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HazMat fee for 500 gram (Estimated)
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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 367-25-9 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 9, p. 3141 - 3152
2
[ 367-25-9 ]
[ 399-74-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 4, p. 727 - 730
[2] Organic Letters, 2017, vol. 19, # 21, p. 5836 - 5839
3
[ 371-40-4 ]
[ 367-25-9 ]
[ 3863-11-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
4
[ 367-25-9 ]
[ 461-96-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 3, p. 486 - 494
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 6, p. 887 - 889
5
[ 367-25-9 ]
[ 367-27-1 ]
Reference：
[1] Chemische Berichte, 1937, vol. 70, p. 2396,2400
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[3] Journal of Organic Chemistry USSR (English Translation), 1974, vol. 10, p. 1237 - 1238[4] Zhurnal Organicheskoi Khimii, 1974, vol. 10, # 6, p. 1228 - 1230
6
[ 367-25-9 ]
[ 3939-09-1 ]
Reference：
[1] Archiv der Pharmazie, 2017, vol. 350, # 2,
7
[ 367-25-9 ]
[ 446-35-5 ]
Reference：
[1] ChemSusChem, 2012, vol. 5, # 2, p. 312 - 319
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1047 - 1051
8
[ 367-25-9 ]
[ 64248-63-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 3, p. 486 - 494
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 6, p. 887 - 889
9
[ 367-25-9 ]
[ 367-34-0 ]
[ 3862-73-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
10
[ 367-25-9 ]
[ 32085-88-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 3, p. 486 - 494
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 6, p. 887 - 889
11
[ 367-25-9 ]
[ 364-30-7 ]
Reference：
[1] Journal of Fluorine Chemistry, 2003, vol. 121, # 2, p. 171 - 175
12
[ 446-35-5 ]
[ 367-25-9 ]
Yield
Reaction Conditions
Operation in experiment
810 mg
With palladium on activated charcoal; hydrogen In methanol at 20℃;
Add in 100mL single-mouth bottles2,4-Difluoro-1-nitrobenzene (1 g), methanol (10 mL) and Pd/C (100 mg) were replaced with hydrogen three times and stirred at room temperature for 2-3 h. Filtration and concentration of the filtrate under reduced pressure afforded 810 mg.
Reference：
[1] Synthetic Communications, 2012, vol. 42, # 2, p. 213 - 222
[2] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2011, vol. 41, # 1, p. 114 - 119
[3] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2> 140, p. 97,111
[4] Chemische Berichte, 1937, vol. 70, p. 2396,2400
[5] Journal fuer Praktische Chemie (Leipzig), 1934, vol. <2> 140, p. 97,111
[6] Chemische Berichte, 1937, vol. 70, p. 2396,2400
[7] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[8] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
[9] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1959, p. 71,73; engl. Ausg. S. 64, 66
[10] Patent: US4375550, 1983, A,
[11] Advanced Synthesis and Catalysis, 2011, vol. 353, # 8, p. 1306 - 1316
[12] Chinese Chemical Letters, 2012, vol. 23, # 5, p. 545 - 548
[13] Chinese Chemical Letters, 2014, vol. 25, # 8, p. 1137 - 1140
[14] Patent: CN108707139, 2018, A, . Location in patent: Paragraph 1043; 1046; 1047; 1048
13
[ 36556-48-6 ]
[ 2613-34-5 ]
[ 367-25-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium hydroxide In hydrogenchloride; methanol; water
Example 7 88 ml of methanol, 44 ml of water, 0.2 g of palladium-on-charcoal containing 10percent Pd and 0.04 mol of 3-chloro-2,4-difluoroaniline are charged to the same reactor as that of Example 6. A hydrogen pressure is introduced in the reactor, which is heated to 90° C. The hydrogen pressure is kept constant at 1.9*106 Pa absolute at 90° C. During the reaction, sodium hydroxide is added in proportion as hydrochloric acid is given off until an amount is reached which is comparable with that used for a corresponding amount of chlorodifluoroaniline in Example 6. After a period of 3 hours, the degree of conversion of the 3-chloro-2,4-difluoroaniline is 100percent and the 2,4-difluoroaniline yield is 99percent. The remainder of the conversion product (1percent) is composed of 4-fluoroaniline and of traces of aniline.
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 52, # 3, p. 307 - 316
21
[ 371-40-4 ]
[ 367-25-9 ]
[ 3863-11-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
22
[ 348-54-9 ]
[ 367-25-9 ]
Reference：
[1] Patent: US4145364, 1979, A,
23
[ 446-35-5 ]
[ 367-25-9 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 11, p. 3203 - 3207[2] Angew. Chem., 2013, vol. 125, # 11, p. 3285 - 3289,5
24
[ 83164-33-4 ]
[ 367-25-9 ]
[ 36701-89-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 5, p. 339 - 344
[2] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 5, p. 339 - 344
25
[ 83164-33-4 ]
[ 609-71-2 ]
[ 98-17-9 ]
[ 367-25-9 ]
[ 130191-66-1 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 5, p. 339 - 344
[2] Bulletin des Societes Chimiques Belges, 1990, vol. 99, # 5, p. 339 - 344
26
[ 1435-43-4 ]
[ 367-25-9 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 52, # 3, p. 307 - 316
27
[ 1435-43-4 ]
[ 367-25-9 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 52, # 3, p. 307 - 316
28
[ 367-25-9 ]
[ 36556-56-6 ]
Yield
Reaction Conditions
Operation in experiment
0.44 mol
With N-chloro-succinimide In dichloromethane at 10℃; for 2 h; Reflux
0.5 mol (1.0 eq) of 2,4-difluoroaniline and 200 ml of dichloromethane were charged into a reaction flask,Stir to dissolve all,Control the internal temperature of 10 ~ 15 in 5 batches into 0.55mol (1.1eq) NCS,Feeding finished,Heated to reflux 2h,In the control,Raw material reaction is complete,Add 10percent dilute hydrochloric acid to the bottle to adjust the pH to 6-7,The organic phase is separated,Washed,Rotate to dryness to give 0.44 mol (0.88 eq) of 2,4-difluoro-5-chloroaniline.0.44 mol of 2,4-difluoro-5-chloroaniline was charged into 1.5 mol (3 eq) of 25percent dilute sulfuric acid,Stirring 0.5h,And then into which 0.75mol (1.5eq) times of sodium phosphite,Control the internal temperature of 30 ~ 35 drop 0.5mol (1eq) sodium nitrite aqueous solution,Dripping finished control kettle temperature rise per hour 4 ~ 5 ,The program temperature,Kettle temperature rose to 60 ,Insulation stirring 2h,Static stratification,The organic phase is washed with water again,For steam distillation,The distilled product was separated from the distillation column by distillation of 3,5-difluorochlorobenzene 0.41 mol (0.82 eq)Purity 99.8percent.
Reference：
[1] Patent: CN106986741, 2017, A, . Location in patent: Paragraph 0017; 0018; 0019; 0020; 0021; 0022
29
[ 367-25-9 ]
[ 13918-92-8 ]
Reference：
[1] Patent: US4600709, 1986, A,
[2] Journal of Chemical Information and Modeling, 2015, vol. 54, # 12, p. 3404 - 3416
30
[ 367-25-9 ]
[ 13656-60-5 ]
Reference：
[1] Journal of Chemical Information and Modeling, 2015, vol. 54, # 12, p. 3404 - 3416
31
[ 367-25-9 ]
[ 367-34-0 ]
[ 3862-73-5 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
32
[ 367-25-9 ]
[ 2267-99-4 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
33
[ 367-25-9 ]
[ 53981-24-1 ]
Reference：
[1] Patent: CN107459495, 2017, A, . Location in patent: Paragraph 0036; 0037; 0044; 0045
34
[ 197565-66-5 ]
[ 201230-82-2 ]
[ 367-25-9 ]
[ 83164-33-4 ]
Yield
Reaction Conditions
Operation in experiment
33%
With sodium carbonate In xylene at 190 - 195℃; for 19 h;
EXAMPLE 6 N-(2,4-Difluorophenyl)-2-[3-(trifluoromethyl)phenoxy]-pyridine-3-carboxamide(Diflufenicam) Analogously to Example 4, 6.84 g (25 mmol) of 3-chloro-2-(3-trifluoromethyl)phenoxypyridine (prepared according to Example 2), 4.84 g (37.5 mmol) of 2,4-difluoroaniline, 2.92 g (27.5 mmol) of sodium carbonate, 17.5 mg (25 μmol) of dichlorobis(triphenylphosphine)-palladium(II) and 0.32 g (0.75 mmol) of 1,4-bis(diphenylphosphino)butane in 25 ml of xylene were reacted under a CO pressure of 15 bar at 190° to 195° C. for 19 hours. The conversion was ca. 80 percent. The mixture was worked up as in Example 3 to give 6 g of crude product in the form of a yellow crystalline solid. It was purified by recrystallization from 50 ml of methylcyclohexane. The yield of the title compound was 3.25 g (33 percent) of a white solid.
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 518 - 525
37
[ 367-25-9 ]
[ 123344-02-5 ]
Yield
Reaction Conditions
Operation in experiment
70.4%
at 0 - 4℃; for 0.5 h;
Dissolve 2,4-difluoroaniline (24.0 g, 186 mmol) in concentrated sulfuric acid (200 mL).Nitric acid (11.7 g, 186 mmol) was slowly added dropwise at 0°C.The temperature was kept below 4°C during the addition.Stir for half an hour in an ice-water bath.After the reaction is over,Pour the reaction mixture into ice water (1L).Sodium hydroxide was slowly added until the pH was 8.Extract with ethyl acetate (1L x 3)Combine the organic phase,The organic phase was washed with saturated brine (1 L).Drying with anhydrous sodium sulfateConcentrate under reduced pressure,The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1).A red solid (22.8 g, yield: 70.4percent) was obtained.
69.3%
Stage #1: at 0 - 5℃; for 0.833333 h; Stage #2: With sodium hydrogencarbonate In diethyl ether
Step 1: synthesis of 2,4-difluoro-5-nitroaniline (71)To a solution of 2,4-difluoroaniline (0.394 mL, 3.87 mmol) in concentrated sulfuric acid (5 mL, 94 mmol) at 0°C was added drop wise nitric acid (0.272 mL, 375 mg, 3.87 mmol) in 20 min. The reaction was stirred under 5°C for 30 min. The reaction mixture was poured in ice cold water and extracted with ether. Organic layer was washed with saturated NaHC03 solution, dried and evaporated to give 2,4-difluoro-5-nitroaniline 71 (467 mg, 69.3 percent). NMR (400 MHz, CDC13) 3.91 (br s, 2H), 6.98 (t, J= 10.2 Hz, 1H), 7.51 (dd, J= 8.6 Hz and 7.0 Hz, 1H).
69.3%
at 0 - 5℃; for 0.833333 h;
Step 1: synthesis of 2,4-difluoro-5-nitroaniline (71) To a solution of 2,4-difluoroaniline (0.394 mL, 3.87 mmol) in concentrated sulfuric acid (5 mL, 94 mmol) at 0° C. was added drop wise nitric acid (0.272 mL, 375 mg, 3.87 mmol) in 20 min. The reaction was stirred under 5° C. for 30 min. The reaction mixture was poured in ice cold water and extracted with ether. Organic layer was washed with saturated NaHCO3 solution, dried and evaporated to give 2,4-difluoro-5-nitroaniline 71 (467 mg, 69.3percent). NMR (400 MHz, CDCl3) 3.91 (br s, 2H), 6.98 (t, J=10.2 Hz, 1H), 7.51 (dd, J=8.6 Hz and 7.0 Hz, 1H).
45%
at 0℃; for 1 h;
In a glass RBF equipped with a Teflon-coated magnetic stirrer was dissolved 2,4- difluoro-phenylamine (1 eq.) in concentrated sulfuric acid (2.4 M). The resulting solution was cooled in an ice-brine bath and then added fuming nitric acid (0.8 eq.) drop-wise over a period of 20 mm. After 1 h of stirring at 0°C, the reaction mixture was poured over ice and carefully adjusted to a pH of —8 with sat. aq. NaHCO3. The resulting suspension was stirred at RT for 15 mm and the solid thus obtained was harvested via filtration. The filter cake thus obtained was washed with copious amount of water and then dried under reduced pressure for 18 h to furnish the desired product as a dark, orange solid (45percent yield).
750 mg
at 0 - 5℃;
Add in a 100mL three-neck bottle2,4-difluoroaniline (630 mg, 4.88 mmol) and concentrated sulfuric acid (10 mL),The ice water bath is cooled to 0-5 °C. Potassium nitrate (542 mg, 1.1 eq) was slowly added in portions, and the reaction was incubated for 1-2 h.Slowly add the reaction solution to pureWater (200 mL), the pH was adjusted to neutral with sodium carbonate solid, extracted three times with ethyl acetate (50 mL×3), and the organic phase was combined and washed twice with saturated brine.Dry over anhydrous sodium sulfate for 30 min, filter,The filtrate was concentrated under reduced pressure to give 750 mg of product.
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 19, p. 8027 - 8054
[2] Patent: CN107793413, 2018, A, . Location in patent: Paragraph 0168-0171
[3] Patent: WO2011/147764, 2011, A1, . Location in patent: Page/Page column 75-76
[4] Patent: US2013/79341, 2013, A1, . Location in patent: Paragraph 0249
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 1, p. 241 - 253
[6] Patent: WO2017/49068, 2017, A1, . Location in patent: Paragraph 00205
[7] Journal of Medicinal Chemistry, 1997, vol. 40, # 13, p. 2053 - 2063
[8] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000178
[9] Patent: CN108707139, 2018, A, . Location in patent: Paragraph 1043; 1049; 1050; 1051
38
[ 367-25-9 ]
[ 821-48-7 ]
[ 115761-79-0 ]
Reference：
[1] European Journal of Pharmaceutical Sciences, 2016, vol. 88, p. 166 - 177
39
[ 367-25-9 ]
[ 140-89-6 ]
[ 80087-71-4 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 120 - 130℃; Inert atmosphere
General procedure: A round-bottomed flask was charged with 2-bromoaniline or 2-fluoro-aniline (>3 g, 1.0 equiv) and potassium O-ethyl carbonodithioate(1.5–1.7 equiv). The mixture was dissolved in DMF (10 volumes) andheated to 120–130 °C until the aniline was fully consumed (3–14 h).The reaction mixture was cooled to r.t. and filtered. The filtrate wasdiluted with H 2 O (50 volumes) and the pH was adjusted to 1–2 usingaqueous 2 M HCl. The solid precipitate was collected, washed withH 2 O and dried to yield the pure product.
Reference：
[1] Organic Letters, 2017, vol. 19, # 21, p. 5836 - 5839
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
[3] Synthesis (Germany), 2018, vol. 50, # 10, p. 2027 - 2032
40
[ 28563-38-4 ]
[ 367-25-9 ]
[ 80087-71-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 4, p. 727 - 730
41
[ 367-25-9 ]
[ 501-53-1 ]
[ 112434-18-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
With pyridine In dichloromethane at 20℃;
To a 250-mL round-bottomed flask was added 2,4-difluoroaniline (11,4.62 mL, 45.4mmol), DCM (103 mL) and pyridine (7.40 mL,91mmol). The solutionwas stirred at rt andwas treatedwith benzylchloroformate (8.15 mL, 54.5mmol) drop wise via an addition funnel.After being stirred at rt overnight, the mixture was poured intowater and was extracted with DCM. The combined extracts werewashed with water, brine, dried with anhydrous sodium sulfate, filtered,and concentrated to give the title compound (11.1 g,42.2mmol, 93percent) as a white solid which was used without furtherpurification. LCMS (ESI, pos. ion) calcd for C14H11F2NO2: 263.1; found:286.1 (M+Na). 1H NMR (400MHz, DMSO-d6) d ppm 9.43 (br s, 1H),7.51–7.66 (m, 1H), 7.24–7.46 (m, 6H), 7.01–7.12 (m, 1H), 5.15 (s, 2H).
85%
With pyridine In dichloromethane at 20℃; for 1.5 h;
Step 1-Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52)To 2,4-difluoroaniline (47, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 52 (15.6 g, 85percent).
85%
With pyridine In dichloromethane at 20℃; for 1.5 h;
To 2,4-difluoroaniline (19, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 0.14 mol) and benzyl chloroformate (20, 11.9 mL, 83.4 mmol) were added. The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and postassium bisulfate solution. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material was crystallized from hexanes to provide the desired compound (21, 15.6 g, 85percent).
85%
With pyridine In dichloromethane at 20℃; for 1.5 h;
To 2,4-difluoroaniline (42, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 613 (15.6 g, 85percent).
85%
With pyridine In dichloromethane at 20℃; for 1.5 h;
Step 1 - Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl ester (32):[0229] To 2,4-difluoro-phenylamine (30, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 0.14 mol) and benzyl chloroformate (31, 11.9 mL, 83.4 mmol) are added. The reaction mixture is stirred at ambient temperature for 1.5 hours. The reaction mixture is concentrated under vacuum and the residue is partitioned between ethyl acetate and potassium bisulfate solution. The organic layer is dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material is crystallized from hexanes to provide the desired compound (32, 15.6 g, 85percent).
85%
With pyridine In dichloromethane at 20℃; for 1.5 h;
To 2,4-difluoro-phenylamine (1, 7 0 mL, 70 0 mmol) in 100 mL of dichloromethane, pyπdine (1 1 mL, 140 0 mmol) and benzyl chloroformate (2, 11 9 mL, 83 4 mmol) were added The reaction mixture was stirred at room temperature for 1 5 hours The reaction mixture was concentrated under vacuum and the residue w as partitioned between ethyl acetate and potassium bisulfate solution The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3,15 6 g, 85percent)
77%
Stage #1: With pyridine In dichloromethane at 20 - 30℃; Stage #2: With hydrogenchloride In water
To 2,4-difluoro-phenylamine (1, 50.00 g. 0.39 mol) were added 550 mL of anhydrous dichloromethane, and anhydrous pyridine (61.27 g, 0.77 mol), followed by addition of benzyl chloroformate (2, 79.28 g, 0.46 mol) dropvvise while maintaining the temperature at <;30 0C. The reaction mixture was stirred at room temperature for 2 hours and an additional 6.61 g (0.04 mol) of benzyl chloroformate was added and the reaction stirred an additional 2 hours, followed by addition of another 6.61 g Li f ben/yl chlorofoπnate. 'I he reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure and diluted with 250 mL of water. The pH was adjusted to 2 with 2 M aqueous hydrochloric acid, then extracted with 3 x 250 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was slurried in hexane, filtered and the solid collected and dried to provide the desired compound (24, 78.6 g, 77percent),
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 36, p. 6393 - 6396
[2] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 393 - 396
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 10, p. 2215 - 2234
[4] Tetrahedron Letters, 2008, vol. 49, # 16, p. 2607 - 2610
[5] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 44-45
[6] Patent: US2009/286783, 2009, A1, . Location in patent: Page/Page column 45-46
[7] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 188
[8] Patent: WO2011/63159, 2011, A1, . Location in patent: Page/Page column 188
[9] Patent: WO2010/129567, 2010, A1, . Location in patent: Page/Page column 67-68
[10] Patent: WO2010/104945, 2010, A1, . Location in patent: Page/Page column 42
[11] Journal of Medicinal Chemistry, 2010, vol. 53, # 21, p. 7699 - 7708
42
[ 108-22-5 ]
[ 367-25-9 ]
[ 274682-91-6 ]
Yield
Reaction Conditions
Operation in experiment
82.9%
Stage #1: With sulfuric acid; sodium nitrite In water at 0 - 15℃; for 0.75 h; Stage #2: With copper(II) sulfate; sodium sulfite In water at 10 - 15℃; for 3 h;
EXAMPLE 6 1-(2,4-Difluoro-phenyl)-propane-2-one With stirring and cooling 132.0 g (1.32 mol) of concentrated sulfuric acid are diluted with 375 ml of water.. At 10-15° C. 78.7 g (0.60 mol) of 2,4-difluoroaniline are added and the resulting suspension is treated with 104.6 g (0.606 mol) of a 40percent solution of sodium nitrite in water at 0-3° C. over 45 minutes. In a separate reactor a mixture is prepared from 6.0 g copper sulfate pentahydrate, 180 ml of water, 0.9 g of concentrated sulfuric acid and 91.2 g (0.90 mol) of isopropenyl acetate.. To this mixture the diazonium salt solution and 50.4 g of an aqueous 20percent sodium sulfite solution is concurrently added over a period of 2 hours at 10-15° C. The mixture is stirred for another hour before it is extracted with two portions of toluene.. The combined organic layers are washed with a diluted bicarbonate solution and brine.. The solvent is removed under reduced pressure and the residual crude oil is distilled at 75-80° C./5 mbar: 85.8 g of pale yellow 1-(2,4-difluoro-phenyl)-propane-2-one are obtained in 82.9percent yield.
A solution of ethyl 2,6-dichloro-5-fluoro nicotinylacetate (4) (8 g) in triethyl orthoformate (7 mL) and acetic anhydride (50 mL) was heated at 130 C. for 1 h with removal of ethyl acetate formed during the reaction. The solution was evaporated under reduced pressure to give mobile oil. The oil was dissolved in methylene chloride (250 mL) and 2,4-difluoroamline (5.2 g) was added to the solution. After standing for 1 h, the solution was evaporated to dryness and the residue recrystallized and washed with hexane to give 9 g of (5). m.p.=138-141 C.
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol ofPotassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled inan ice bath and stirred for 10 to 20 min, and then 0.1 mol bromine in glacialacetic acid was added dropwise at such a rate to keep the temperature below 10C throughout the addition. Theprogress of the reaction was monitored by Thin Layer Chromatography usingtoluene: acetone (8:2) solvent system. The reaction mixture was stirredat room temperature for 2 to 4 hrs, the hydrobromide (HBr) salt thus separatedout was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH)and the resulting precipitate was filtered, washed with water and dried to getthe desired product 2a-q.
With sulfuric acid; nitric acid; at 0 - 4℃; for 0.5h;
Dissolve 2,4-difluoroaniline (24.0 g, 186 mmol) in concentrated sulfuric acid (200 mL).Nitric acid (11.7 g, 186 mmol) was slowly added dropwise at 0C.The temperature was kept below 4C during the addition.Stir for half an hour in an ice-water bath.After the reaction is over,Pour the reaction mixture into ice water (1L).Sodium hydroxide was slowly added until the pH was 8.Extract with ethyl acetate (1L x 3)Combine the organic phase,The organic phase was washed with saturated brine (1 L).Drying with anhydrous sodium sulfateConcentrate under reduced pressure,The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1).A red solid (22.8 g, yield: 70.4%) was obtained.
69.3%
Step 1: synthesis of 2,4-difluoro-5-nitroaniline (71)To a solution of 2,4-difluoroaniline (0.394 mL, 3.87 mmol) in concentrated sulfuric acid (5 mL, 94 mmol) at 0C was added drop wise nitric acid (0.272 mL, 375 mg, 3.87 mmol) in 20 min. The reaction was stirred under 5C for 30 min. The reaction mixture was poured in ice cold water and extracted with ether. Organic layer was washed with saturated NaHC03 solution, dried and evaporated to give 2,4-difluoro-5-nitroaniline 71 (467 mg, 69.3 %). NMR (400 MHz, CDC13) 3.91 (br s, 2H), 6.98 (t, J= 10.2 Hz, 1H), 7.51 (dd, J= 8.6 Hz and 7.0 Hz, 1H).
69.3%
With sulfuric acid; nitric acid; at 0 - 5℃; for 0.833333h;
Step 1: synthesis of 2,4-difluoro-5-nitroaniline (71) To a solution of 2,4-difluoroaniline (0.394 mL, 3.87 mmol) in concentrated sulfuric acid (5 mL, 94 mmol) at 0 C. was added drop wise nitric acid (0.272 mL, 375 mg, 3.87 mmol) in 20 min. The reaction was stirred under 5 C. for 30 min. The reaction mixture was poured in ice cold water and extracted with ether. Organic layer was washed with saturated NaHCO3 solution, dried and evaporated to give 2,4-difluoro-5-nitroaniline 71 (467 mg, 69.3%). NMR (400 MHz, CDCl3) 3.91 (br s, 2H), 6.98 (t, J=10.2 Hz, 1H), 7.51 (dd, J=8.6 Hz and 7.0 Hz, 1H).
45%
With sulfuric acid; nitric acid; at 0℃; for 1h;
In a glass RBF equipped with a Teflon-coated magnetic stirrer was dissolved 2,4- difluoro-phenylamine (1 eq.) in concentrated sulfuric acid (2.4 M). The resulting solution was cooled in an ice-brine bath and then added fuming nitric acid (0.8 eq.) drop-wise over a period of 20 mm. After 1 h of stirring at 0C, the reaction mixture was poured over ice and carefully adjusted to a pH of -8 with sat. aq. NaHCO3. The resulting suspension was stirred at RT for 15 mm and the solid thus obtained was harvested via filtration. The filter cake thus obtained was washed with copious amount of water and then dried under reduced pressure for 18 h to furnish the desired product as a dark, orange solid (45% yield).
With sulfuric acid; nitric acid; at -10 - 0℃; for 1.25h;
A solution 2,4-difluoroaniline 94 was cooled to -10C, sulphuric acid (4 mL) was added slowly through addition funnel. Then the nitrating mixture prepared by mixing sulphuric acid (1 mL) and fuming nitric acid (0.161 mL) was added slowly over 15 mm.Then the reaction mixture was stirred for lh at -10C to 0C. The reaction was monitored by TLC, after the completion of reaction, the reaction mixture was poured into crushed ice and extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (50 mL) and dried over sodium sulphate and evaporated under reduced pressure to obtain crude product 95. The crude product was taken to next step without further purification(5.0 g, 75% yield). MS: 173.1 (M-H)+.
750 mg
With sulfuric acid; potassium nitrate; at 0 - 5℃;
Add in a 100mL three-neck bottle2,4-difluoroaniline (630 mg, 4.88 mmol) and concentrated sulfuric acid (10 mL),The ice water bath is cooled to 0-5 C. Potassium nitrate (542 mg, 1.1 eq) was slowly added in portions, and the reaction was incubated for 1-2 h.Slowly add the reaction solution to pureWater (200 mL), the pH was adjusted to neutral with sodium carbonate solid, extracted three times with ethyl acetate (50 mL×3), and the organic phase was combined and washed twice with saturated brine.Dry over anhydrous sodium sulfate for 30 min, filter,The filtrate was concentrated under reduced pressure to give 750 mg of product.
With hydrogenchloride; n-butyllithium; diisopropylamine; In tetrahydrofuran; 1,4-dioxane; chloroform;
EXAMPLE H-4 2-(2,4-Difluoroanilino)-4,5-difluorobenzoic Acid Lithium diisopropylamide was generated at -5 C. by combining diisopropylamine (7.2 mL, 51 mmol) and n-butyl lithium (33 mL, 53 mmol) in 150 mL of dry THF. After 30 minutes, the solution was cooled to -78 C. and 2,4-difluoroaniline (3.46 mL, 34 mmol) was added and stirred for 2 hours. <strong>[446-17-3]2,4,5-Trifluorobenzoic acid</strong> (3.0 g, 17 mmol) was added, and the mixture was allowed to warm to room temperature over 17 hours. A saturated solution of HCl/dioxane (10 mL) was added, and after 1 hour the mixture was concentrated to a solid. The solid was redissolved in chloroform and washed with 1N HCl, water, and brine. The solution was dried and concentrated to afford 4.54 g of the title compound as a solid. 1H NMR (CDCl3) delta8.95 (bs, 1H), 7.80 (m, 2H), 7.24 (m, 1H) 6.90 (m, 2H), 6.48 (m, 1H).
To a 250-mL round-bottomed flask was added 2,4-difluoroaniline (11,4.62 mL, 45.4mmol), DCM (103 mL) and pyridine (7.40 mL,91mmol). The solutionwas stirred at rt andwas treatedwith benzylchloroformate (8.15 mL, 54.5mmol) drop wise via an addition funnel.After being stirred at rt overnight, the mixture was poured intowater and was extracted with DCM. The combined extracts werewashed with water, brine, dried with anhydrous sodium sulfate, filtered,and concentrated to give the title compound (11.1 g,42.2mmol, 93%) as a white solid which was used without furtherpurification. LCMS (ESI, pos. ion) calcd for C14H11F2NO2: 263.1; found:286.1 (M+Na). 1H NMR (400MHz, DMSO-d6) d ppm 9.43 (br s, 1H),7.51-7.66 (m, 1H), 7.24-7.46 (m, 6H), 7.01-7.12 (m, 1H), 5.15 (s, 2H).
85%
With pyridine; In dichloromethane; at 20℃; for 1.5h;
Step 1-Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52)To 2,4-difluoroaniline (47, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 52 (15.6 g, 85%).
85%
With pyridine; In dichloromethane; at 20℃; for 1.5h;
To 2,4-difluoroaniline (19, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 0.14 mol) and benzyl chloroformate (20, 11.9 mL, 83.4 mmol) were added. The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and postassium bisulfate solution. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material was crystallized from hexanes to provide the desired compound (21, 15.6 g, 85%).
85%
With pyridine; In dichloromethane; at 20℃; for 1.5h;
To 2,4-difluoroaniline (42, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 613 (15.6 g, 85%).
85%
With pyridine; In dichloromethane; at 20℃; for 1.5h;
Step 1 - Preparation of (2,4-difluoro-phenyl)-carbamic acid benzyl ester (32):[0229] To 2,4-difluoro-phenylamine (30, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 0.14 mol) and benzyl chloroformate (31, 11.9 mL, 83.4 mmol) are added. The reaction mixture is stirred at ambient temperature for 1.5 hours. The reaction mixture is concentrated under vacuum and the residue is partitioned between ethyl acetate and potassium bisulfate solution. The organic layer is dried with magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting material is crystallized from hexanes to provide the desired compound (32, 15.6 g, 85%).
85%
With pyridine; In dichloromethane; at 20℃; for 1.5h;
To 2,4-difluoro-phenylamine (1, 7 0 mL, 70 0 mmol) in 100 mL of dichloromethane, py?dine (1 1 mL, 140 0 mmol) and benzyl chloroformate (2, 11 9 mL, 83 4 mmol) were added The reaction mixture was stirred at room temperature for 1 5 hours The reaction mixture was concentrated under vacuum and the residue w as partitioned between ethyl acetate and potassium bisulfate solution The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3,15 6 g, 85%)
77%
To 2,4-difluoro-phenylamine (1, 50.00 g. 0.39 mol) were added 550 mL of anhydrous dichloromethane, and anhydrous pyridine (61.27 g, 0.77 mol), followed by addition of benzyl chloroformate (2, 79.28 g, 0.46 mol) dropvvise while maintaining the temperature at <;30 0C. The reaction mixture was stirred at room temperature for 2 hours and an additional 6.61 g (0.04 mol) of benzyl chloroformate was added and the reaction stirred an additional 2 hours, followed by addition of another 6.61 g Li f ben/yl chlorofo?nate. 'I he reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure and diluted with 250 mL of water. The pH was adjusted to 2 with 2 M aqueous hydrochloric acid, then extracted with 3 x 250 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was slurried in hexane, filtered and the solid collected and dried to provide the desired compound (24, 78.6 g, 77%),
To a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (4.2g, 18.95mmol) and triethylamine (5.3ml, 38mmol) in TetaF (100ml) was added 2,4- difluoroaniline (2.1ml, 20.58mmol). The mixture was stirred for 2h, and methyl {bis[(2,2,2- trifluoroethyl)oxy]phosphoryl}acetate (6.Og, 18.95mmol) was added. The mixture was stirred for 18h, diluted with DCM (200ml) and washed with water (2 x 100ml). The dried (Na2SO4) organic phase was filtered and evaporated. Flash chromatography (EtOAc/ etaexane, 1 :5) provided the title compound as a cream solid (2.5g, 40%): LC-MS m/z 340 (M+eta)+ retention 3.24min.
To 100 ml of toluene were added 5.8 g (45 mmol) of 2,4-difluoroaniline and 5.5 g (54 mmol) of triethylamine, then 20 ml of a toluene solution containing 7.9 g (45 mmol) of <strong>[80099-98-5]6-chloropicolinic chloride</strong> was gradually added to the mixture, and the resulting mixture was stirred under room temperature for 5 hours. [0328] Toluene was added to the resulting mixture, the organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. [0329] After concentration by an evaporator, the resulting crystalline was washed with hexane to obtain 6.56 g (an yield was 54%) of the desired compound.
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; 1,4-di(diphenylphosphino)-butane; In xylene; at 190 - 195℃; under 11251.1 Torr; for 19.0h;
EXAMPLE 6 N-(2,4-Difluorophenyl)-2-[3-(trifluoromethyl)phenoxy]-pyridine-3-carboxamide(Diflufenicam) Analogously to Example 4, 6.84 g (25 mmol) of 3-chloro-2-(3-trifluoromethyl)phenoxypyridine (prepared according to Example 2), 4.84 g (37.5 mmol) of 2,4-difluoroaniline, 2.92 g (27.5 mmol) of sodium carbonate, 17.5 mg (25 mumol) of dichlorobis(triphenylphosphine)-palladium(II) and 0.32 g (0.75 mmol) of 1,4-bis(diphenylphosphino)butane in 25 ml of xylene were reacted under a CO pressure of 15 bar at 190 to 195 C. for 19 hours. The conversion was ca. 80 percent. The mixture was worked up as in Example 3 to give 6 g of crude product in the form of a yellow crystalline solid. It was purified by recrystallization from 50 ml of methylcyclohexane. The yield of the title compound was 3.25 g (33 percent) of a white solid.
2,4-difluoro-N-(4-sulfamoylbenzylidene)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
75(i) 2,4-Difluoro-N-(4-sulfamoylbenzylidene)aniline Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 2,4-difluoroaniline as starting materials, the title compound was obtained as a white powder (yield 47%). Nuclear Magnetic Resonance Spectrum (270 MHz, hexadeuterated dimethyl sulfoxide) δ ppm: 8.79 (1H, singlet); 8.12 (2H, doublet, J=8 Hz); 7.97 (2H, doublet, J=8 Hz); 7.58-7.34 (4H, multiplet); 7.21-7.13 (1H, multiplet).
With sodium hydroxide;palladium; In hydrogenchloride; methanol; water;
Example 7 88 ml of methanol, 44 ml of water, 0.2 g of palladium-on-charcoal containing 10% Pd and 0.04 mol of <strong>[2613-34-5]3-chloro-2,4-difluoroaniline</strong> are charged to the same reactor as that of Example 6. A hydrogen pressure is introduced in the reactor, which is heated to 90 C. The hydrogen pressure is kept constant at 1.9*106 Pa absolute at 90 C. During the reaction, sodium hydroxide is added in proportion as hydrochloric acid is given off until an amount is reached which is comparable with that used for a corresponding amount of chlorodifluoroaniline in Example 6. After a period of 3 hours, the degree of conversion of the <strong>[2613-34-5]3-chloro-2,4-difluoroaniline</strong> is 100% and the 2,4-difluoroaniline yield is 99%. The remainder of the conversion product (1%) is composed of 4-fluoroaniline and of traces of aniline.
The overall yield of Examples 1 and 2 for the preparation of 2,4-difluoroaniline by catalytic hydrogenation from <strong>[3847-58-3]3-chloro-2,4-difluoronitrobenzene</strong> is 97.1%.
N-(2,4-difluorophenyl)-2-(3-α,α,α-trifluoromethylphenoxy)-6-pyridinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In thionyl chloride; dichloromethane;
EXAMPLE 24 Preparation of N-(2,4-difluorophenyl)-2-(3-alpha,alpha,alpha-trifluoromethylphenoxy)-6-pyridinecarboxamide 6-(3-alpha,alpha,alpha-Trifluoromethylphenoxy)picolinic acid (7.1 g) in thionyl chloride (50 ml) was refluxed for 1 hour. The excess thionyl chloride was evaporated in vacuo and dichloromethane added to the residual picolinoyl chloride. A solution of 2,4-difluoroaniline (3.3 g) and triethylamine (2.6 g) in dichloromethane (50 ml) was then added dropwise with stirring at ambient temperature. After stirring a further 1 hour, the reaction mixture was washed with water, dried over anhydrous magnesium sulphate and the dichloromethane evaporated. The residue was purified on a silica gel column using dichloromethane as eluant to give the title compound (6.9 g) as a white solid of melting point 110-111 C. m/e Theory: Found 394:394
With triethylamine; In thionyl chloride; dichloromethane;
Example 24 Preparation of N-(2,4-difluorophenyl)-2-(3-alpha,alpha,alpha-trifluoromethylphenoxy)-6-pyridinecarboxamide 6-(3-alpha,alpha,alpha-Trifluoromethylphenoxy)picolinic acid (7.1g) in thionyl chloride (50ml) was refluxed for 1 hour. The excess thionyl chloride was evaporated in vacuo and dichloromethane added to the residual picolinoyl chloride. A solution of 2,4-difluoroaniline (3.3g) and triethylamine (2.6g) in dichloromethane (50ml) was then added dropwise with stirring at ambient temperature. After stirring a further 1 hour, the reaction mixture was washed with water, dried over anhydrous magnesium sulphate and the dichloromethane evaporated. The residue was purified on a silica gel column using dichloromethane as eluant to give the title compound (6.9g) as a white solid of melting point 110-111C.
With triethylamine; In thionyl chloride; dichloromethane; water;
EXAMPLE 21 Preparation of N-(2,4-difluorophenyl)-2-chloro-6-pyridinecarboxamide 6-Chloropicolinic acid (25 g) in thionyl chloride (50ml) was stirred and heated to reflux for 1.5 hours. The excess thionyl chloride was evaporated in vacuo and dichloromethane (100 ml) added to the residual <strong>[80099-98-5]6-chloropicolinoyl chloride</strong>. A solution of 2,4-difluoroaniline (20.5 g) and triethylamine (16 g) in dichloromethane (50 ml) was added with stirring, maintaining the temperature below 20 C. After the addition, the reaction mixture was stirred a further 1 hour at ambient temperature. Water was then added to the reaction mixture and the dichloromethane phase separated. After a further washing with water, brine and drying over anhydrous magnesium sulphate, the dichloromethane was removed to give the title compound (42 g) as a pale yellow solid of melting point 86-87 C. m/e Theory: Found 268:268 The compounds of general formula IV listed in Table 3 below were prepared by the method of Example 21.
With triethylamine; In thionyl chloride; dichloromethane; water;
Example 21 Preparation of N-(2,4-difluorophenyl)-2-chloro-6-pyridinecarboxamide 6-Chloropicolinic acid (25g) in thionyl chloride (50ml) was stirred and heated to reflux for 1.5 hours. The excess thionyl chloride was evaporated in vacuo and dichloromethane (100ml) added to the residual <strong>[80099-98-5]6-chloropicolinoyl chloride</strong>. A solution of 2,4-difluoroaniline (20.5g) and triethylamine (16g) in dichloromethane (50ml) was added with stirring, maintaining the temperature below 20C. After the addition, the reaction mixture was stirred a further 1 hour at ambient temperature. Water was then added to the reaction mixture and the dichloromethane phase separated. After a further washing with water, brine and drying over anhydrous magnesium sulphate, the dichloromethane was removed to give the title compound (42g) as a pale yellow solid of melting point 86-87C. The compounds of general formula IV listed in Table 3 below were prepared by the method of Example 21.
EXAMPLE VI A suspension of triethyl amine (15 ml, 0.11 mol), 2,4-difluoroaniline (25 ml, 0.24 mol), copper bronze (2.7 g., 0.04 mol), in hot DMF (25 ml) was treated with a solution of <strong>[110877-64-0]2-chloro-4,5-difluorobenzoic acid</strong> (23 g., 0.12 mol) in 25 ml of DMF and the temperature was maintained at 85 C. for 8 hours. The reaction mixture was allowed to cool to room temperature and was then stirred overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ether and aqueous ammonium chloride. The organic phase was washed with 2N HCl and saturated aqueous lithium chloride solution. The ether was dried over sodium sulfate, treated with darco and then filtered and evaporated. The residue was crystallized from hexane-ether to afford 21.6 g (62%) of 2-(2,4-difluorophenylamino)-4,5-difluorobenzoic acid; m.p.: 215-216 C.
ethyl 1-(2,4-difluorophenylaminocarbonyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
triethylamine;
Preparation of ethyl 1-(2,4-difluorophenylaminocarbonyl)cyclopropanecarboxylate 1-Carboethoxycyclopropanecarboxylic acid 7.00 grams, 0.04 mole), ethyl chloroformate (4.8) grams, 0.04 mole) and 2.4-difluoroaniline (5.72 grams, 0.04 mole) were reacted sequentially in the presence of triethylamine (4.51 grams, 0.04 mole) in a manner similar to that described in Example XXXIII to give 7.13 grams (0.03 mole) of ethyl 1-(2,4-difluorophenylaminocarbonyl)cyclopropanecarboxylate as a white crystalline solid having a melting point of 79 C.-80.5 C. Elemental analysis of the product indicated the following: Analysis: C13 H13 F2 NO3; Calculated: C, 57.99; H, 4.87. Found: C, 58.36; H, 5.17.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Cooling with ice;
In a 50 mL round bottom flask, add 2,4-difluoroaniline (65.0 mg, 0.5 mmol), 2-(3-trifluoromethyl)phenoxynicotinic acid E1 (170.0 mg, 0.6 mmol), 10 mL of anhydrous dichloromethane (DCM) was added, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI · HCl, 124.5 mg, 0.65 mmol) was added under an ice bath. 4-Dimethylaminopyridine (DMAP, 1.2mg, 0.01mmol), the mixed system was stirred at room temperature, after TLC detected the reaction was complete, Saturated sodium bicarbonate (NaHCO3, 5 mL) was added to quench the reaction, and extracted with dichloromethane (DCM) three times (10 mL × 3), Washed with water (10mL × 3), washed with saturated sodium chloride solution (10mL × 3), dried over anhydrous sodium sulfate (Na2SO4), concentrated under reduced pressure, and separated by column chromatography (V petroleum ether: V ethyl acetate, 8:1) ,173mg of Diflufenican was obtained as a white solid with a yield of 88%.
With thionyl chloride; triethylamine; In dichloromethane; water; toluene;
EXAMPLE 2 A mixture of thionyl chloride (465 ml) and 2-(3-trifluoromethylphenoxy)nicotinic acid [930 L g; described by F. J. Villani et al, J. Med. Chem. 18, 1 (1975)] was allowed to stand at ambient temperature for 18 hours and was then heated at reflux for 1 hour. Toluene (1 liter) was then added and the solution was evaporated under reduced pressure. The residue thus obtained was dissolved in methylene chloride (3 liters) and treated, with stirring, with triethylamine (453 ml) at ambient temperature. 2,4-Difluoroaniline (422 g) was then added over 1 hour while maintaining the temperature at 10 to 15 C. and the mixture was then heated at reflux for 2 hours. The methylene chloride was removed by distillation and the residue was treated with water (4 liters). A solid of spongy texture was obtained which was filtered off, dried at 50 C. and recrystallized from a mixture of toluene and hexane (2:3; 15 liters), to give N-(2,4-difluorophenyl)-2-(3-trifluoromethylphenoxy)nicotinamide (720 g), m.p. 160-161 C. as a colourless crystalline solid.
With bromine; sodium acetate; In water; acetic acid;
METHOD A Preparation of 2-bromo-4,6-difluoroaniline. A solution of bromine (16.0 g; 0.10 mol) in glacial acetic acid (25 ml) is added dropwise to a solution of 2,4-difluoroaniline (12.9 g; 0.10 mol) in glacial acetic acid (75 ml) while maintaining the temperature of the reaction mixture below 25 C. The reaction mixture is stirred an additional 0.5 hour during which time a solution of sodium acetate (5.48 g; 0.137 mol) in water (100 ml) is added. The reaction mixture is then diluted with water (300 ml), the precipitated purple solid is filtered, washed with water (100 ml) and dried under vacuum. Recrystallization of the solids from aqueous ethanol affords 14.14 g of product, m.p. 40-42 C. (yield: 68%).
With sodium nitrite; trichloroacetic acid;copper(I) chloride; In benzene;
EXAMPLE 1 2,4-difluorobiphenyl A mixture of 2,4-difluoroaniline (3.52 g; 0.0273 mole), trichloroacetic acid (6 g; 0.0367 mole), cuprous chloride (0.14 g; 0.0014 mole) and of trimethylorthoformate (5.8 g; 0.0548 mole) in benzene (140.6 g; 1.8 moles) was heated to 60 C. under nitrogen. Aliquots of sodium nitrite (2.1 g; 0.0304 mole) were added to the thus obtained mixture. After having been kept under stirring for 16 hours, the reaction mixture was hydrolyzed with water and diluted hydrochloric acid. The organic layer was separated and washed with water till neutralization dried over sodium sulphate and concentrated. The residue was purified via chromatography on silica gel 60 (Merck 70-230 mesh) column; eluent, petroleum ether (40-60 C.). The solvent was removed and 4.7 g of 2,4-difluorobiphenyl melting at 63-65 C. were thus obtained. Yield, 90%.
The starting material was prepared as follows. 2,4-Difluoroaniline and butyl nitrite were reacted with benzene in a modified Gomberg reaction to give 2,4-difluorobiphenyl, m.p. 63-65C. which was reacted with acetyl chloride in a Friedel-Crafts reaction to give 4-acetyl-2',4'-difluorobiphenyl, m.p. 82.5-83.5C.
4-(2,4-Difluorophenyl)piperazine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In butan-1-ol;
Formula X A mixture of 0.1 mol of bis-bromoethylamine hydrobromide and 0.1 mol of 2,4-difluoroaniline in 50 ml of butan-1-ol is heated at the boil for 14 hours. The reaction mixture is then cooled and the precipitate obtained is filtered off. The crystals are taken up with water and the mixture is rendered basic in the cold with a 10% solution of sodium hydroxide. The aqueous phase is extracted with chloroform and the extract is washed with water, dried over sodium carbonate and filtered. The chloroform is evaporated off and the residue obtained is taken up with acetone. Hydrogen chloride gas is bubbled through this solution, with stirring, until the pH is acid, and the crystals formed are allowed to settle. The crystals obtained are filtered off and then washed with acetone and dried. 4-(2,4-Difluorophenyl)piperazine dihydrochloride is thus recovered in the form of crystals melting at 205 C.
N-(2,4-difluorophenyl)-6-chloropicolinic anilide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With triethylamine; In toluene;
Second step: Synthesis of N-(2,4-difluorophenyl)-6-chloropicolinic anilide. To 100 ml of toluene were added 5.8 g (45 mmol) of 2,4-difluoroaniline and 5.5 g (54 mmol) of triethylamine, then 20 ml of a toluene solution containing 7.9 g (45 mmol) of <strong>[80099-98-5]6-chloropicolinic chloride</strong> was gradually added to the mixture, and the resulting mixture was stirred under room temperature for 5 hours. Toluene was added to the resulting mixture, the organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration by an evaporator, the resulting crystalline was washed with hexane to obtain 6.56 g (an yield was 54%) of the desired compound.
Step A Preparation of 2,4-difluorobiphenyl To a 50 liter resin pot equipped with stirrer, thermometer, nitrogen-inlet, internal steam coil and reflux condenser is charged 31.5 liters of benzene, 1.025 liters of isoamyl nitrite and 700 g. (5.43 moles) of 2,4-difluoroaniline. The reaction mixture is heated to reflux. Vigorous nitrogen evolution begins at 70 C. Reflux begins at 74 and rises to 77 during the reaction period. The batch is refluxed for 5 hours. The benzene is atmospherically distilled (required 3.5 hours) and the residue is steam distilled until a single-phase distillate is collected (required 10 hours). The layers are separated and the aqueous portion is extracted with 2*2.6 liters of benzene. The combined benzene extracts are washed with 2*2.6 liters of water, dried over anhydrous magnesium sulfate and filtered. This dried benzene layer is combined with that from an identical run and the benzene is removed in vacuo. The residue, crude 2,4-difluorobiphenyl, weighed 1.321 kg. This crude is dissolved in a mixture of 4.4 liters isopropanol and 2.2 liters of water at 65. The solution is cooled slowly to 25, seeding during the cooling period, and aged at 25 for one hour. The batch is cooled to 0-5, aged at 0-5 for one hour, and the solids are filtered, washed with 3*360 ml. of cold (0) isopropanol/water (2/1) and then slurry-washed with 3.6 liters of water. The cake is air dried. Yield, 1.092 kg. (52.5%), m.p. 61-63.
With sodium hydrogencarbonate; potassium carbonate; benzotriazol-1-ol; In N,N-dimethyl-formamide;
Example 15 Production of 10-(benzoxazol-2-ylthio)-N-(2,4-difluorophenyl)decanamide: WSC (990 mg, 5.2 mmols) and HOBt (698 mg, 5.2 mmols) were added to a DMF (10 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and <strong>[50530-12-6]10-bromodecanoic acid</strong> (1.18 g, 4.7 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=10/1), and the resulting crystals were recrystallized from ether-hexane to obtain 763 mg (yield: 45%) of 10-bromo-N-(2,4-difluorophenyl)decanamide as colorless needle-like crystals. Potassium carbonate (46 mg, 0.33 mmols) and 18-crown-6 (8 mg, 0.03 mmols) were added to a DMF (2 ml) solution of the resulting anilide (109 mg, 0.3 mmols) and 2-mercaptobenzoxazole (45 mg, 0.3 mmols), and stirred at 80 C. for 1 hour. The reaction mixture was diluted with water, and extracted with ether. The organic layer was washed with water, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the residue was purified through preparative thin-layer chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane. 80 mg (yield: 61%) of the intended product was obtained as colorless needle-like crystals. m.p.: 102-103 C. IR (KBr) cm-1: 3436, 3296, 1658, 1534, 1507 1H-NMR (CDCl3) delta: 1.25-1.55 (10H, m), 1.64-1.87 (4H, m), 2.39 (2H, t, J=7.3 Hz), 3.31 (2H, t, J=7.3 Hz), 6.81-6.91 (2H, m), 7.17-7.32 (3H, m), 7.43 (1H, m), 7.60 (1H, m), 8.26 (1H, m) EIMS m/z (relative intensity): 432 (M+, 100)
Example 41; 3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)pyrazine-2-carboxamide, bis(trifluoroacetic acid) salt; A) 3-Chloro-N-(2,4-difluorophenyl)pyrazine-2-carboxamide; To a mixture of <strong>[27398-39-6]3-chloropyrazine-2-carboxylic acid</strong> (Tyger Scientific, 500 mg, 3.15 mmol) in methylene chloride (30 mL) and DMF (0.1 mL) was added oxalyl chloride (593 mg, 4.7 mmol). After stirring 30 min the reaction mixture was concentrated in vacuo. The residue was taken up in acetonitrile (12 mL) and was treated with triethylamine (920 mg, 9.1 mmol) and 2,4-difluoroaniline (430 mg, 3.3 mmol) and stirred 30 min. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over anhydrous MgSO4, and then concentrated in vacuo. The resulting solid was recrystallized (ethyl acetate/hexanes) to give the amide (455 mg, 53percent) as a solid. MS(ESI+) m/z 270 (M+H)+.
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 255h;
Example 1; 4-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide, hydrochloride salt; A) 4-Chloro-N-(2,4-difluorophenyl)nicotinamide; To a mixture of <strong>[10177-29-4]4-chloronicotinic acid</strong> (Lancaster Synthesis, 0.31 g, 2.0 mmol) and 2,4-difluoroaniline (Aldrich, 0.20 mL, 2.0 mmol) in anhydrous dichloromethane (5 mL) was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP, Novabiochem, 1.4 g, 3.0 mmol) followed by diisopropylethylamine (1.1 mL, 6.4 mmol). Anhydrous DMF (2 mL) was added to the mixture and the reaction stirred at ambient temperature. After 255 hours, the reaction mixture was partitioned between chloroform and 10% LiCl (aq). The organic layer was washed three times with 10% LiCl (aq), dried over anhydrous MgSO4, then concentrated in vacuo. Purification of the residue by flash column chromatography (SiO2, eluting with 1:1 hexane/EtOAc) afforded the desired compound (0.23 g, 42%). 1H NMR (DMSO-d6) delta 10.58 (s, 1H), 8.78 (s, 1H), 8.66 (d, 1H, J=5.4 Hz), 7.82-7.88 (m, 1H), 7.71 (d, 1H, J=5.4 Hz), 7.37-7.43 (m, 1H), 7.14-7.19 (m, 1H); MS(ESI+) m/z 269 (M+H)+.
EXAMPLE 6 1-(2,4-Difluoro-phenyl)-propane-2-one With stirring and cooling 132.0 g (1.32 mol) of concentrated sulfuric acid are diluted with 375 ml of water.. At 10-15 C. 78.7 g (0.60 mol) of 2,4-difluoroaniline are added and the resulting suspension is treated with 104.6 g (0.606 mol) of a 40% solution of sodium nitrite in water at 0-3 C. over 45 minutes. In a separate reactor a mixture is prepared from 6.0 g copper sulfate pentahydrate, 180 ml of water, 0.9 g of concentrated sulfuric acid and 91.2 g (0.90 mol) of isopropenyl acetate.. To this mixture the diazonium salt solution and 50.4 g of an aqueous 20% sodium sulfite solution is concurrently added over a period of 2 hours at 10-15 C. The mixture is stirred for another hour before it is extracted with two portions of toluene.. The combined organic layers are washed with a diluted bicarbonate solution and brine.. The solvent is removed under reduced pressure and the residual crude oil is distilled at 75-80 C./5 mbar: 85.8 g of pale yellow 1-(2,4-difluoro-phenyl)-propane-2-one are obtained in 82.9% yield.
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 150℃; for 1.0h;Microwave irradiation;
TD 2,4-difluoru-phenylami?e (1, 5 11 niL, 50.7 rnmol) in 250 mL of tetrahydrofuran, cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) was added slowly. After 30 minutes, l,2-bis-(chloro-dimethyl-silanyl)-efhane (1 1.5 g, 53.4 mmol) dissolved in 40.0 mL of tetrahydrofuran was added slowly. After 1 hour, n-butyllifhium ( 1.60 M in hexane, 31.9 mL, 51.1 mmol) was added slowly. The reaction was stirred at -78 0C for 30 minutes and then allowed to warm to room temperature over 40 minutes. The reaction was cooled to -78 C and n- butylhthium (1.60 M in hexane, 35 1 mL, 56.1 mmol) was added slowly. After 70 minutes, benzyl chloroformate (2, 7.97 mL, 55.8 mmol) was added to the reaction, l he reaction mixture was stirred at -78 "C overnight follow ed by addition of 120 mL of 2 N aqueous hydrochloric acid. The reaction was allowed to warm to room tempeiature for 2 hours The organic layer was separated The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum, l he desired compound was isolated by silica gel column chromatography (ethyl acetate tiexane 20%) to give a colorless oil (3, 10.6 g, 79.7%), MS(ESI) [M+Hf] f = 264.1.
To 2,4-difluoro-phenylamine (42, 5.11 mL, 50.7 mmol) in tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) slowly. After 30 minutes, l,2-Bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in tetrahydrofuran (40.0 mL) was added to the reaction slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL, 51.0 mmol) was added slowly to the reaction. The reaction was stirred at -78 0C for 30 minutes and then allowed to warm to room temperature over 40 minutes. The reaction was cooled to -78 0C, followed by addition of n-butyllithium (1.60 M in hexane, 35.1 mL, 56.2 mmol) slowly. After 70 minutes, benzyl chloroformate (7.97 mL, 55.8 mmol) was added to the reaction. The reaction mixture was stirred at -78 C overnight followed by addition of 2 N HCl (120 mL). The reaction was allowed to warm to room temperature for 2 hours. The EPO <DP n="76"/>organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (43, 10.6 g, 79.7%). MS(ESI) [M+irT = 264.1.
79.7%
To 2,4-difluoro-phenylammc (1, 5 11 mL, 50 7 mmol) in tetrahydrofuran (250 mL), cooled with dry ice/acetone bath under an atmosphere of nitrogen, was added n-butyllithium (1 60 M m hexane, 34 0 mL, 54 4 mmol) slowly After 30 minutes, l ,2-Bis-(chloro-dimethyl-silanyl)-ethane (1 1 5 g, 53 4 mmol) dissolved in tetrahydrofuran (40 0 mL) was added to the reaction slowly After 1 hour, n-butyllithium (1 60 M in hexane, 31 9 mL, 51 0 mmol) was added slowly to the reaction The reaction was stirred at -78 0C for 30 minutes and then allowed to warm to room temperature over 40 minutes The reaction was cooled to -78 0C, followed by addition of n-butylhthmm (1 60 M in hexane, 35 1 mL, 56 2 mmol) slowly After 70 minutes, benzyl chloroformate (7 97 mL, 55 8 mmol) was added to the reaction The reaction mixture was stirred at -78 0C overnight followed by addition of 2 N HCl (120 mT ) The reaction was allowed to warm to room temperature for 2 hours The organic layer was separated The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate The organic layers were combined and washed with brine, dned over anhydrous sodium sulfate, filtrated and concentrated The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (50, 10 6 g, 79 7%) MS(ESI) [M+H+]+ = 264 1
Stage #1: 5-methyl-4-iodo-3-phenylisoxazole With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 1h;
Stage #2: methyl 3,3,3-trifluoropyruvate In tetrahydrofuran at -78 - 0℃; for 1h;
Stage #3: 2,4-difluorophenylamine In tetrahydrofuran at 0 - 20℃;
Representative procedure for the synthesis of a-hydroxy a-trifluoromethyl amides 8
General procedure: preparation of 3,3,3-trifluoro-2-hydroxy-1-morpholino-2-phenylpropan-1-one 8b (Table 2, entry 1). To a solution of phenyl iodide 5a (300 lL, 2.68 mmol)in THF (4 mL) at 0 C, isopropylmagnesium chloride in THF (1338 lL,2.68 mmol, 2 M) was added dropwise. After stirring at 0 C for 1 h, a solutionof methyl trifluoropyruvate 7a (273 lL, 2.68 mmol) in THF (3 mL) was addeddropwise at 78 C. The mixture was stirred at 78 C for 1 h and thenwarmed to 0 C, morpholine 6b (350 lL, 4.01 mmol) and isopropylmagnesiumchloride (2.0 mL, 4.01 mmol, 2 M) were added dropwise. At the end of theaddition, the external cooling was removed, and the reaction was aged at roomtemperature overnight. At 0 C, the reaction mixture was quenched with slowaddition of satd. NH4Cl and extracted with EtOAc. The combined organic layerswere dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.Purification by flash chromatography (0-60% EtOAc/hexane) provided thedesired amide
N-((1H-benzo[d]imidazol-2-yl)methyl)-2,4-difluoroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.7%
With sodium carbonate; In ethanol; for 24h;Reflux;
General procedure: A mixture of compound 2 (1.669 g, 0.01 mol), 2-fluoroaniline (1.110 g, 0.01 mol) and sodium carbonate (1.276 g, 0.012 mol) in ethanol (20 mL) was refluxed for 24 h. Upon completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulphate and further purified by silica gel column chromatography (eluent, petroleum ether/ethyl acetate (5/1, V/V)) to afford the desired compound 3a as yellow solid. Yield: 73.1%;
79%
General procedure: A mixture of compound 1 (1.669 g, 0.01 mol) and 3,5-bis(trifluoromethyl)aniline (2.234 g, 0.01 mol) was refluxed in ethanol (20 mL). After 24 h, potassium carbonate (1.279 g, 0.012 mol) was added with continuous stirring for another 12 h. Upon completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulfate and further purified bysilica gel column chromatography (eluent, petroleum ether/ethyl acetate (5/1,V/V)) to afford the desired compound 2a as yellow solid
3-bromo-N-(2,4-difluorophenyl)-5-nitropyridine-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.0%
In dimethyl sulfoxide; at 100℃; for 2h;
Example 67a 3-bromo-N-(2,4-difluorophenyl)-5-nitropyridin-2-amine A mixture of <strong>[5470-17-7]3-bromo-2-chloro-5-nitropyridine</strong> (2.374 g, 10 mmol) and 2,4-difluoroaniline (2.58 g, 20 mmol) in dimethylsulfoxide (20 mL) was heated at 100 C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate filtered, and concentrated. The residue was purified on silica gel eluting with 1:20 ethyl acetate/heptanes to give the title compound (1.75 g, 5.30 mmol, 53.0% yield) as yellow crystals.
53%
In dimethyl sulfoxide; at 100℃; for 2h;
A mixture of 3-bromo-2-chloi^5-ritropyj^ine (2.374 g, 10 mmol) and 2,4- diftaoiOaniline (2.58 g, 20 mmol) in DMS O (20 mL) was heated at 100 - for 2 houE . After cooling, the reaction mixture was partitioned betweenwater and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were was hed with s atorated aqueous sodium chloride s ohition, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified b flash chromatography on silica gel, elutin wifh 1 :20 ethyl acetate/ heptans to give the title compound ( 1.75 g, 5.30 mmol, 53 JO % yield) as yellow crys tals
53%
In dimethyl sulfoxide; at 100℃; for 2h;
A mixture of <strong>[5470-17-7]3-bromo-2-chloro-5-nitropyridine</strong> (2.37 g, 10.0 mmol) and 2,4-difluoroaniline (2.58 g, 20.0 mmol) in dimethyl sulfoxide (20 mL) was heated at 100 C for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on (silica gel, 5% ethyl acetate in heptanes) to provide the title compound (1.75 g, 53.0%). 1H NMR (400 MHz, DMSO-d6) delta 9.23 (s, 1H), 8.84 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 7.52 - 7.41 (m, 1H), 7.38 - 7.28 (m, 1H), 7.15 - 7.05 (m, 1H). MS (ESI-) m/z 328.0, 330.0 (M-H)+.
5-chloro-N-(2,4-difluorophenyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 110℃; for 18h;Sealed tube; Inert atmosphere;
A mixture of 2,4-di.luoroaniline (0.433 g, 3.36 mmol), 4,5-dichloropyrirnidi (0.5 g, 336 mmol ces ium carbonate (2.187 g, 6.71 mmol). (9,9-dirnethyl-9H-xaril jene-4,5- diyl)bis (diphjenylplijosphine) (0.097 g, 0.168 mmol) and diacetoxypalladium(0D38 g, 0.168 mmol) were comb ined in toluene (4 mL), sealed, sparged for 15 minutes with argon and heated at 1 10 *C for 18 houE . The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous s odium sulfate), treated with 3-mercaptopropyl functfonahzed silica, filtered and concentrated. Ruificationb y chromatography (silica gel, 10-50% ethyl acetate in heptanes) afforded the title compound (0.66 g, 81%).
General procedure: Anhydride 1 (100 mg, 0.757 mmol) was dissolved in a minimal amount of dry CH2Cl2 and corresponding aniline 2-13 (1 eq) was added in dry CH2Cl2. The solution was stirred for 24 h at room temperature. The solvent was evaporated and the monoamides 14-25 were air-dried, and used without further purification. Appropriate monoamide (14-25) (0.5 mmole) was dissolved in dry, freshly distilled THF (10 ml) at room temperature under argon. BOP (1.05 eq) was added to the mixture followed by the solution of triethylamine (TEA) (0.5 ml) in THF (1 ml). The reaction mixture was then stirred at room temperature for 20 min and another portion of BOP (0.5 eq) was added. After 40 min the solvent was evaporated. The residue was dissolved in CHCl3 and washed with 10% citric acid solution, sat. Na2CO3 solution, water and brine. Combined organic layers were dried over MgSO4, filtered and evaporated to dryness. Imides 26-37 were purified by column chromatography on silica gel using mixture hexan/EtOAc (0-15% v/v) as eluent. Yields are listed in Table 1.
2-Fluoronicotinic acid methyl ester (0.4 g, 2.58 mmol) and 2,4-difluoroaniline (0.3 10 ml,3.09 mmol) were heated by microwave irradiation at 130 C for 20 mm. Some DCM was added and the mixture was washed twice with 1120. Organic phase was dried over Na2SO4,filtered and evaporated. 0.554 g of the title compound was obtained.1H NMR (400 MHz, CDC13) 6 ppm 3.95 (s, 3H) 6.76 (dd, 1 H) 6.84 - 6.95 (m, 2 H) 8.26 (dd, 1 H) 8.34 - 8.46 (m, 2 H) 10.19 (br. s., I H).
General procedure: GP2-1: In a flask were added by ammoniumthiocyanate (2.2 eq) and HOAc (5 volume), bromine (1.1 eq) in HOAc (5 volume)was added dropwise under ice-cooled condition, which was stirred at 10 0Cfor 30 min. After filtering off the solid, the filtrate was collected.In aseparate flask, aniline (1.0 eq) and HOAc (5 volume) were added. Then thefiltrate prepared above was added dropwise under 0 0C within 5 min.The mixture was kept stirring at rt overnight. After removal of solvent underreduced pressure, the residue was diluted with EA, neutralized with saturatedNa2CO3 solution, separated, passed through a pad ofCelite, and concentrated to dryness. The crude was purified by silica gelcolumn.GP2-2: To a round-bottomed flaskwas added 2-aminobenzothiazole (1.0eq) and CuCl2 (1.2 eq) in acetonitrile (10 volume), followed by slowaddition of tert-butyl nitrite (1.2eq). The gas evolved immediately. The reaction was greatly exothermic, and, ifnecessary, ice-water cooling was applied. The mixture was then stirred at rtfor hours, which was monitored by TLC. After completion, the reaction wasquenched by 1M HCl, washed by 1 M HCl twice and extracted by EA. The combinedorganic layer was washed by brine, dried over Na2SO4, concentrated and purifiedby flash column to give the product.
3-[(2,4-difluorophenyl)amino]-4-nitropyridin-1-ium-1-olate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.9%
In ethanol; at 70℃; for 16h;
A mixture of <strong>[769-54-0]3-fluoro-4-nitropyridine N-oxide</strong> (2.OOg, 12.7mmol) and 2,4- difluoroaniline (2.96mL, 29.lmmol) in EtOH (6OmL) was stirred at 70C for 16h. The reaction mixture was cooled to RT and the precipitate isolated by vacuum filtration to give the title compound (2.16g, 63.9%) as a yellow solid. LCMS (ESj: 268.0 [M+H]. HPLC: Rt: 5.14mm, 99.3% purity.
General procedure: In a flask charged with diethylene glycol monomethyl ether (8 mL)added equimolar quantities (25 mmol) of appropriate amine (1a-w)and bis(2-chloroethyl)amine hydrochloride (2). The resulting mixturewas heated for 150 C for 16-48 h under N2 atmosphere in the presenceof catalytic amount of KI (3 mol%). The progress of the reaction wasmonitored using TLC with the mobile phase toluene: acetone (8:2).After the completion of the reaction, the mixture was cooled to roomtemperature and dissolved in methanol (25 mL), and ethyl acetate(100 mL) was added. The precipitate thus obtained were filtered,washed with ethyl acetate and the resulting salt was then convertedto free amines upon treating with Na2CO3 and extracted with ethyl acetate(2 × 25 mL). The combined organic phase was dried over MgSO4and evaporated to give analytically pure piperazine derivatives 3a-win reasonably good yields.
4-[(2,4-difluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.3%
In toluene; at 90℃; for 3h;
General procedure: A mixture of substituted anilines (4.70 mmol) in toluene (25 mL) was added to the above reaction solution, followed by stirring for 3 h. Upon completion of the reaction, the resulting mixture was cooled to 20 C.The solid thus obtained was filtered under a reduced pressure and washed with toluene (20 mL). Isopropanol (18 mL) was added to thesolid, which was then stirred for 5 h. The resulting solid was filtered and washed with isopropanol (10 mL). The solid was dried at 50 C in the oven to afford 3a-f as white powder.
5-amino-1-(2,4-difluorophenyl)-3-cyano-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46.5%
Add 0.01 mol of 2,4-difluoroaniline and a small amount of ethanol to a 250 mL round bottom three-necked flask.Under ice bath, 3.0 mL (0.035 mol) of concentrated hydrochloric acid was added dropwise with stirring.0.018 mol of sodium nitrite was dissolved in 10 mL of water, and slowly dropped into the flask. After the completion of the dropwise addition, the reaction was carried out for 0.5 h to obtain a yellow diazonium salt solution.Add 0.01 mol of <strong>[40497-11-8]ethyl 2,3-dicyanopropionate</strong> to a three-necked flask.The prepared diazonium salt solution was dropped into the flask, and the reaction was added dropwise for 2 hours.Ammonia water was added, the pH was adjusted to 9-10, and the reaction was carried out for 2 h at room temperature.After the reaction was completed, it was extracted with 40 mL of dichloromethane, and the organic layer was washed with water (2×30 mL).Wash with saturated sodium chloride solution (1×40 mL), dry over anhydrous magnesium sulfate.The solvent was decanted under reduced pressure to obtain a product of 1.02 g.Yield 46.5%
With pyridine; In dichloromethane; at 20 - 45℃;Inert atmosphere;
General procedure: To a solution of 76 (120 mg, 0.37 mmol) in dry pyridine (12 mL) under N2 at RT, was added 2,4-difluorobenzenesulphonyl chloride (159 mg, 0.74 mmol) in CH2Cl2 (1.5 mL) dropwise over 5 min. The mixture was stirred at 45 C under N2 for 16 , and the solvent then removed under reduced pressure. The reaction was quenched with a little water and the resulting solid collected by filtration and washed with water and Et2O. Purification was carried out by trituration with hot CH2Cl2/MeOH solution to give 4 as a pale brown solid (65%)
2,3,4,5-tetrafluoro-benzoyl ethyl acetate (11.89g, 45mmol) was added to the triethyl orthoformate (11.24mL, 67.5mmol) and acetic anhydride (20mL), heated to 140 The reaction 1h, the solvent was evaporated under reduced pressure to give a pale yellow liquid. The resulting pale yellow liquid was dissolved in dichloromethane (150 mL), under an argon atmosphere, cooled with ice bath, was added 2,4-difluoroaniline (6.87mL, 67.5mmol), the reaction temperature IH, spin under reduced pressure the solvent gave a yellow solid, recrystallized from petroleum ether to give a white solid (2- (2,3,4,5-tetrafluoro-benzoyl) -3- (2,4-difluorophenyl) - ethyl acrylate, hereinafter referred to as compound MH3-1) 15.44g.
General procedure: The main procedure is shown in Scheme 2. The raw products of compound 7 were synthesized via one-pot method in a flask containing compounds 5 (30 mmol), 6 (30 mmol), K2CO3 (15 mmol) and PEG1000 (0.45 mmol). The reactions were carried out under stirring at 185 C and were monitored by TLC. After reactions completion, the desired diphenylamine derivatives 7 were obtained via column chromatographic purification. Next, compounds 7 (20 mmol), reductive iron powder (60 mmol), solid NH4Cl (60 mmol) and ethanol aqueous solution (75%, 50 mL) were added. The reactions proceeded with refluxing for 3 h at 90 C and compounds 8 were obtained. Then, compound 3 (30 mmol) and SOCl2 (thionylchloride, 30 mL) were added. The mixture was heated to reflux at 90 C for 3 h. Residual SOCl2 was removed by vacuum distillation in order to obtain compound 4. Finally, the primary amines 8 (10 mmol) dissolved in dichloromethane (CH2Cl2, 5 mL) and triethylamine(Et3N, 10 mL) were added. The mixture was cooled to 0 C and compound 4 (20 mmol) dissolved in dichloromethane (CH2Cl2, 10 mL) was added dropwise under stirring at a temperature not exceeding 5 C. The final mixture was stirred at room temperature for 10 h and the target compounds 9a, 9b and 9c were purified via column chromatography and recrystallization.
3-[(2,4-difluorophenyl)carbamoyl]pyrazine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: Pyrazine-2,3-dicarboxylic anhydride (1.0 g, 6.7 mmol) was dissolved in tetrahydrofuran (40 mL)in an Erlenmeyer flask and the corresponding substituted aniline (6.7 mmol, 1 equiv.) was added in one dose. The reaction mixture was stirred for 1 hour at laboratory temperature. Water (30 mL) was added into the mixture followed by the saturated aqueous solution of NaHCO3 until pH 6 to form thecorresponding 3-(phenylcarbamoyl)pyrazine-2-carboxylic acid 1-18. Obtained crystals were filtered off and washed with water. The progress of the procedure was monitored by TLC eluted with thesystem water/butanol/acetic acid 5:4:1.
4,6-dichloro-N-(2,4-difluorophenyl)pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
A 0.25M solution of 2,4-difluoroaniline (129 mg, 1 mmol) in THF stirred under nitrogen at -70 C. was treated with a 0.6M solution of NaHMDS in toluene (1.1 mmol). After 15 min, the mixture was treated with <strong>[4489-34-3]4,6-dichloro-2-(methylsulfonyl)pyrimidine</strong>. After stirring at -70 C. for 2 h, the reaction mixture was quenched with AcOH, partitioned between brine and EtOAc, and separated. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with a gradient of EtOAc (0 to 60%) in DCM to afford the title compound (172 mg, 71%) as a white solid. LCMS (M+H)+277
5-bromo-2,6-dichloro-N-(2,4-difluorophenyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium acetate; In tetrahydrofuran; water; at 20 - 25℃; for 18h;
5-Bromo-2,4,6-trichloropyrimidine (2.50 g, 9.05 mmol) was dissolved in THF (16 mL) and water (8 mL), and sodium acetate (2.23 g, 27.2 mmol), followed by 2,4-difluoroaniline (1.18 g, 0.92 mL, 9.14 mmol) were added. The mixture was stirred at room temperature for 18 h. After that, a saturated aqueous solution of sodium hydrogencarbonate (30 mL) was added and the resulting mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 120 g, eluting with ethyl acetate / n-heptane, gradient 0: 100 to 5:95) to yield, after drying in vacuo (40C, 5 mbar), the title compound as an off-white solid (2.22 g, 69%). HPLC (method LCMS_fastgradient) tR = 1.39 min. 1H NMR (CDC13, 300 MHz): delta 6.91- 7.03 (m, 2 H), 7.56 (br s, 1 H), 8.16 (ddd, 7 = 5.8, 9.7, 9.7 Hz, 1 H). MS (ES+) m/z 353.9, 355.9, 357.9 [M+H, Br & 2 CI isotopes].
5,7‑dichloro‑3‑(2,4‑difluorophenyl)‑2‑methylquinazolin‑4(3H)‑one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With magnetic nanoparticles-supported tungstic acid; In neat (no solvent); at 80℃; for 9h;Green chemistry;
General procedure: We run multicomponent reaction between antranilic acids, acetic anhydride and primary amines in the present of MNPTA for synthesis of 3-substituted 2-methylquinazoline-4-(3H)-one derivatives (Scheme 1).Into a canonical flask (25 ml), a mixture of anthranilic acid (1 mmol), acetic anhydride (1.2 mmol) with selected aromatic amines (1 mmol) and MNP-TA (0.058 g, 5 mol%) was heated at 80 C for 4-12 h. After completion the reaction,monitored by TLC, the catalyst was separated by external magnet. The precipitated solid was filtered. Then, the pure product was obtained by its recrystallization in dichloromethane/petroleum ether solvent system and compounds that did not reach this level were purified by column chromatography on silica gel using petroleum ether/ethyl acetate aselution afforded the pure 3-substituted 2-methylquinazoline-4(3H)-one derivatives (Fig. 3).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 16h;
To a solution of compound 3-1 (10 g, 77.46 mmol, 1.00 eq) and compound 3-2 (20.13 g, 77.46 mmol, 1.00 eq) in acetonitrile (200 mL) was added N,N-diisopropylethylamine (22.02 g, 170.40 mmol, 2.20 eq) at room temperature. The reaction mixture was stirred at 100C for 16 h, then cooled to room temperature and subsequently added to ethyl acetate. The organic layer was washed sequentially with water and a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and then purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to afford compound 3-3. MS (ESI) m/z: 227.9 [M+1]
3-chloro-5-[(2,4-difluorophenyl)sulfamoyl]-4-hydroxybenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With pyridine; at 25℃;
Into a 25-mL round-bottom flask, was placed 3-chloro- 5-(chlorosulfonyl)-4-hydroxybenzoic acid (500 mg, 1.84 mmol, 1.00 equiv), 2,4-difluoroaniline (259.73 mg, 2.01 mmol, 1.09 equiv), pyridine (6 mL). The resulting solution was stirred overnight at 25 C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18; mobile phase, water: acetonitrile=90:10 increasing to water: acetonitrile=0:100 within 30 min; Detector, UV 250 nm. This resulted in 460 mg (69%) of 71.1 as an off-white solid. (ES, m/z): [M-H]- 361.9.
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