nitroaniline
REFERENCE EXAMPLE 3 2-Chloro-3,4-difluoro-6-nitroaniline Into a solution of 4,5-difluoro-2-nitroaniline (20 g) in acetic acid (200 ml) was boubled chlorine gas at 13° to 15° C. during 45 minutes. The reaction mixture was poured into ice water (500 ml) and extracted with dichloromethane. The organic layer was washed with 6% aqueous sodium carbonate and with water successively, dried over anhydrous sodium sulfate and then concentrated. The residue was purified with silica gel chromatography eluding with dichloromethane-n-hexane (1:4) and further recrystallized from hexane to give the title compound (2.91 g) as yellow needles, mp 86°-88° C. Analysis (%) for C6 H3 ClF2 N2 O2, Calcd (Found): C, 34.56 (34.58); H, 1.45 (1.37); N, 13.43 (13.41).
In acetic acid
6 Reference example 3 2-Chloro-3,4-difluoro-6-nitroaniline
Reference example 3 2-Chloro-3,4-difluoro-6-nitroaniline Into a solution of 4,5-difluoro-2-nitroaniline (20 g) in acetic acid (200 ml) was boubled chlorine gas at 13 to 15 °C during 45 minutes. The reaction mixture was poured into ice water (500 ml) and extracted with dichloromethane. The organic layer was washed with 6% aqueous sodium carbonate and with water successively, dried over anydrous sodium sulfate and then concentrated. The residue was purified with silica gel chromatography eluding with dichloromethane-n-hexane (1:4) and further recrystallized from hexane to give the title compound (2.91 g) as yellow needles, mp 86-88 °C. Analysis (%) for C6H3ClF2N2O2, Calcd. (Found): C, 34.56 (34.58); H, 1.45 (1.37); N, 13.43 (13.41).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;
Example 1N-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide Hydrochloride Stage I: 4-fluoro-5-morpholin-4-yl-2-nitrophenylamineA solution of 26 g of 4,5-difluoroaniline in 500 mL of DMF is stirred at 22 C. 39 mL of morpholine and 61.3 g of sodium bicarbonate are added. The reaction medium is heated at 80 C. using an oil bath for one hour. A yellow solid precipitates. The medium is cooled to ambient temperature and then 800 mL of distilled water are added. The medium is cooled using an ice bath. The solid is filtered off, washed with water and then dried under vacuum in the presence of potassium hydroxide until the weight is constant. 35.1 g of 4-fluoro-5-morpholin-4-yl-2-nitrophenylamine are obtained in the form of a yellow solid. Melting point: 190-192 C. (Kofler bench). 1H NMR (400 MHz, (CD3)2SO, delta in ppm): 3.15 (m: 4H); 3.73 (m:4H); 6.43 (d, J=8 Hz:1H), 7.37 (broad s: 2H); 7.66 (d, J=15 Hz: 1H).
With potassium nitrate; In dichloromethane; sulfuric acid;
REFERENCE EXAMPLE 23 To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60 C. The mixture is stirred at 60 C. for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g.). NMR (CDCl3) delta: 5.76-6.40 (2H, m), 6.60 (1H, dd, J=12 Hz, 7 Hz), 7.97 (1H, dd, J=10.5 Hz, 8.5 Hz).
With potassium nitrate; In dichloromethane; sulfuric acid;
REFERENCE EXAMPLE 23 To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60 C. The mixture is stirred at 60 C. for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g). NMR (CDCl3) delta: 5.76-6.40 (2H, m), 6.60 (1H, dd, J=12 Hz, 7 Hz), 7.97 (1H, dd, J=10.5 Hz, 8.5 Hz)
With potassium nitrate; In dichloromethane; sulfuric acid;
REFERENCE EXAMPLE 23 To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850 ml) is added gradually with stirring potassium nitrate (55.5 g) at room temperature during which the temperature raises to 60 C. The mixture is stirred at 60 C. for one hour. The reaction mixture is poured into ice water, and the precipitated crystals are taken by filtration. The precipitates are dissolved in dichloromethane and washed with aqueous sodium hydrogen carbonate, water and aqueous sodium hydrogen carbonate, water and aqueous saturated sodium chloride in this order and dried. The solvent is removed by concentration and washed with n-hexane. The resulting crystals are taken by filtration and dried to give 2-nitro-4,5-difluoroaniline (54 g). NMR (CDCl3) delta: 5.76-6.40 (2H, m), 6.60 (1H, dd, J=12 Hz, 7 Hz), 7.97 (1H, dd, J=10.5 Hz, 8.5 Hz)
Example 365; (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester4,5-Difluoro-2-nitro-phenylamine (6.0 g, 34 mmol, 1 equiv.) was added to a solution of di- tert-butyl dicarbonate (14.8 g, 68 mmol, 2 equiv.) and DMAP (211 mg, 0.2 mmol, 0.05 in THF (100 mL) and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and cooled to 0 C. Trifluoroacetic acid (7.75 g, 68 mmol, 2 equiv) were added slowly and the mixture stirred for 48h at 0 C. 2 N NaOH was added to adjust the pH to 7. The organic layer was separated and evaporated. The residue was taken up in ethyl acetate and the product extracted from aq. NaHCU3. The intermediate was isolated via Kieselgel chromatography. 4.28 g (16mmol, 1 equiv.) were dissolved in DMF (50 ml) and 13 ml of a saturated NH4Cl solution added. Zink powder (5.1 g, 78 mmol, 5 equiv.) was added and the suspension stirred for 30 minutes at 800C and another 2 hours at room temperature. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from ethyl actetate and aq. NaHCtheta3 and further purified via Kieselgel chromatography.
To a solution of di-tert-butyl dicarbonate (14.8 g, 67.8 mmol, 2.0 equiv; [CAS RN 24424-99-5]) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol, 0.05 equiv; DMAP; [CAS RN 1122-58-3]) in THF (100 mL) was added 4,5-difluoro-2-nitro-phenylamine (5.9 g, 33.9 mmol, 1.0 equiv; [CAS RN 78056-39-0]) and the mixture was stirred at rt for 72 h. The solvent was evaporated under reduced pressure and the crude reaction product extracted from a sat. solution of NaHCO3 with ethyl acetate. The organic phases were dried over Na2SO4, the residue taken up in dichloromethane and cooled to 0 C. Trifluoroacetic acid (7.73 g, 67.8 mmol, 2.0 equiv) was added slowly and the reaction mixture stirred at 0 C. for 48 h. A solution of 2 N NaOH was added to adjust the pH of the solution to 7. The organic layer was separated and evaporated under reduced pressure. The residue was taken up in ethyl acetate and the product extracted from a sat. solution of NaHCO3, the organic phase dried over Na2SO4 and the intermediate isolated via Kieselgel chromatography. The purified product (4.28 g, 15.6 mmol, 1.0 equiv) was dissolved in DMF (50 mL) and a sat. solution of NH4Cl (13 mL) was added. Zinc powder (5.10 g, 78.0 mmol, 5.0 equiv) was added and the suspension stirred for 30 min at 80 C. and for an additional time period of 2 h at rt. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from a sat. solution of NaHCO3 with ethyl actetate, the organic layer dried over Na2SO4 and the crude reaction product purified via Kieselgel chromatography. 1H NMR (300 MHz, DMSO): delta1.46 ( s, 9H), 5.03 (br s, 2H), 6.65 (dd, J=8.2 Hz, J=12.9 Hz, 1H), 7.30 (dd, J=8.9 Hz, J=12.3 Hz, 1H), 8.38 (br s, 1H). MS (ISN): 243.4 [M-H]-.
Example 1; 2-[2-(3-Chloro-benzyl)-5,6-difluoro-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide; Step 1: (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester; To a solution of di-tert-butyl dicarbonate (14.8 g, 67.8 mmol, 2.0 equiv; [CAS RN 24424-99-5]) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol, 0.05 equiv; DMAP; [CAS RN 1122-58-3]) in THF (100 mL) was added 4,5-difluoro-2-nitro-phenylamine (5.9 g, 33.9 mmol, 1.0 equiv; [CAS RN 78056-39-0]) and the mixture was stirred at rt for 72 h. The solvent was evaporated under reduced pressure and the crude reaction product extracted from a sat. solution of NaHCO3 with ethyl acetate. The organic phases were dried over Na2SO4, the residue taken up in dichloromethane and cooled to 0 C. Trifluoroacetic acid (7.73 g, 67.8 mmol, 2.0 equiv) was added slowly and the reaction mixture stirred at 0 C. for 48 h. A solution of 2 N NaOH was added to adjust the pH of the solution to 7. The organic layer was separated and evaporated under reduced pressure. The residue was taken up in ethyl acetate and the product extracted from a sat. solution of NaHCO3, the organic phase dried over Na2SO4 and the intermediate isolated via Kieselgel chromatography. The purified product (4.28 g, 15.6 mmol, 1.0 equiv) was dissolved in DMF (50 mL) and a sat. solution of NH4Cl (13 mL) was added. Zinc powder (5.10 g, 78.0 mmol, 5.0 equiv) was added and the suspension stirred for 30 min at 80 C. and for an additional time period of 2 h at rt. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from a sat. solution of NaHCO3 with ethyl actetate, the organic layer dried over Na2SO4 and the crude reaction product purified via Kieselgel chromatography. 1H NMR (300 MHz, DMSO): delta1.46 (s, 9H), 5.03 (br s, 2H), 6.65 (dd, J=8.2 Hz, J=12.9 Hz, 1H), 7.30 (dd, J=8.9 Hz, J=12.3 Hz, 1H), 8.38 (br s, 1H). MS (ISN): 243.4 [M-H]-.
With sodium hydride In N,N-dimethyl-formamide at 20℃;
137.2
A mixture of Compound 137.1 (369 mg, 1.198 mmol) and 4,5-difluoro-2- nitroaniline (220 mg, 1.26 mmol) was dissolved in 5 ml dry DMF, sodium hydride (60 mg of 60% in mineral oil suspension, 1.5 mmol) was added, followed by an additional 5 ml of dry DMF. The reaction was stirred overnight at room temperature, then flooded with 80 ml EtOAc, rinsed with 2 x 40 ml water, 40 ml brine, dried over sodium sulfate, and evaporated to dryness to yield compound 137.2 as an orange solid that was used without further purification. ES (+) MS m/e = 463 (M+l).
With concentrated hydrochloric acid In NaOH; ethanol; water
4 EXAMPLE 4, 1-Carboxymethyl-6,7-difluoroquinoxaline-2,3(1H,4H)-dione
EXAMPLE 4 1-Carboxymethyl-6,7-difluoroquinoxaline-2,3(1H,4H)-dione 4,5-difluoro-2-nitroaniline (2.17 g, 12.5 mmol) was dissolved in 55 ml of ethanol and 250 mg of 10% palladium on carbon was added. The mixture was hydrogenated until the theoretical amount of hydrogen had been absorbed, using a low pressure hydrogenation apparatus. The catalyst was filtered off and the filtrate, containing 4,5-difluoro-o-phenylenediamine, was kept under a nitrogen atmosphere at 0°C followed by addition of a solution of glyoxylic acid hydrate (1.28 g, 13.7 mmol) in water (3 ml). When the addition was complete the reaction temperature was allowed to reach room temperature during 2 h and 30 ml of water was added. The precipitate was filtered off and dissolved in 60 ml of 5% NaOH solution at 50°C followed by addition of activated carbon. The mixture was filtered and the filtrate was acidified (PH = 1) by addition of concentrated hydrochloric acid. The pinky precipitate was filtered off, washed with water and dried to afford 1.25 g (55%) of 6,7-difluoroquinoxalin-2(1H)-one melting at 284-85°C. 1-NMR (DMSO-d6: 7.27 (m, 1H), 7.95 (m, 1H), 8.20 (s, 1H), 12.55 (s,1H).
With lithium hydroxide; In water; dimethyl sulfoxide; at 55℃; for 16h;
Heat a solution [OF 2-FLUORO-5-TRIFLUOROMETHYL-BENZONITRILE (L. OG,] 5.74 mmol) with <strong>[78056-39-0]4,5-difluoro-2-nitro-phenylamine</strong> (1.09g, 5.74 mmol) and lithium hydroxide monohydrate (0. [48G,] 11.49 mmol) in DMSO (12 ml) to 55 [C] for 16 hours. Cool the reaction to ambient temperature and then add approximately 150 ml of ice water and stir the mixture for one hour. Extract with three 200 ml portions of dichloromethane. Combine organic layers, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a linear gradient starting with 100% hexanes and going to 70% hexanes: 30% ethyl acetate to obtain 0.995g (2.90 mmol, 50% yield) of the title compound as a yellow amorphous solid: Mass Spectrum [(M/E)] : 344 [(M+1).]
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 50℃; for 18h;
Step 1: 4-FLUORO-2-NITRO-5- (LH-PYRROL-1-YL) benzenamine (211): [0366] To a stirred solution of 206 (500 mg, 2.87 MMOL) and pyrrole (210,239 uL, 3.44 MMOL) in DMF (10 mL), was added NaH (207 mg, 5.17 MMOL). The reaction mixture was stirred for 18 hours at 50, quenched with water (100 mL) and extracted with DCM (2X50 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluents hexanes-EtOAc 4: 1, then hexanes-EtOAc 1: 1, to afford the title compound 211 (145 mg, 25% yield).'H NMR: (DMSO) 5 : 7.94 (d, J=12.0 Hz, 1H), 7.12 (q, J=2. 4,4. 4 Hz, 2H), 7.02 (d, J=6.8 Hz, 1H), 6.32 (t, J=2. 4, 4.8 Hz, 2H). MS: (CALC.) 221.8 ; (obt.) 222.1 (MH) +.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 5h;
Step 1: 5- (L-METHYL-LH-IMIDAZOL-2-YLTHIO)-4-FLUORO-2-NITROBENZENAMINE (208a): [0363] To a stirred solution of 206 (500mg, 2.8 MMOL) in DMF (20 mL), was added 1-METHYL-LH- IMIDAZOLE-2-THIOL (207a, 2.8 MMOL, 328 mg) and potassium carbonate (1.58 g, 11.49 MMOL). The reaction mixture was stirred at 60 FOR 5 hours. Ethyl acetate was added and K2CO3 was removed by filtration. The filtrate was concentrated, evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1: 2), then EtOAc (100%) to afford 208a (751MG, 98% yield). MS: (CALC.) 268.3 ; (obt. ) 269.1 (MH) +.
EXAMPLE 10; 5, 6-DIFLUORO-N-(F 1-1 (4-HYDROXYTETRAHYDRO-2H-PYRAN-4-YL) METHYLLPIPERIDIN-4- YLLMETHYL)-3-ISOPROPYL-2-OXO-2, 3-DIHYDRO-LH-BENZIMIDAZOLE-L-CARBOXAMIDE hydrochloride; Step 1; 4, 5-DIFLUORO-N-ISOPROPYL-2-NITROANILINE; <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (3. 48 g, 20 mmol), 2,2-dimethoxypropane (11.9 mL, 100 mmol), and trifluoroacetic acid (1.6 mL, 21 mmol) were dissolved in toluene (40 mL) and stirred at room temperature for 1 h. A boron-pyridine complex (2.12 mL, 21 mmol) was slowly added. The reaction mixture was stirred for 20 h. The solvent was evaporated in vacuo, and the residue was taken up into water and extracted with dichloromethane. The organic extract was dried (NA2S04) and concentrated in vacuo. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (30 : 1) to give 2.42 g (56%) of the title compound as a bright orange solid. 1H NMR (CDCl3): No. 8.05 (1 H, dd, J=10.8, 8.6 Hz), 6.61 (1 H, dd, J=12.6, 6.8 Hz), 3.77-3. 62 (1 H, m), 1.33 (6 H, d, J=6.2 Hz).
A flame-dried round-bottomed flask was charged with 4, 5-difluoro-2-nitroaniline (2. 00g, 11.49 mmol) and N, Ndimethylethanolamine. Pyridine (44 mL) was added followed by slow addition of NaH (60% in mineral oil, 965mg, 24.1 mmol). The mixture was put under N2 atmosphere, stirred at rt for 16 h and quenched with H20. Solvents were removed in vacuo and the residue was partitioned between H20 and EtOAc. The organic layer was extracted twice with HCI 1N, the combined acidic extracts were neutralized with saturated NaHCO3 to form a precipitate which was allowed to stand overnight, collected by filtration and purified by flash chromatography using MeOH/CHCI3 with increasing polarity (10: 90 to 15: 85) to afford the title compound 180 (1.30g, 47% yield). lH NMR: (CD30D) 8 (ppm): 7.76 (d, J= 11.7 Hz, 1H), 6.53 (d, J= 7.4 Hz, 1H), 4.19 (t, J= 5.5 Hz, 2H), 2.84 (t, J= 5.5 Hz, 2H), 2.37 (s, 6H). m/z: 244.2 (MH+).
With hydrogenchloride In ethanol at 20℃; for 2h; Heating / reflux;
1
4,5-Difluoro-2-nitro-phenylacetamide (51.00 g, 235.96 mmol) was added to a solution of hydrochloric acid (100 mL) in ethanol (300 mL). The mixture was refluxed for 2 hrs. After the mixture was cooled down to room temperature, it was poured onto ice (1000 g). The precipitate was filtered and was washed with cold water to give a solid. ¹H NMR (300 MHz, CDCl3): 8 8.02-7.96 (m, 1H), 6.70-6.64 (m, 1H), 6.15 (br, 2H).
EXAMPLE 1; Preparation of l-(4,5-difluoro-2-nitrophenyl)-H-pyrrole; [0070] A 250 ml round bottom flask was charged with 5.0 g (0.028 mol) of 4,5 -difluoro- 2-nitroaniline, 4.0 ml (0.030 mol) of 2,5- dimethoxy -tetrahydrofuran and 30 ml of acetic acid. The mixture was heated to 100 C for 3 hours, after which time the reaction was complete. The solution was concentrated and the residue diluted with 10 ml saturated sodium bicarbonate solution and extracted 3 times with 20 ml of ethyl acetate. The organic layers were combined , dried (MgSO4) and concentrated. The crude solid was filtered through a plug of silica gel eluting with 20% ethyl acetate rhexane and the filtrate concentrated to afford 5.9 g (92%) of product as a dark oil which slowly solidified.IH NMR (DMSO-d6): delta 8.43 (m,lH, ArH)3 7.94 (m, IH, ArH), 6.96 (s,2H,ArH), 6.29 (s,2H,ArH);MS (ESI) m/z 223 ([M-H]-);Anal, calcd for C10H6F2N2O2: C:53.58 H:2.70 N: 12.50 Found: C:53.53 H:2.77N:12.32.
(4,5-difluoro-2-nitro-phenyl)-methyl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaH In N,N-dimethyl-formamide
129.a a
a Preparation of (4,5-difluoro-2-nitro-phenyl)-methyl-amine: To a solution of 4,5-difluoro-2-nitro-phenylamine (407 mg) in DMF (5 ml) was added NaH (60%, 95 mg) at room temperature. The mixture was stirred for ten minutes and then methyl iodide (0.15 ml) was added to the mixture. The mixture was further stirred at room temperature for 3 hours and was diluted with ethyl acetate. This solution was washed with water 3 times and brine, then it was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate affording the titled compound as a yellow solid (120 mg). EI-MS: m/z 188 (M+); 1H-NMR (CDCl3): δ 3.01 (3H, d, J=5.3 Hz), 6.61 (1H, dd, J=6.9, 12.5 Hz), 8.07 (1H, dd, J=8.6, 10.6 Hz).
4-fluoro-5-(5-isoquinolylsulfanyl)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In N,N-dimethyl-formamide
34 4-Fluoro-5-(5-isoquinolylsulfanyl)-2-nitroaniline
EXAMPLE 34 4-Fluoro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 5-Isoquinolinethiol 1.00 g (6.2 mmol) was dissolved in DMF 25 ml, potassium carbonate 1.60 g (11.6 mmol) and 4,5-difluoro-2-nitroaniline 1.00 g (5.5 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and the resulting precipitates were collected and washed with water to give 4-fluoro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 1.95 g (quantitative). Melting point: 217-220° C. Mass spectrometry (m/z): 316 (M+1) Nuclear magnetic resonance spectrum (DMSO-d6) δ: 9.48(1H,s), 8.61(1H,d), 8.41(1H,s), 8.21(1H,d), 7.93(1H,d), 7.79-7.85(2H,m), 7.20(2H,s), 6.06(1H,s).
4,5-Difluoro-1,2-phenylenediamine (10)
4,5-Difluoro-1,2-phenylenediamine (10) To a solution of 5.55 g (31.876 mmole) of 4,5-difluoro-2-nitroaniline in 50 mL of MeOH, were added 100 mL of 2 N HCl and 8.90 g (159.380 mmole) of iron powder. The reaction mixture was stirred at room temperature for 2 hr and then filtered. The filtrate was neutralized with conc. NH4 OH to ~pH 8. The resulting suspension was filtered again and the filter cake was washed thoroughly with MeOH. The filtrate and washings were combined, concentrated to ~100 mL, and extracted with CHCl3 (100 mL*3). The CHCl3 solution was washed with a sat. NaCl solution (100 mL*2), dried (Na2 SO4), and evaporated. The residue was coevaporated with CHCl3 to give 3.515 g (77%) of 10. This material was used in the next reaction without further purification. A brown crystalline sample of 10 was obtained by recrystallization from CCl4. 1 H NMR (DMSO-d6): d6.44 (t, 2,3-H and 6-H, JF-H =10.5 H), 4.59 (br. s, 4,2*NH2).
With N-chloro-succinimide In N,N-dimethyl-formamide
4
2-Chloro-3,4-difluoro-6-nitroaniline 2-Chloro-3,4-difluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 4,5-difluoro-2-nitroaniline (500 mg, 2.87 mmol) in DMF (16 mL) under N2 was added N-chlorosuccinimide (401 mg, 3.00 mmol) in DMF. The reaction was allowed to stir 48 h. The solution was then poured into 75 mL H2 O. the cloudy orange suspension which formed was then extracted with 4*25 mL of methylene chloride. The combined organic extracts were washed with 5*20 mL of H2 O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1 H NMR showed this solid to be mixture of chlorinated product and starting material. The mixture was separated by flash chromatography (silica gel, 3:1 hexanes:ethyl acetate) to yield 162 mg of a yellow crystalline solid (27%). 1 H NMR (CDCl3) δ6.60 (br s, 2H, NH2), 8.00 (m, 1H, H-5). There was 17% starting material contamination by NMR.
N-[(4,5-difluoro-2-nitrophenyl)carbamoyl]glycine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine In tetrahydrofuran; ethyl acetate
4 Preparation of N-[(4,5-Difluoro-2-nitrophenyl)carbamoyl]glycine methyl ester STR38
EXAMPLE 4 Preparation of N-[(4,5-Difluoro-2-nitrophenyl)carbamoyl]glycine methyl ester STR38 A solution of 4,5-difluoro-2-nitroaniline (1.07 g, 6.15 mmol) in tetrahydrofuran is cooled to 2° C., treated with phosgene (3.8 mL, 1.93M, 7.33 mmol), stirred at ice-bath temperature for 2 hours, treated with glycine methyl ester hydrochloride (1.02 g, 8.12 mmol), treated with pyridine (1 mL, 12.64 mmol), stirred at room temperature for 3 days, diluted with concentrated ammonia solution and water, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and an ethyl acetate/hexanes (1:3) solution gives the title product as a solid, mp 118.9°-122.9° C.
REFERENCE EXAMPLE 11 2-Bromo-3,4-difluoro-6-nitroaniline Into a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50 l to 56 C. and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105 C. Analysis (%) for C6 H3 BrF2 N2 O2, Calcd. (Found): C. 28.48 (28.62); H, 1.20 (1.15); N, 11.07 (11.00).
With bromine; In acetic acid;
REFERENCE EXAMPLE 8 2-Bromo-3,4-difluoro-6-nitroaniline Into a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50 to 56 C. and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105 C. Analysis (%) for C6 H3 BrF2 N2 O2, Calcd. (Found): C, 28.48 (28.62); H, 1.20 (1.15); N, 11.07 (11.00).
With bromine; In acetic acid;
Reference example 13 2-Bromo-3,4-difluoro-6-nitroaniline Into a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50 to 56 C and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105 C. Analysis (%) for C6H3BrF2N2O2, Calcd. (Found): C, 28.48 (28.62); H, 1.20 (1.15); N, 11.07 (11.00).
With bromine; acetic acid; at 20℃; for 2h;
Step 1<strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (4.26 g, 24.47 mmol) was dissolved in acetic acid (40.8 ml). Bromine (1.336 ml, 25.9 mmol) was added drop wise at room temperature. The reaction mixture was stirred for 2 hours then poured into ice water (200 ml). The mixture was allowed to stand overnight. The mixture was filtered to afford a yellow solid, which was purified by a silica gel column eluted with ethyl acetate/hexane 0-40%. This resulted in 2-bromo-3,4-difluoro-6- nitroaniline as yellow solid. LC-MS (ES, m/z) C6H3BrF2N202: 253; Found: 254 [M+H]+.
With N-Bromosuccinimide; In N,N-dimethyl-formamide;
2-Bromo-3,4-difluoro-6-nitroaniline 2-Bromo-3,4-difluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (500 mg, 2.87 mmol) in DMF (25 mL) under N: was added all at once N-bromosuccinimide (511 mg, 2.87 mmol) in dry DMF (16 mL). The reaction was allowed to stir overnight. TLC (1:1 hexanes:ethyl acetate) showed still some starting material present. Additional N-bromosuccinimide (100 mg) was added and the reaction stirred another 12 h. The solution was then poured into 100 ml H2 O and the resulting cloudy suspension extracted with 3*20 mL methylene chloride. The combined organic phases were washed with 4*25 mL H2 O and 25 mL saturated NaCl solution and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a yellow brown oil which slowly crystallized to yield 700 mg (96%). 1 H NMR (CDCl3) delta6.70 (br s, 2H, NH2), 7.99 (m, 1H, H-5).
D. Preparation of 8-Azido-7-fluorotetrazoles 4,5-Difluoro-2-nitroaniline (20.00 g, 115 mmol) was catalytically hydrogenated by H2 in 275 ml EtOH over 10% Pd/C at room temperature for 4 hours. The mixture was filtered to remove Pd/C, and EtOH was removed in vacuo to afford 14.63 g of a dark green solid difluorophenylenediamine. This compound (14.48 g, 100 mmol) was combined with glyoxalic acid hydrate (11.97 g, 130 mmol) in 250 ml of absolute EtOH and heated at reflux under N2 for 20 hours. Upon cooling and standing for 24 hours, the resultant purple solid was collected by filtration, yielding 14.6 g of 6,7-difluoroquinoxalin-2-one.
1.25 g (55%)
With hydrogenchloride;palladium; In sodium hydroxide; ethanol; water;
EXAMPLE 4 1-Carboxymethyl-6,7-difluoroquinoxaline-2,3(1H,4H)-dione <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (2.17 g, 12.5 mmol) was dissolved in 55 ml of ethanol and 250 mg of 10% palladium on carbon was added. The mixture was hydrogenated until the theoretical amount of hydrogen had been absorbed, using a low pressure hydrogenation apparatus. The catalyst was filtered off and the filtrate, containing 4,5-difluoro-o-phenylenediamine, was kept under a nitrogen atmosphere at 0 C. followed by addition of a solution of glyoxylic acid hydrate (1.28 g, 13.7 mmol) in water (3 ml). When the addition was complete the reaction temperature was allowed to reach room temperature during 2 h and 30 ml of water was added. The precipitate was filtered off and dissolved in 60 ml of 5% NaOH solution at 50 C. followed by addition of activated carbon. The mixture was filtered and the filtrate was acidified (pH=1) by addition of concentrated hydrochloric acid. The pinky precipitate was filtered off, washed with water and dried to afford 1.25 g (55 %) of 6,7-difluoroquinoxalin-2(1H)-one melting at 284-85 C. 1 H-NMR (DMSO-d6): 7.27 (m, 1H), 7.95 (m, 1H), 8.20 (s, 1H), 12.55 (s,1H).
3 Ethyl 6,7-Difluoro-3,4-dihydro-3-oxo-2-quinoxaline Carboxylate.
A reaction mixture was prepared containing 8.75 g. of 4,5-difluoro-2-nitroaniline, 200 ml. of ethanol, and as a catalyst 1 g. of 10 percent palladium-on-carbon. The mixture was hydrogenated until the theoretical amount of hydrogen had been absorbed, using a low-pressure hydrogenation apparatus. The catalyst was separated by filtration using standard precautions and the product of the reaction, 4,5-difluoro-o-phenylenediamine, was reacted with diethyl mesoxalate following the procedure of Preparation 1 without further purification. The product of this reaction, ethyl 6,7-difluoro-3,4-dihydro-3-keto-2-quinoxaline carboxylate, melted at about 193°-195° C.
2-nitro-4,5-difluoro-6-methylthiomethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-chloro-succinimide; triethylamine In dichloromethane
R.24 REFERENCE EXAMPLE 24
REFERENCE EXAMPLE 24 To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethylsulfide (1.79 g) in dichloromethane (40 ml) is added gradually N-chlorosuccinimide (3.82 g) with stirring at below 15° C. The mixture is stirred for 30 minutes, and thereto is added triethylamine (2.89 g), and the mixture is refluxed for 21 hours. After allowing to cool, the reaction mixture is washed with 10% aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried. The solvent is removed by concentration, and the resulting residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=30:1) and then recrystallized from n-hexane to give 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellow needles, m.p. 110°-111.5° C.
With N-chloro-succinimide; triethylamine In dichloromethane
R.24 REFERENCE EXAMPLE 24
REFERENCE EXAMPLE 24 To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethylsulfide (1.79 g) in dichloromethane (40 ml) is added gradually N-chlorosuccinimide (3.82 g) with stirring at below 15° C. The mixture is stirred for 30 minutes, and thereto is added triethylamine (2.89 g), and the mixture is refluxed for 21 hours. After allowing to cool, the reaction mixture is washed with 10% aqueous sodium hydroxide, water and aqueous sodium chloride in this order and dried. The solvent is removed by concentration, and the resulting residue is purified by silica gel column chromatography (solvent, n-hexane:ethylacetate=30:1) and then recrystallized from n-nexane to give 2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellow needles, m.p. 110°-111.5° C.
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 60℃; for 0.5h;
Example 21N-[3-(5-fluoro-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]piperidine-1-carboxamide Stage I: 4-(5-amino-2-fluoro-4-nitrophenyl)piperazine-1-carboxylic Acid Tert-Butyl Ester 2.4 g of potassium bicarbonate and 1 g of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> are added to a solution of 3.3 g of piperazine-1-carboxylic acid tert-butyl ester in 30 mL of anhydrous DMF. The reaction medium is heated at 60 C. using an oil bath for 30 minutes. The reaction medium is cooled to ambient temperature, then 150 mL of water are added thereto, and precipitation occurs. The precipitate is filtered off through sintered glass. The solid is dried in an oven at 50 C. 1.4 g of 4-(5-amino-2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, delta in ppm): 1.42 (s, 9H); 3.14 (m, 4H); 3.46 (m, 4H); 6.43 (d, J=8.0 Hz, 1H); 7.36 (broad s, 2H); 7.66 (d, J=14.5 Hz, 1H). EI mass spectrum: m/z=340 M+., m/z=284 (M-C4H+., m/z=264 (m/z=284-HF)+, m/z=57 C4H+ (base peak).
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2h;
EXAMPLE 19; 5-(4-Benzhydryl-piperazin-1-yl)-2-(1-ethyl-propyl)-6-fluoro-1H-benzoimidazole; Step a: 5-(4-Benzhydryl-piperazin-1-yl)-4-fluoro-2-nitro-phenylamine; A mixture of mono-benzhydrylpiperazine (2.6 g, 10.3 mmol), <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (1.97 g, 1.1 eq) and potassium carbonate (2.16 g, 1.5 eq) in DMF (25 mL) was stirred at 50 C. for 2 hours. The mixture was quenched with water and the pH of the aqueous was adjusted to pH 9-10 by addition of NaOH 2N. The aqueous phase was extracted with AcOEt. The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude orange oil. This oil was sonicated in Et2O/Hexanes and the resulting precipitate was filtered off and washed with Hexanes. After high-vacuum drying, 5-(4-benzhydryl-piperazin-1-yl)-4-fluoro-2-nitro-phenylamine (3.3 g, 78.8% yield) was obtained as an orange powder.LC/MS: r.t. 4.82 min, 407.2 [M+H]
b) (2-Amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester; 4,5-Difluoro-2-nitro-phenylamine (6.0 g, 34 mmol, 1 equiv.) was added to a solution of di-tert-butyl dicarbonate (14.8 g, 68 mmol, 2 equiv.) and DMAP (211 mg, 0.2 mmol, 0.05 in THF (100 mL) and the mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the crude extracted from ethylacetate and aq. NaHCO3. The residue was taken up in DCM and cooled to 0 C. Trifluoroacetic acid (7.75 g, 68 mmol, 2 equiv) were added slowly and the mixture stirred for 48 h at 0 C. 2 N NaOH was added to adjust the pH to 7. The organic layer was separated and evaporated. The residue was taken up in ethyl acetate and the product extracted from aq. NaHCO3. The intermediate was isolated via Kieselgel chromatography. 4.28 g (16 mmol, 1 equiv.) were dissolved in DMF (50 ml) and 13 ml of a saturated NH4Cl solution added. Zink powder (5.1 g, 78 mmol, 5 equiv.) was added and the suspension stirred for 30 minutes at 80 C. and another 2 hours at room temperature. The remaining solid was filtered off and the organic layer evaporated. The product was extracted from ethyl actetate and aq. NaHCO3 and further purified via Kieselgel chromatography.
Stage #1: 1-piperidinoethanol With sodium hydride In N,N-dimethyl-formamide at 0℃;
Stage #2: 4,5-difluoro-2-nitroaniline With sodium hydrogencarbonate In N,N-dimethyl-formamide at 22 - 90℃; for 3h;
3.I
Example 3N-{3-[5-fluoro-6-(2-piperidin-1-ylethoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide Hydrochloride Stage I: 4-fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamineA solution of 1.11 g of 2-piperidin-1-ylethanol in 20 mL of N,N-dimethylformamide (DMF) is cooled to 0° C. with an ice bath. 689 mg of sodium hydride (60% in suspension in oil) are added in small portions. The suspension obtained is added dropwise to a suspension containing 500 mg of 4,5-difluoro-2-nitrophenylamine and 724 mg of sodium bicarbonate in 15 mL of DMF. The reaction medium is stirred at ambient temperature (22° C.) for 2 hours and then heated at 90° C. for 1 hour. The solvent is concentrated to dryness, then the reaction crude is taken up in 30 mL of ethyl acetate and the organic phase is washed with 2×30 mL of distilled water and 1×30 mL of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under vacuum in a rotary evaporator. The crude is triturated in ethyl ether and the solid is filtered through sintered glass and rinsed with ethyl ether. 443 mg of 4-fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamine in the form of a red solid are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.37 (m, 2H); 1.48 (m, 4H); 2.43 (m, 4H); 2.69 (t, J=6.5 Hz, 2H); 4.13 (t, J=6.5 Hz, 2H); 6.65 (d, J=8.0 Hz, 1H); 7.48 (broad s, 2H); 7.75 (d, J=12.0 Hz, 1H).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 80℃;
Stage I: 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrophenylamine 36.2 g of sodium bicarbonate and 29.5 g of N-methyl-homopiperazine are added to a solution of 15 g of 4,5-difluoro-2-nitroaniline in 120 mL of anhydrous DMF. The reaction medium is heated at 80 C. using an oil bath for 2H30. The reaction medium is cooled to ambient temperature, and then poured into 400 mL of water. The mixture is cooled using an ice bath and stirred, and precipitation occurs. The precipitate is filtered off through sintered glass. The yellow solid is rinsed with water. The solid is dried in an oven at 40 C. 21 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrophenylamine are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, delta in ppm): 1.90 (m, 2H); 2.27 (s, 3H); 2.50 (m masked, 2H); 2.64 (m, 2H); 3.46 (m, 2H); 3.52 (m, 2H); 6.21 (d, J=9.0 Hz, 1H); 7.24 (broad s, 2H); 7.59 (d, J=16.0 Hz, 1H). EI mass spectrum: m/z=268: M+. (base peak)-m/z=253: (M-CH3)+-m/z=198: (M-C4H8N)+-m/z=70: C4H8N+-m/z=57: C3H7N+.
Stage #1: 4-piperidin-1-yl-butan-1-ol With sodium hydride In N,N-dimethyl-formamide for 2h;
Stage #2: 4,5-difluoro-2-nitroaniline In N,N-dimethyl-formamide at 0 - 20℃;
9.I
Stage I: 4-fluoro-2-nitro-5-(4-piperidin-1-ylbutoxy)-phenylamine382 mg of sodium hydride (60% in suspension in oil) are added in small portions, over two hours, to a solution of 4-piperidin-1-ylbutan-1-ol in 10 mL of DMF, cooled to 0° C. with an ice bath. A solution of 4,5-difluoro-2-nitroaniline in 5 mL of N,N-dimethylformamide is then added dropwise. The medium is stirred at ambient temperature for 24 hours. 60 mL of distilled water are added and the reaction medium is extracted with 3×30 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus with an Analogix RS-12 silica cartridge, with a 100% to 85/15 dichloromethane/-methanol elution gradient. 700 mg of 4-fluoro-2-nitro-5-(4-piperidin-1-ylbutoxy)phenylamine are isolated in the form of a red oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): from 1.29 to 1.62 (m, 8H); 1.75 (m, 2H); 2.28 (m, 6H); 4.07 (t, J=6.5 Hz, 2H); 6.62 (d, J=7.5 Hz, 1H); 7.48 (broad s, 2H); 7.74 (d, J=12.0 Hz, 1H).
With sodium hydrogencarbonate In N,N-dimethyl-formamide for 2h; Reflux;
15.I
Example 153-{3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-diethylurea Trifluoroacetate Stage I: N3-(2-dimethylaminoethyl)-4-fluoro-6-nitro-benzene-1,3-diamineA solution of 4,5-difluoro-2-nitroaniline in 10 mL of DMF is stirred at ambient temperature and 2.53 g of sodium bicarbonate and 1.67 g of N,N-dimethylenediamine are added. The reaction medium is refluxed for two hours. 30 mL of water are added and the aqueous phase is then extracted with 4×15 mL of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is taken up in isopropyl ether and the solid is triturated, and then filtered through sintered glass. The solid is dried under vacuum at 40° C. until the weight is constant. 1.23 g of N3-(2-dimethylaminoethyl)-4-fluoro-6-nitrobenzene-1,3-diamine are recovered in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 2.19 (s, 6H); 2.45 (t, J=6.5 Hz, 2H); 3.19 (m, 2H); 6.03 (d, J=8.0 Hz, 1H); 6.58 (broad t, J=5.5 Hz, 1H); 7.37 (broad s, 2H); 7.58 (d, J=13.0 Hz, 1H).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;
11.I
Example 111,1-diethyl-3[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]urea Stage I: 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-yl-phenylamine 19.4 g of potassium carbonate and 11.9 g of homomorph-oline hydrochloride are added to a solution of 5 g of 4,5-difluoro-2-nitroaniline in 98 mL of anhydrous DMF. The reaction medium is heated at 80° C. using an oil bath for 2 hours. The reaction medium is cooled to ambient temperature, then 300 mL of water are added thereto, and precipitation occurs. The precipitate is filtered through sintered glass. The yellow solid is rinsed with 3 times 100 mL of water. The solid is dried in an oven at 70° C. 6.5 g of 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-ylphenylamine are obtained in the form of an orange solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.91 (m, 2H); from 3.52 to 3.61 (m, 4H); 3.66 (m, 2H); 3.74 (m, 2H); 6.28 (d, J=8.5 Hz, 1H); 7.24 (broad s, 2H); 7.61 (d, J=15.5 Hz, 1H).
Stage #1: 3-Dimethylamino-1-propanol With sodium hydride In tetrahydrofuran at 0℃; Cooling with ice;
Stage #2: 4,5-difluoro-2-nitroaniline With sodium hydrogencarbonate In tetrahydrofuran at 22 - 80℃;
5.I
Example 53-{3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-diethylurea Trifluoroacetate Stage I: Preparation of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitrophenylamine A solution of 6.1 mL of 3-dimethylamino-1-propanol in 100 mL of anhydrous THF is cooled using an ice bath. Under argon, 1.1 g of NaH are added in small portions (solution A). The reaction medium is left stirring for 1 hour at 0° C. A solution of 3 g of 4,5-difluoroaniline in 100 mL of anhydrous THF is stirred at 22° C. 4.3 g of sodium bicarbonate are added. The solution containing the alkoxide (solution A) is added dropwise. The reaction medium is heated at 80° C. using an oil bath for 30 minutes. The reaction medium is cooled to ambient temperature and 100 mL of water are added. The aqueous phase is extracted with three times 100 mL of EtOAc. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The orangey-yellow solid is taken up in pentane, triturated, filtered, rinsed with pentane and dried. 3.5 g of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitro-phenylamine are obtained in the form of a brown solid. Analytical LC/MS: tr=2.16 min; [M+H]+=258.27; ELSD=100%. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.9 (m, J=6.0 Hz, 2H); 2.13 (s, 6H); 2.35 (t, J=6.0 Hz, 2H); 4.08 (t, J=6.0 Hz, 2H); 6.64 (d, J=8.0 Hz, 1H); 7.47 (s, 2H); 7.73 (d, J=11.0 Hz, 1H).
Stage #1: 3-Dimethylamino-1-propanol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 4,5-difluoro-2-nitroaniline In tetrahydrofuran at 0 - 50℃; for 16h;
185; 203
Synthesis of 5-(3-(dimethylamino)propoxy)-4-fluoro-2-nitrobenzenamine Into a 250- mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(dimethylamino)propan-1 -ol (888.81 mg, 8.615 mmol, 1.5 equiv) in THF (50 ml_). NaH (689.17 mg, 28.718 mmol, 3 equiv) was added portionwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Then a solution of 4,5-difluoro-2- nitrobenzenamine (1 g, 5.744 mmol, 1.0 equiv) in anhydrous THF (50 ml.) was added dropwise at 0°C. The resulting solution was stirred at 50°C for 16 hours in an oil bath. After reaction completed, the reaction mixture was quenched with ice-water and extracted with DCM (5*10 ml), the organic layer was washed with saturated NaCI solution, dried over Na2S04 and concentrated in vacuo. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10:1 ) to afford 5-(3-(dimethylamino)propoxy)-4-fluoro-2- nitrobenzenamine
Stage #1: 3-piperidinopropan-1-ol With sodium hydride In N,N-dimethyl-formamide at 0℃;
Stage #2: 4,5-difluoro-2-nitroaniline With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20 - 90℃; for 2h;
6.I
Example 61,1-diethyl-3-{3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea Hydrochloride Stage I: Preparation of 4-fluoro-2-nitro-5-(3-piperidin-1-ylpropoxy)phenylamineA solution of 1.3 mL of 3-piperidin-1-ylpropan-1-ol in 16 mL of N,N-dimethylformamide (DMF) is cooled to 0° C. with an ice bath. 345 mg of sodium hydride (60% in suspension in oil) are added in small portions. The suspension obtained is added dropwise to a suspension containing 500 mg of 4,5-difluoro-2-nitrophenylamine and 724 mg of sodium bicarbonate in 15 mL of DMF. The reaction medium is stirred for one hour at ambient temperature and then heated for 1 hour at 90° C. The cooled reaction medium is treated with 70 mL of ethyl acetate and 70 mL of distilled water. The aqueous phase is extracted with 70 mL of ethyl acetate. The combined organic phases are washed with 100 mL of distilled water and 100 mL of a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is concentrated to dryness in a rotary evaporator and the crude is then purified by chromatography on a 50 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 300 mg of 4-fluoro-2-nitro-5-(3-piperidin-1-ylpropoxy)phenylamine are isolated in the form of a yellow oil which crystallizes. Analytical LC/MS: Tr=2.26 min, [M+H]+=298.04 DAD=87%.
10% Pd/C (2 g) was added to a solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (40 g, 0.229 mol) in methanol (500 mL). The reaction mixture was hydrogenated at room temperature for 3 h and treated with the mixture of compound methyl 2,2-diethoxyethanimidoate (71 g, 0.23 mol) with acetic acid (60 g). After 16 h at room temperature, the reaction mixture was evaporated, washed with the 10% K2CO3 solution (1 L), and the product was extracted with ether (300 mL). The organic extract was evaporated, and the residue was purified on silica gel (ethyl acetate/hexane 1:5) to give 48 g of 2-(diethoxymethyl)-5,6-difluoro-1/-/-benzimidazole.
pour dropwise, at a temperature close to 20 C., a solution of 500 mg of 1-(2,6-dichlorophenyl)-ethanol in 10 cm3 of tetrahydrofuran into a suspension of 115 mg of sodium hydride (at 60% in the oil) in 4 cm3 of tetrahydrofuran. Stir the suspension obtained for 2.5 hours at about 20 C. A solution of 456 mg of 4,5-difluoro-2-nitroaniline in 15 cm3 of tetrahydrofuran is then poured in dropwise at about 20 C. After stirring for about 1.5 h at a temperature close to 20 C., 150 cm3 of a saturated aqueous solution of sodium chloride is added to the reaction mixture. The resultant mixture is extracted five times with 50 cm3 of ethyl acetate, then the organic phases are dried over magnesium sulphate, filtered and then concentrated under reduced pressure (0.2 kPa). We thus obtain 953 mg of 5-[1-(2,6-dichlorophenyl)ethoxy]-4-fluoro-2-nitroaniline in the form of a dark orange solid, which has the following characteristics:Melting point: 188 C. (Koefler)Mass spectrum: LC-MS-DAD-ELSD: 343(-)=(M-H)(-); 345(+)=(M+H)(+)
With hydrogenchloride; sodium methylate In methanol
1 Step 1:
Step 1: Preparation of 4-fluoro-5-methoxy-2-nitroaniline To an ice cooled 100 ml round bottom flask charged with methanol (30 mL) was added sodium methoxide (1.551 g, 28.7 mmol). After the solution was homogeneous, 4,5-difluoro-2-nitroaniline (2 g, 11.49 mmol) was added portion wise. The solution turns a bright yellow and slowly yellow precipitation was observed. Solvent was removed under reduced pressure and the residue was diluted with water and acidified using 1.5N HCl solution. The aqueous layer was extracted with ethyl acetate twice, the combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated to dryness to get 4-fluoro-5-methoxy-2-nitroaniline (1.8 g, 9.48 mmol, 82% yield) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.76 (d, J=12.55 Hz, 1H) 7.54 (br. s., 2H) 6.65 (s, 1H) 3.86 (s, 3H). 19F NMR: δ ppm -147.64 (1F); MS:MS m/z 185.2 (M+-1)
35.1 Step 1: preparation of 4-fluoro-5-methoxy-2-nitroaniline
Step 1: preparation of 4-fluoro-5-methoxy-2-nitroaniline 3.4g 2-amino-4,5-difluoronitrobenzene was added to a 100mL round-bottomed flask, and dissolved by adding 30mL MeOH. 2.16g sodium methoxide was slowly added at room temperature. The mixture was reacted for another 12h at room temperature before the reaction was stopped. The reaction solution was filtered, and the filter cake was washed with 10mL cold MeOH, and dried in vacuum to give the title compound, which was used directly in the next step. LC-MS m/z: [M+H]+ =187.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In toluene; at 160℃; for 24h;Schlenk technique; Inert atmosphere; Sealed tube;
General procedure: GeneralProcedure for the preparation of 2-Phenyl-1H-benzoimidazole (3aa): A 25mL over-dried Schlenk tube was charged with 2-nitroaniline (41.4 mg, 0.3 mmol),benzyl alcohol (97.2 mg, 0.90 mmol) and Pd(dppf)Cl2 (12.2 mg, 0.015mmol). The tube was purged with nitrogen three times. Toluene (1 mL) was addedto the sealed reaction vessel by syringe. The reaction mixture was stirred in apreheated oil bath at 160 oC for 24 h. After cooling to roomtemperature, the reaction mixture was then concentrated in vacuo, and theresidue was purified by column chromatography (silica gel, petroleumether/ ethyl acetate = 4:1) to give 3aa as a pale yellow solid (56.5 mg, 97%).
With sulfuric acid; arsenic pentoxide pentahydrate; In water; at 80 - 120℃; for 4.5h;
The reaction was performed according to a literature knownprocedure [20]. Aniline 1b (5.0 g, 29 mmol) and arsenic pentoxidehydrate (4.5 g, 5.8 mmol) were dissolved in a mixture of sulfuricacid (70%, 15 mL) and water (9 mL). This solution was heated upto 80 C, and at constant temperature ADEA (6.2 mL, 41 mmol) wasadded dropwise during 3 h with a syringe pump. After completionof addition the solution was heated up to 120 C for 90 min withvigorous stirring. The mixture was allowed to cool down, waspoured onto an ice/water mixture (100 mL) and the resultingsuspension wasfiltered. Aqueous ammonia was added dropwise tothefiltrate until reaching pH6. The crude mixture was extractedwith dichloromethane (350 mL). The organic phase was washedwith brine and dried over anhydrous Na2SO4. 2b was obtained as ayellow solid after sublimation (70 C/2*102mbar) of the crudeproduct in 33% yield (2.0 g, 9.5 mmol).
2-(3,5-dibromo-2-((2-chlorobenzoyl)oxy)phenyl)acetic acid[ No CAS ]
2,4-dibromo-6-(2-((4,5-difluoro-2-nitrophenyl)amino)-2-oxoethyl)phenyl 2-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃;Inert atmosphere;
General procedure: To a solution of 2-(3,5-dibromo-2-((2-chlorobenzoyl)oxy)phenyl)acetic acid (0.181 g, 0.4035 mmol) in ACN (8.07 mL) was added 3-nitroaniline (0.0613 g, 0.4439 mmol) followed by EDC (0.1423 g, 0.807 mmol) and DMAP (0.0049 g, 0.0403 mmol). The resulting mixture was allowed to react at room temperature overnight and was concentrated to dryness. The residue was suspended in CHCl3, washed with 1 M HCl, sat. NaHCO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using a gradient of hexanes to EtOAc, affording 1.1 mg of the desired product (0.5% yield).
Stage #1: cis,trans-2,5-dimethoxytetrahydrofuran; 4,5-difluoro-2-nitroaniline With acetic acid for 2h; Reflux;
Stage #2: With iron; ammonium chloride In water for 4h; Reflux;
Stage #1: cis,trans-2,5-dimethoxytetrahydrofuran; 4,5-difluoro-2-nitroaniline With acetic acid for 2h; Reflux;
Stage #2: With iron; ammonium chloride In water for 4h; Reflux;
Stage #1: cis,trans-2,5-dimethoxytetrahydrofuran; 4,5-difluoro-2-nitroaniline With acetic acid for 3h; Reflux;
Stage #2: With iron; ammonium chloride In water for 5h; Reflux;
1,2-difluoro-4-isocyanato-5-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene for 16h; Reflux;
66.1 Step 1: 1,2-Difluoro-4-isocyanato-5-nitrobenzene.
To a suspension of 4,5- difluoro-2-nitroaniline (1.7 g, 10 mmol) in toluene (40 mL) was added diphosgene (2.95 g, 15 mmol) and the reaction mixture heated to reflux for 16 hrs. The solution was concentrated in vacuo to afford the crude oil, which was used without further purification.
With dodecacarbonyl-triangulo-triruthenium; cesiumhydroxide monohydrate; 1,3-bis-(diphenylphosphino)propane In tert-Amyl alcohol at 150℃; for 12h; Schlenk technique; Inert atmosphere;
To a cooled solution of <strong>[78056-39-0]4,5-difluoro-2-nitroaniline</strong> (5.0g, 0.287mmol, l .Oeq) in dichloromethane (lOOmL) was added dropwise triethylamine (9.6mL, 0.0686mmol, 2.39eq) followed by methane sulfonyl chloride (4.8mL, 0.0619mmol, 2.16eq). Reaction mixture was stirred at room temperature for 18h. After completion of reaction, reaction mixture was transferred into water and extracted with dichloromethane. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane as eluent to obtain intermediate 5.2g. To this intermediate was added 1M sodium hydroxide (50mL) in mixture of water and tetrahydrofuran. Reaction mixture was stirred at room temperature for 18h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 30% ethyl acetate in hexane as eluent to obtain intermediate 183.1. (2.1g, 29.00%). MS(ES): m/z 253.19 [M+H]+
4,5-Difluoro-2-nitroaniline (compound 6, 5 g, 28.7 mmol) and triethylamine (13 mL,93 mmol) were dissolved in toluene (100 mL). Triphosgene (2.5 g, 8.4 mmol) was slowly added to thesolution under vigorous stirring. The reaction mixture was stirred under room temperature overnight.The precipitate was collected by filtration and washed with water several times to removetriethylamine hydrochloride. The remaining solid was recrystallized from EtOH to give thedinitrourea 7 as a light-yellow solid. Yield: 1.8 g, 33%. 1H NMR (300 MHz, DMSO-d6) delta 10.27 (s,2H), 8.32 (t, 2H, J = 9.3), 8.13 (dd, J = 12.1, 7.9 Hz, 2H).
5-(cyclopropylmethoxy)-4-fluoro-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: Cyclopropylmethanol With potassium <i>tert</i>-butylate at 0℃; for 0.166667h;
Stage #2: 4,5-difluoro-2-nitroaniline In tetrahydrofuran at 20 - 70℃; for 5.16667h;
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;
General procedure: To a flame-dried 100 mLround bottom flask equipped with a stir bar was added 4,5-difluoro-2-nitroaniline(814 mg, 4.68 mmol, 1.0 equiv) and L4 (1.3g, 4.68 mmol, 1.0 equiv). After the flask was evacuated and backfilled with N2twice, anhydrous NMP (7 mL), DIPEA (2.4 mL, 14.04 mmol, 3.0 equiv) were addedvia syringes. The resulting mixture was stirred at 90 °C for 12 hours. Themixture was cooled to room temperature. H2O (70 mL) was added, whichwas extracted with EtOAc (50 mL × 2). The combined organic layers were driedover anhydrous Na2SO4. After concentration in vacuo, the residue was subsequentlypurified through column chromatography (hexanes/EtOAc: from 9:1 to 3:2) toafford the product 5-C4 as a yellow solid (1.37 g, 68 %yield).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;
General procedure: To a flame-dried 100 mLround bottom flask equipped with a stir bar was added 4,5-difluoro-2-nitroaniline(814 mg, 4.68 mmol, 1.0 equiv) and L4 (1.3g, 4.68 mmol, 1.0 equiv). After the flask was evacuated and backfilled with N2twice, anhydrous NMP (7 mL), DIPEA (2.4 mL, 14.04 mmol, 3.0 equiv) were addedvia syringes. The resulting mixture was stirred at 90 °C for 12 hours. Themixture was cooled to room temperature. H2O (70 mL) was added, whichwas extracted with EtOAc (50 mL × 2). The combined organic layers were driedover anhydrous Na2SO4. After concentration in vacuo, the residue was subsequentlypurified through column chromatography (hexanes/EtOAc: from 9:1 to 3:2) toafford the product 5-C4 as a yellow solid (1.37 g, 68 %yield).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;
General procedure: To a flame-dried 100 mLround bottom flask equipped with a stir bar was added 4,5-difluoro-2-nitroaniline(814 mg, 4.68 mmol, 1.0 equiv) and L4 (1.3g, 4.68 mmol, 1.0 equiv). After the flask was evacuated and backfilled with N2twice, anhydrous NMP (7 mL), DIPEA (2.4 mL, 14.04 mmol, 3.0 equiv) were addedvia syringes. The resulting mixture was stirred at 90 °C for 12 hours. Themixture was cooled to room temperature. H2O (70 mL) was added, whichwas extracted with EtOAc (50 mL × 2). The combined organic layers were driedover anhydrous Na2SO4. After concentration in vacuo, the residue was subsequentlypurified through column chromatography (hexanes/EtOAc: from 9:1 to 3:2) toafford the product 5-C4 as a yellow solid (1.37 g, 68 %yield).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;
General procedure: To a flame-dried 100 mLround bottom flask equipped with a stir bar was added 4,5-difluoro-2-nitroaniline(814 mg, 4.68 mmol, 1.0 equiv) and L4 (1.3g, 4.68 mmol, 1.0 equiv). After the flask was evacuated and backfilled with N2twice, anhydrous NMP (7 mL), DIPEA (2.4 mL, 14.04 mmol, 3.0 equiv) were addedvia syringes. The resulting mixture was stirred at 90 °C for 12 hours. Themixture was cooled to room temperature. H2O (70 mL) was added, whichwas extracted with EtOAc (50 mL × 2). The combined organic layers were driedover anhydrous Na2SO4. After concentration in vacuo, the residue was subsequentlypurified through column chromatography (hexanes/EtOAc: from 9:1 to 3:2) toafford the product 5-C4 as a yellow solid (1.37 g, 68 %yield).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;
General procedure: To a flame-dried 100 mLround bottom flask equipped with a stir bar was added 4,5-difluoro-2-nitroaniline(814 mg, 4.68 mmol, 1.0 equiv) and L4 (1.3g, 4.68 mmol, 1.0 equiv). After the flask was evacuated and backfilled with N2twice, anhydrous NMP (7 mL), DIPEA (2.4 mL, 14.04 mmol, 3.0 equiv) were addedvia syringes. The resulting mixture was stirred at 90 °C for 12 hours. Themixture was cooled to room temperature. H2O (70 mL) was added, whichwas extracted with EtOAc (50 mL × 2). The combined organic layers were driedover anhydrous Na2SO4. After concentration in vacuo, the residue was subsequentlypurified through column chromatography (hexanes/EtOAc: from 9:1 to 3:2) toafford the product 5-C4 as a yellow solid (1.37 g, 68 %yield).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;
General procedure: To a flame-dried 100 mLround bottom flask equipped with a stir bar was added 4,5-difluoro-2-nitroaniline(814 mg, 4.68 mmol, 1.0 equiv) and L4 (1.3g, 4.68 mmol, 1.0 equiv). After the flask was evacuated and backfilled with N2twice, anhydrous NMP (7 mL), DIPEA (2.4 mL, 14.04 mmol, 3.0 equiv) were addedvia syringes. The resulting mixture was stirred at 90 °C for 12 hours. Themixture was cooled to room temperature. H2O (70 mL) was added, whichwas extracted with EtOAc (50 mL × 2). The combined organic layers were driedover anhydrous Na2SO4. After concentration in vacuo, the residue was subsequentlypurified through column chromatography (hexanes/EtOAc: from 9:1 to 3:2) toafford the product 5-C4 as a yellow solid (1.37 g, 68 %yield).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
