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Structure of 3863-11-4 * 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.
With hydrogenchloride; N-chloro-succinimide; trifluoroborane diethyl ether; triethylamine In tetrahydrofuran; diethyl ether; dichloromethane; chloroform; water
EXAMPLE 1 Preparation of 5,6-difluoroisatin and 4,5-difluoroisatin STR9 To a solution of 3,4-difluoroaniline (12.98 g, 0.100 mol) in 325 mL of methylene chloride at -65° C. was added a solution of t-butylhypochlorite (10.86 g, 0.100 mol) in 52 mL of methylene chloride. The mixture was stirred for 10 min. A solution of ethyl thiomethylacetate (13.49 g, 0.100 mol) in 65 mL of methylene chloride was added dropwise to the mixture and stirred at -65° C. for 1 h. Triethylamine (10.17 g, 0.100 mol) in 65 mL of methylene chloride was added and the reaction mixture was warmed to room temperature and stirred for 3 h. Water was added and the methylene chloride layer was separated and concentrated under reduced pressure to yield an oil. The resulting oil was diluted with 300 mL of diethyl ether and 80 mL of 2N HCl, and stirred for 24 h. A precipitate was formed, filtered and washed with 50 mL of diethyl ether to give a mixture of 5,6- and 4,5-difluoro-3-thiomethyloxindoles in 70percent yield. The crude oxindoles (11.64 g, 0.054 mol) were reacted with N-chlorosuccinimide (7.26 g, 0.05 mol) in 500 mL of chloroform at room temperature for 1 h. The reaction mixture was concentrated and the resulting residue was dissolved in 70 mL of THF. To this solution was added red mercury (II) oxide (11.78 g, 0.054 mol), boron trifluoride etherate (7.72 g, 0.05 mol), and 400 mL of aqueous 20percent THF. The slurry was stirred for 3 h, diluted with 1000 mL of chloroform and filtered through celite. The resulting solids were washed with chloroform and the chloroform layer was separated and concentrated. Chromatography on silica gel eluding with 1percent isopropyl alcohol:chloroform gave 5,6-difluoroisatin (Saul Kadin, U.S. Pat. No. 4,721,712) and 4,5-difluoroisatin in 31percent and 4percent yield, respectively. 4,5-Difluoroisatin: mp 140° C. (dec); 1 H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 7.7 (dd, 1H), 6.7 (dd, 1H).
Reference：
[1] Patent: US5441955, 1995, A,
2
[ 3863-11-4 ]
[ 774-47-0 ]
Reference：
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 1858,1860
3
[ 302-17-0 ]
[ 3863-11-4 ]
[ 774-47-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 8, p. 3436 - 3453
4
[ 369-34-6 ]
[ 3863-11-4 ]
Yield
Reaction Conditions
Operation in experiment
93.8%
With palladium on activated charcoal; hydrogen In toluene at 25 - 35℃; Autoclave
Taken 200.Og of 3,4-difluoro nitro benzene, 600.Oml of Toluene and 12.Og of pd/C into autoclave at 25°C-35°C. Apply the Hydrogen gas 2.0-6.0Kg/Cm2 and maintained the reaction for 3-4 hrs at 25°C-35°C Check the reaction mass TLC to conform reactioncompletion. After reaction complies unload the reaction mass and filter through hyflow bed and wash with toluene (200.OmI). Take the filtrate and distilled under vacuum at below 50°C. the obtained 3,4-Difluoro aniline crude weight 152.Og,.Yield:93.8percent,purity by HPLC:95 .85percent.
77%
With iron; ammonium chloride In methanol; water at 90℃; for 12 h;
To a stirred solution of 1, 2-difluoro-4-nitrobenzene (4 g, 1 mmol) in methanol and water (25 mL: 5 mL) at RT, iron powder (2.5 g) and ammonium chloride (2 g) were added. The reaction mixture was refluxed for 12 h and the progress of reaction was monitored by TLC. After 12 h reaction time, the reaction mixture was filtered using celite pad. Then the solvent was evaporated under reduced pressure, water was added and the product was extracted with ethyl acetate and dried over anhydrous sodium sulphate. The crude product was purified by using column chromatography by eluting with ethyl acetate: hexane (30:70 v/v) which afforded the title compound in 77percent yield (2.5 g, brown liquid). 1H NMR (300 MHz, CDCl3): δ 6.88-6.94 (m, 1H, Ar-H), 6.43-6.47 (m, 1H, Ar-H), 6.31-6.34 (m, 1H, Ar-H), 3.60 (s, 2H, NH2). 13C NMR (75 MHz, CDCl3): δ 150.83, 147.60, 143.39, 140.02, 115.80, 108.57, 101.89. IR (CHCl3, νmax cm-1): 3383, 2360, 1617, 1521, 1266, 1213. MS (ESI, m/z) [M+H]+ 130.
43%
With iron; ammonium chloride In methanol; water at 60℃; for 5 h; Heating / reflux
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1, 2-difluor nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ML) and heated to 60 °C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture REFLUXED for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1, 2-difluoro-4- aminobenzene (7 g, 43percent). [00147] BC13 (6.2 ML, 1M in DCM) was added drop wise to 1,2- DIFLUORO-4AMINOBENZENE (0.5 g, 0.004 mol) in trichloroethylene (6.5 ML) at 0°C and this mixture stirred for 15 min. 4-Cyanopyridine (0.48 g, 0.005 mol) was added and the solution was warmed to RT and stirred for 30 min. The solution was then heated at 80-90 °C for 1 h. The resulting solution was REFLUXED at 160°C for 4 hr and stirred at RT over night. 3N HCI was added to the reaction mixture and refluxed at 110 °C for 1.5 h. The reaction mixture was cooled to RT and made basic (pH = 12) with 6N NaOH. The reaction mixture was diluted with water and DCM. The resulting two layers were separated and the aqueous layer was extracted with DCM, dried over sodium sulphate and concentrated. The compound was purified by column chromatography using silica gel to yield title compound (0.25 g, 27percent).
Reference：
[1] Patent: WO2015/68171, 2015, A1, . Location in patent: Page/Page column 9; 16
[2] Tetrahedron Letters, 2010, vol. 51, # 5, p. 786 - 789
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 613 - 617
[4] ChemPlusChem, 2018, vol. 83, # 5, p. 375 - 382
[5] Synthesis, 2001, # 1, p. 81 - 84
[6] Patent: WO2004/46092, 2004, A2, . Location in patent: Page 48
[7] Journal of the American Chemical Society, 1951, vol. 73, p. 5884
[8] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[9] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[10] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 165 - 180
[11] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6492 - 6499
5
[ 250372-11-3 ]
[ 3863-11-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 20℃; for 0.25 h;
General procedure: In a typical experiment, benzyl 4-methoxyphenyl carbamate (1a, 1 mmol) and 10 cm3 methanol were placed in a 100 cm3 round-bottomed flask fitted with a water condenser and placed over a magnetic stirrer. Nickel(II) chloride hexahydrate (5 mmol) was added to the flask, followed by slow addition of sodium borohydride (15 mmol) with vigorous stirring. A vigorous reaction took place and the reaction mixture turned black due to in situ formation of nickel boride. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate 80:20, v/v). After completion, the reaction mixture was filtered through a Celite pad (~2.5 cm) and washed with methanol (3x10 cm3). The solution was concentrated ona rotavapor and diluted with water (~50 cm3), followed by extraction with dichloromethane (3x10 cm3). The combined dichloromethane extract was washed with water and dried over anhyd. K2CO3. The solvent was removed ona rotary evaporator and the product was dried. 4-Anisidine(2a) was obtained as colourless solid in 88percent yield. The products were identified by m.p., IR, and NMR spectra. The products Scheme 1, entry 24 and Scheme 2, entry 8 were purified by flash column chromatography on silica gel using petroleum ether:ethyl acetate (95:5, v/v) as eluent.
COMPARATIVE EXAMPLE 1 (Process wherein reduction and a diazochlorination method are used in combination) 10 g of 3,4-difluoronitrobenzene was dissolved in 20 and 2 g of methanol and 10 g of concentrated hydrochloric acid and 2 g of iron powder were added thereto. The mixture was stirred at 60° C. for two hours, and then distilled to obtain 3,4-difluoroaniline. The reduction yield was 86percent.
Reference：
[1] Patent: US5208394, 1993, A,
7
[ 85118-04-3 ]
[ 3863-11-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
8
[ 1321455-41-7 ]
[ 3863-11-4 ]
Reference：
[1] Green Chemistry, 2011, vol. 13, # 8, p. 1986 - 1989
9
[ 5216-25-1 ]
[ 3863-11-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
10
[ 2494-79-3 ]
[ 3863-11-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
11
[ 62574-66-7 ]
[ 3863-11-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
12
[ 127269-25-4 ]
[ 3863-11-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
13
[ 127986-80-5 ]
[ 3863-11-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 7, p. 2010 - 2017
14
[ 371-40-4 ]
[ 367-25-9 ]
[ 3863-11-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
15
[ 367-11-3 ]
[ 3863-11-4 ]
Reference：
[1] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 165 - 180
16
[ 3282-30-2 ]
[ 3863-11-4 ]
[ 754-10-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine In dichloromethane
Part A Preparation of N-trimethylacetyl-3,4-difluoroanilide To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl and extracted with methylene chloride (3*100 mL) and the combined organic extracts were dried over anhydrous NaSO4 and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92percent yield).
92%
With triethylamine In dichloromethane
Part A: Preparation of N-trimethylacetyl-3,4-difluoroanilide. To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0°C was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3h. The reaction-mixture was poured onto 3N HCl and extracted with methylene chloride (3x100 mL) and the combined organic extracts were dried over anhydrous NaSO4 and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92percent yield).
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[2] Molecular crystals and liquid crystals, 1984, vol. 112, # 3-4, p. 165 - 180
20
[ 3863-11-4 ]
[ 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
21
[ 371-40-4 ]
[ 367-25-9 ]
[ 3863-11-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 2005, vol. 126, # 4, p. 661 - 667
22
[ 3863-11-4 ]
[ 64465-53-8 ]
Reference：
[1] Patent: US6136823, 2000, A,
23
[ 3863-11-4 ]
[ 64695-79-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2459 - 2462
[2] Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 1999, vol. 439, # 2, p. 149 - 157
[3] Patent: WO2006/98912, 2006, A1, . Location in patent: Page/Page column 55
[4] Patent: WO2007/56210, 2007, A2, . Location in patent: Page/Page column 44
[5] Patent: WO2016/33228, 2016, A1, . Location in patent: Page/Page column 52; 53; 67; 68
24
[ 3863-11-4 ]
[ 85462-60-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2459 - 2462
25
[ 3863-11-4 ]
[ 71294-07-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1980, vol. 15, # 4, p. 330 - 332
[2] Patent: US2013/35364, 2013, A1,
[3] ChemMedChem, 2015, vol. 10, # 9, p. 1548 - 1558
26
[ 3863-11-4 ]
[ 113046-72-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
27
[ 3863-11-4 ]
[ 112984-60-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
28
[ 3863-11-4 ]
[ 113028-17-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
29
[ 3863-11-4 ]
[ 123447-62-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
With iodine; sodium hydrogencarbonate In water at 20℃; for 0.5 h;
3,4-Difluoroaniline (645mg, 5mmol) was suspended in water (25 mL). Sodium bicarbonate (630 mg, 7.5 mmol) was added and then iodine (1.65 g, 6.5 mmol). The reaction mixture was stirred vigorously at ambient temperature for 30min and then poured into saturated sodium thiosulphate solution (50 mL) and extracted with ethyl acetate (2x25 mL). The combined extracts were washed with sodium thiosulphate (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to give the title compound as a dark oil. (1.24g, 97percent).
69%
With N-iodo-succinimide In dichloromethane at 20℃; Inert atmosphere
At room temperature, a solution of 3,4-difluoroaniline (100 μL, 1 mmol) and N-iodosuccinimide (225 mg, 1 mmol) in anhydrous dichloromethane (4 mL) was stirred overnight under argon atmosphere. Then an aqueous solution of sodium sulfite was added and the reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 1/0 to 8/2) to afford 4,5-difluoro-2-iodoaniline (175 mg, 69percent) as a red oil. ESI-MS m/z 255.9 (M+H)+.
12 g
With iodine; sodium hydrogencarbonate In water at 20℃; for 1 h;
Reference Example 3a 2-methyl-5,6-fluoro-2,3-dihydro-1H-indole Step 1a:4,5-Difluoro-2-iodoaniline 16.5 g of iodine and 6.3 g of sodium bicarbonate are added, at ambient temperature, to a suspension of 6.45 g of 3,4-difluoroaniline in 250 ml of water. The reaction medium is stirred at ambient temperature for 1 hour.A saturated sodium thiosulfate solution is added and then the resulting mixture is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give 12 g of 4,5-difluoro-2-iodoainiline, the characteristics of which are the following:Mass spectrometry: method ARetention time Tr (min)=0.90; [M+H]+: m/z 256; base peak: m/z 297
With sodium tetrahydridoborate; water monomer at 0 - 20℃; for 4h;
95%
With formic acid at 55 - 60℃; for 8h; Inert atmosphere; Reflux;
1.1; 2-8; 1 (1) Synthesis of 3,4-difluoroaniline
Into a 2L glass three-necked bottle, add 1mol,159g of 3,4-difluoronitrobenzene (compound 1),550 g of formic acid with a weight percentage of 50 wt % was added in batches with 40 g of Raney nickel (Johnson Matthey, model A-50E0) to obtain a first reaction system.The mass ratio of 3,4-difluoronitrobenzene, Raney nickel and formic acid was 159:40:275.Under nitrogen protection,The first reaction system is heated,start the reduction reaction,The temperature of the heating process is 55 to 60 °C,The time is 8h, and the first stirring is carried out simultaneously in this heating process,The first stirring time was 8 h, and after the reduction reaction was completed, the temperature was lowered to room temperature to obtain a solid-liquid mixture containing compound 1. Formate was removed by filtration,The remaining mixed solution adopts dichloromethane to carry out the first extraction,The target product layer was washed with water and concentrated to obtain 123 g of 3,4-difluoroaniline (compound 2).The yield of 3,4-difluoroaniline was measured to be 95%,Its purity was determined to be 98% by gas chromatography (GC).This compound 2 was used directly in the next preparation without purification.
93.8%
With palladium on activated charcoal; hydrogen In toluene at 25 - 35℃; Autoclave;
1; a
Taken 200.Og of 3,4-difluoro nitro benzene, 600.Oml of Toluene and 12.Og of pd/C into autoclave at 25°C-35°C. Apply the Hydrogen gas 2.0-6.0Kg/Cm2 and maintained the reaction for 3-4 hrs at 25°C-35°C Check the reaction mass TLC to conform reactioncompletion. After reaction complies unload the reaction mass and filter through hyflow bed and wash with toluene (200.OmI). Take the filtrate and distilled under vacuum at below 50°C. the obtained 3,4-Difluoro aniline crude weight 152.Og,.Yield:93.8%,purity by HPLC:95 .85%.
82%
With cyclohexa-1,4-diene; 5%-palladium/activated carbon In methanol at 120℃; for 0.0833333h; Microwave irradiation;
77%
With iron(0); ammonia hydrochloride In methanol; water monomer at 90℃; for 12h;
Synthesis of 3, 4-difluoroaniline (2)
To a stirred solution of 1, 2-difluoro-4-nitrobenzene (4 g, 1 mmol) in methanol and water (25 mL: 5 mL) at RT, iron powder (2.5 g) and ammonium chloride (2 g) were added. The reaction mixture was refluxed for 12 h and the progress of reaction was monitored by TLC. After 12 h reaction time, the reaction mixture was filtered using celite pad. Then the solvent was evaporated under reduced pressure, water was added and the product was extracted with ethyl acetate and dried over anhydrous sodium sulphate. The crude product was purified by using column chromatography by eluting with ethyl acetate: hexane (30:70 v/v) which afforded the title compound in 77% yield (2.5 g, brown liquid). 1H NMR (300 MHz, CDCl3): δ 6.88-6.94 (m, 1H, Ar-H), 6.43-6.47 (m, 1H, Ar-H), 6.31-6.34 (m, 1H, Ar-H), 3.60 (s, 2H, NH2). 13C NMR (75 MHz, CDCl3): δ 150.83, 147.60, 143.39, 140.02, 115.80, 108.57, 101.89. IR (CHCl3, νmax cm-1): 3383, 2360, 1617, 1521, 1266, 1213. MS (ESI, m/z) [M+H]+ 130.
76%
With palladium on activated charcoal; tetrabutylammonium bromide; water monomer; sodium hydroxide; silicon at 100℃; for 6h;
75%
With hydrogenchloride; indium powder In tetrahydrofuran at 20℃; for 0.5h;
43%
With iron(0); ammonia hydrochloride In methanol; water monomer at 60℃; for 5h; Heating / reflux;
17 Example 17: Synthesis of (2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone
Iron powder (28.1 g, 0.502 mol) was added as small portions to 1, 2-difluor nitrobenzene (20.0 g, 0.126 mol) in methanol (200 ML) and heated to 60 °C. Ammonium chloride (48.4 g, 0.91 mol) in water (100 ml) was added drop wise and the reaction mixture REFLUXED for 5 hr. The reaction mixture was filtered over Celite and washed with methanol. Methanol was removed, and the aqueous layer was extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentrated to yield 1, 2-difluoro-4- aminobenzene (7 g, 43%). [00147] BC13 (6.2 ML, 1M in DCM) was added drop wise to 1,2- DIFLUORO-4AMINOBENZENE (0.5 g, 0.004 mol) in trichloroethylene (6.5 ML) at 0°C and this mixture stirred for 15 min. 4-Cyanopyridine (0.48 g, 0.005 mol) was added and the solution was warmed to RT and stirred for 30 min. The solution was then heated at 80-90 °C for 1 h. The resulting solution was REFLUXED at 160°C for 4 hr and stirred at RT over night. 3N HCI was added to the reaction mixture and refluxed at 110 °C for 1.5 h. The reaction mixture was cooled to RT and made basic (pH = 12) with 6N NaOH. The reaction mixture was diluted with water and DCM. The resulting two layers were separated and the aqueous layer was extracted with DCM, dried over sodium sulphate and concentrated. The compound was purified by column chromatography using silica gel to yield title compound (0.25 g, 27%).
With ethanol; nickel Hydrogenation;
With hydrogenchloride; iron(0)
With iron(0); ammonia hydrochloride
With hydrogenchloride; iron(0)
With tin(II) chloride dihydrochloride In ethyl acetate for 2.5h; Reflux; Inert atmosphere;
General procedure for the reduction: (11)
General procedure: A mixture of 10, (7.8 mmol) and SnCl2.2H2O (39 mmol) in EtOAc (75 mL) was stirred at reflux under nitrogen for 2.5 h. Upon cooling, saturated NaHCO3 (150 mL) was added. The organic layer was separated and the aqueous layer washed with EtOAc (2 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated to dryness to give 11 as a white solid (86%).
to a stirred solution of H2SO4 (7.78 mL) in Ac2O (0.778 L, 8.21 mol),3,4-difluoroaniline (500.00 g, 3.88 mol) [30] was added at about 10 C, and then stirred at roomtemperature for 30 min. The mixture was poured into ice water, filtered, the filter cake was washedwith water and dried to give an o-white solid (604.00 g, 91%). 1H-NMR (400 MHz, CDCl3) δ 7.63-7.56(m, 1H), 7.53 (s, 1H), 7.12±7.03 (m, 2H), 2.17 (s, 3H). ESI-MS (m/z): 171.9 [M + H]+.
With pyridine In tetrahydrofuran at 20℃; for 0.5h;
19.A
A.. (3,4-Difluoro-phenyl)-carbamic acid ethyl esterTo a solution of 3,4-difluoro-phenylamine (1.0 g, 7.45 mmol) and pyridine (751 μL, 9.29 mmol) in THF (10 mL) is added ethyl chloroformate (888 μL, 9.29 mmol) dropwise over a 30s period. This mixture is stirred at rt for 30 min. The reaction mixture is partitioned between H2O and EtOAc. The two layers are separated, and the organic layer is washed with HCI (1 M), H2O, and brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 1.43 g (95%) of the product as a brown solid. 1H NMR (CDCI3): δ 7.45-7.35 (m, 1 H), 7.07 (q, J = 8.9 Hz,1 H), 7.00-6.90 (m, 1 H), 6.55 (br s, 1 H), 4.23 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H); 19 F NMR (CDCI3): δ -135.33 (m, 1 F), -143.85 (br m, 1 F); MS 243 (M+CH3CN+1 , 100%), 202 (M+1 ).
With triethylamine; In dichloromethane; at 0 - 25℃;
General procedure: 2-Chloroacetyl chloride (24 mmol) was slowly added dropwise to a mixture of R-NH2 (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2Cl2 (20 mL) at 0 C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3 × 20 mL) and the precipitate was separated by filtration. The crude product was purified by crystallization from a mixture solvent of Et2O/petroleum.
91.5%
In 1,4-dioxane; for 1h;Heating / reflux;
Description 5: 2-Chloro-lambda/-(3,4-difluorophenyl)acetamide; A mixture of 3,4-difluoroaniline (6.46g; 50mmol) and chloroacetyl chloride (5.65g; 50mmol) in dioxan (50ml) was heated with stirring for 1 h. The solution was concentrated, cooled to room temperature and water added. The resulting precipitate was filtered off and dried to afford the title product (9.41g; 91.5%). 1H NMR (CDCI3) delta: 4.20 (2H, s), 7.13 - 7.16 (2H, m), 7.63 - 7.68 (1 H, s), 8.23 (1 H, br s).
91.5%
In 1,4-dioxane; for 1h;Heating / reflux;
Description 7: 2-Chloro-lambda/-(3,4-difluorophenyl)acetamide; A mixture of 3,4-difluoroaniline (6.46g; 50mmol) and chloroacetyl chloride (5.65g; 50mmol) in dioxan (50ml) was heated with stirring for 1 h. The solution was concentrated, cooled to room temperature and water added. The resulting precipitate was filtered off and dried to afford the title product (9.41g; 91.5%). 1H NMR (CDCI3) delta: 4.20 (2H, s), 7.13 - 7.16 (2H, m), 7.63 - 7.68 (1 H, s), 8.23 (1 H, br s).
91.5%
In 1,4-dioxane; for 1h;Heating / reflux;
A mixture of 3,4-difluoroaniline (commercially available; 6.46g; 50mmol; 5ml) and chloroacetyl chloride (5.65g; 50mmol; 4ml) in dioxan (50ml) was heated with stirring for 1 h. The solution was concentrated to 25ml, cooled to room temperature and some water added. The resulting precipitate was filtered off and dried to afford the title product. The product was further dried overnight in an oven (9.41g; 91.5%). 1H NMR (CDCI3) delta: 4.20 (2H, s), 7.13 - 7.16 (2H, m), 7.63 - 7.68 (1 H, s), 8.23 (1 H, br s).
84.3%
With pyridine; In toluene; at 5 - 20℃;
To a stirred solution of 3,4-difluoroaniline (10 mmol) in toluene (5 mL) and pyridine (10 mmol) maintained at 5-10 deg C was added chloroacetyl chloride (10 mmol) in toluene (5 mL) dropwise. The mixture was allowed to stand overnight at room temperature. The organic layer was then separated and the residue was mixed with water (60 mL). The separated solid product was recrystallized from toluene to give N-(3,4-difluorophenyl) chloroacetamide (8.6 g, 84.3% yield). 1HNMR (300 MHz, CDCl3) delta 8.24 (s, 1H, NH), 7.63 (td, J=8.1 Hz, 1H, Ar-H), 7.16-7.12 (m, 2H, Ar-H), 4.19 (s, 2H, COCH2Cl).
In 1,4-dioxane; for 1h;Heating / reflux;
Description 20: 2-Chloro-N-(3,4-difluorophenyl)acetamide; A mixture of 3,4-difluoroaniline (5.65g; 50mmol) and chloroacetyl chloride (6.46g; 50mmol) in dioxan (50ml) was refluxed for 1 h, cooled to room temperature and concentrated under reduced pressure to a volume of 25ml. Water was added to and the solid desired product separated by filtration and dried overnight (yield 9.41 g).
With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Cooling with ice;
General procedure: The appropriate 3,4-disubstituted aniline (50 mmol) and TEA(60 mmol, 8.45 mL) in THF (150 mL) were mixed on ice bath.Chloroacetyl chloride (60 mmol, 4,81 mL) in THF (20 mL) wasadded dropwise to this solution. After completion, the reactionmixture was stirred at room temperature for 1 h. The precipitated product was fltered washed with water, dried and thenrecrystallized from ethanol.
44.1 Step-1
Di-tert-butyl dicarbonate (3.0 g, 23.2 mmol) was added to 3,4-difluoroaniline (5.5 g, 25.2mmol) in dry THF (45 mL) and the resultant reaction mixture was stirred at RT for 12 h(TLC indicated complete consumption of starting material). Volatiles were removed underreduced pressure and the residue was washed with hexanes (15 mL). The white solid obtainedwas dried under high vacuum to afford tert-butyl N-(3,4-difluorophenyl)carbamate (5 g,93%) which was used for the next step without any purification.1H NMR [400 MHz, CDCh]: 8 7.45-7.40 (m, 1H), 7.08-7.01 (m, 1H), 6.92-6.89 (m, 1H),6.45 (brs, 1H), 1.51 (s, 9H).LCMS: m/z: 174.4 [M+H-56t.
92.8%
In tetrahydrofuran at 60℃; for 16h;
91%
In tetrahydrofuran at 70℃; for 96h;
A12.A
Intermediate A12: 6-amino-2,3-difluorobenzamide; Step A/Intermediate A13: 1 ,1-dimethylethyl (3,4-difluorophenyl)carbamate; To a solution of 3,4-difluoro aniline (1 Og, 77.5 mmol, Aldrich) in tetrahydrofuran (300 ml.) was added BoC2O (20.3g, 93 mmol, 1.2 equiv, Aldrich). The resulting solution was stirred at 7O0C for 2 days, at which time additional BoC2O (20.3g, 93 mmol, 1.2 equiv) was added and the resulting reaction is maintained at 7O0C for an additional 2 days. After 4 days of heating, the tetrahydrofuran was removed under reduced pressure and the product recrystallized from hexanes to afford 1 ,1-dimethylethyl (3,4- difluorophenyl)carbamate cleanly as a white solid (16.1g, 70 mmol, 91% yield). 1 H NMR (400 MHz, CDCI3) δ ppm 1.48 (s, 9 H), 6.42 (s, 1 H), 6.87 (d, J = 8 Hz, 1 H), 7.02 (q, J=8.97 Hz, 1 H), 7.40 (s, 1 H).
65%
In tetrahydrofuran at 20℃; for 12h;
In tetrahydrofuran at 60℃; for 16h;
3.1
Step 1 : preparation of λ/-(tert-butoxycarbonyl)-3.4-difluoroaniline; To a flask equipped with a reflux condenser was charged 3,4-difluoroaniline (13.2 g) and dry THF (100 ml_). The resulting solution was treated with di-tert-butyl dicarbonate (24.5 g) and heated to 60 0C for 16 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (150 mL) and washed successively with 1 % aqueous HCI solution (2 x 100 mL) and 5% aqueous sodium bicarbonate solution (2 x 100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a tan residue. The residue was crystallized from hexanes to provide the title compound as a white solid (19.6 g). 1H NMR (300 MHz, CDCI3) δ ppm 7.38 - 7.48 (1 H, m), 6.99 - 7.10 (1 H, m). 6.87 - 6.94 (1 H, m), 6.58 (1 H, br. s.), 1.51 (9 H, s).
With bromine; potassium carbonate; In dichloromethane; at -15 - 20℃; for 0.25h;
Scheme i-8; Preparation of 2-(bromomethyl)-S,6-difluoroquinoline (i-8d); Step A: Preparation of (2-bromo-4,5-difluorophenyl)amine (i-8a); Potassium carbonate (2.76 g, 20.0 mmol) was added to a stirred solution of 3,4- difluoroaniline (2.58 g, 20.0 mmol) in DCM (100 mL) at room temperature, and the resulting mixture was cooled to -15 0C. A solution of bromine (3.20 g, 20.0 mmol) in DCM (10 mL) was added dropwise via syringe. After 15 min, the reaction mixture was poured into ice/water and extracted three times with DCM. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 10-20% EtOAc/Hexanes as eluent) to afford the title compound i-8a, m/z (ES) 210 (MH)+.
With bromine; potassium carbonate; In dichloromethane; at -15 - 20℃; for 0.25h;
Potassium carbonate (2.76 g, 20.0 mmol) was added to a stirred solution of 3,4- difluoroaniline (2.58 g, 20.0 mmol) in DCM (100 mL) at room temperature, and the resulting mixture was cooled to -15 0C. A solution of bromine (3.20 g, 1.02 mL, 20.0 mmol) in DCM (10 mL) was added dropwise via syringe. After 15 min, the reaction mixture was poured into ice/water and extracted three times with DCM. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 10-20% EtOAc/Hexanes as eluent) to afford the title compound i-2a, m/z (ES) 210 (MH)+.
With bromine; potassium carbonate; In dichloromethane; at -15℃; for 1.5h;
A solution of bromine (30.9 g, 194 mmol) in DCM (100 mL) was added dropwise into a suspension of 3,4-difluoroaniline (25 g, 194 mmol) and potassium carbonate (26.72 g, 194 mmol) in DCM (800 mL) at -1 5 C. After the addition was completed, the mixture was stirred at the same temperature for 30 min and then poured into ice water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound. 1H NMR (400 MHz, CDCl3): delta 7.24-7.22 (m, 1 H), 6.60-6.55 (m, 1H), 3.99 (bs, 2H); MS (ESI): m/z: calcd 130.11 (M + H), found 130.1.
With tert.-butylnitrite; trimethylsilylazide In acetonitrile at 0 - 20℃; for 2h;
96.1%
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With sodium azide In water at 0℃; for 1h;
6 General procedure for preparation of aryl azides (24a-i)
General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 15% HCl (60 mL), NaNO2 (5 g, 0.072 mol) in H2O (200 mL) was added drop-wise at 0 C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min. A solution of sodium azide (7.8 g, 0.12 mol in 30 ml H2O) was added in a dropwise manner to the reaction mixture at 0 C. After addition maintained the reaction at 0 C for 1 h, the progress of the reactionwas monitored by TLC. The product was extracted by using ethylacetate followed by washing with water up to neutral pH. Organiclayer was dried with anhydrous sodium sulfate and then concentratedby distillation at room temperature to afford 24a-i as yellow to brown oil. 7.2.6. 4-azido-1,2-difluorobenzene (24f); Light yellow oil; Yield: 96.1%; MS (ESI) m/z (%): 156.1 [M+H]+.
96.1%
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃;
Stage #2: With sodium azide In water at 0℃;
8 General procedure for preparation intermediates of aryl azides (22a-h)
General procedure: To a mixture of substituted phenyl amine (0.08mol) and 15% HCl (80mL), NaNO2 (6.7g, 0.096mol) in H2O (200mL) was added drop-wise at 0°C. After the completion of addition, the reaction mixture was stirred at this temperature for 30min. A solution of sodium azide (7.9g, 0.13mol in 30mLH2O) was added dropwise to the reaction mixture at 0°C. After addition the reaction mixture was maintained at 0°C for 1h. The product was extracted by using ethyl acetate followed by washing with water up to neutral pH. Organic layer was dried with anhydrous sodium sulfate and then concentrated by distillation to afford 22a-h as yellow to brown oil.
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at -5℃; for 1h;
Stage #2: With sodium azide; sodium acetate In water at -5 - 20℃;
With tert.-butylnitrite; trimethylsilylazide In acetonitrile at 20℃; for 4h;
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water for 0.666667h; Cooling with ice;
Stage #2: With sodium azide In water at 20℃; for 8h;
With tert.-butylnitrite; trimethylsilylazide In acetonitrile at 0 - 20℃; for 2.5h;
3 1-(3,4-Difluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole
EXAMPLE 3 STR14 1-(3,4-Difluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (300 mg, 1.18 mmol), 3,4-difluoroaniline (0.13 ml, 1.3 mmol) and p-toluenesulfonic acid (25 mg) in toluene (80 ml) was heated to reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude dark orange solid (700 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 1-(3,4-difluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (370 mg, 90%) as a white solid: mp (DSC) 151° C. Anal Calc'd. for C18 H15 NSO2 F2: C, 62.24; H, 4.35; N, 4.03. Found: C, 62.08; H, 4.52; N, 4.05.
74%
With toluene-4-sulfonic acid In toluene for 20h; Heating;
74%
With toluene-4-sulfonic acid In ethanol at 160℃; for 0.75h; Microwave irradiation;
With toluene-4-sulfonic acid In toluene for 20h; Ambient temperature;
With toluene-4-sulfonic acid In ethanol at 160℃; for 0.75h; Microwave irradiation;
General procedure for the synthesis of diarylpyrroles (7a-d).
General procedure: Following the procedure for the Paal-Knorr reaction, a solution of 6 (0.58 g, 2.28 mmol), the opportune aniline (2.28 mmol) and p-toluenesulfonic acid (30 mg, 0.17 mmol) in ethanol (2 mL) was microwave irradiated using a CEM apparatus for 45 min at 160 °C (150 W, internal pressure of 150 psi). The reaction mixture was cooled and concentrated. The crude material was purified by chromatography on aluminum oxide with a 3:1 cyclohexane/ethyl acetate mixture, as the eluant, to give the expected 1,5-diarylpyrrole 7 as white needles in satisfactory yield.
Stage #1: propane-1,2,3-triol; 3,4-difluoro-phenylamine With sulfuric acid at 90℃; for 0.666667h;
Stage #2: With iodine; potassium iodide In lithium hydroxide monohydrate at 130℃; for 4h;
1 1st step: synthesis of 6, 7 - difluoro-quinoline
The 18.4 M sulfuric acid (220 g, 2.25 µM) slowly adding glycerin (138 g, 1.5 µM) in, then adding 3, 4 - difluoroaniline (65 g, 0.5 µM), after adding up to 90 °C stirring 40 min, then adding potassium iodide (4.7 g, 0 . 027 µM), I2(5.5 G, 0 . 022 µM), water (25 ml), heated to 130 °C, stirring 4 h. TLC confirmed after the reaction is complete, after cooling to room temperature the reaction solution is poured into a large amount of ice in, and adding dichloromethane (1 L), then the NaOH to adjust the pH to the alkaline, filtered, filtrate layer, the aqueous layer then dichloromethane (500 ml) extraction 2 times, the organic layer after the merger turns on lathe does, coils of column, silica gel is in the 300 - 400 mesh silica gel, mobile phase (petroleum ether: ethyl acetate=10:1) after washing, to obtain 6, 7 difluoro quinoline (60 g, 73%).
56%
With sulfuric acid; m-nitrobenzene sulfonic acid sodium salt at 140℃; for 4h;
Stage #1: propane-1,2,3-triol; 3,4-difluoro-phenylamine With sulfuric acid at 0 - 90℃; for 0.666667h;
Stage #2: With iodine; potassium iodide In lithium hydroxide monohydrate at 0 - 130℃; for 4h;
31.1 step 1: Preparation of 6,7-difluoroquinoline (Compound 31A)
glycerol (21.40g, 232.36mmol) was added to the there-necked flask, concentrated sulfuric acid (34.18g, 348.54mmol) was added dropwise at 0°C, then 3,4-difluoroaniline (10g, 77.45mmol) was added, and the reaction was heated to 90°C. 40min, then cooled to 0°C, potassium iodide (643mg, 3.87mmol) and iodine (885mg, 3.49mmol) were added, then water (3.8mL) was added dropwise, and the temperature was raised to 130°C for 4h. The reaction solution was poured into a 1 mol/L aqueous sodium hydroxide solution to quench the reaction, adjust pH=9, filter, extract the filtrate three times with DCM, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The compound 31A was obtained by chromatographic separation and purification.
2
To a OC solution of 5.250 g (40.663 mmol) 3,4-difluoroanailine in 75 ml dichloromethane was added 5.487 mL (44.729mmol) pivaloyl chloride and 6.8 mL (48.796mmol) triethylamine. After stirring 1 h from OC to room temperature, the reaction mixture was diluted with CH2Cl2, washed with water and brine. The organic layer was dried over NaSθ4, filtered and concentrated in vacuo. Afforded 8.660 g (99%) N-(3,4- difluorophenyl)-2,2-dimethylpropanamide. 1H NMR (CDCI3, 400 MHz) δ 7.68 - 7.63 (m, IH, ArH); 7.09 - 7.06 (m, 2H, ArH); 1.31 (s, 9H, O=C(CH3)3). ES MS+1 = 214.1.
98%
With triethylamine In benzene at 0℃;
18 Example 18: Synthesis of (6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone
To 3, 4-Difluoroaniline (2.0 g, 0.0153 mol) and triethylamine (3. 1g, 0.0307 mol) in dry benzene (100 ML) was added trimethylacetylchloride (2.3 g, 0.0184 mol) slowly at 0°C and the reaction mixture stirred at RT overnight. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. Compound was RECRYSTALLIZED from petroleum ether yielding 3.2 g, 98 %. [00149] This protected 3, 4-difluoroaniline (2.7 g, 0.0126 mol) was taken in dry THF (25 ml) and under nitrogen t-butyllithium (2.02 g, 0.032 mol) was added drop wise at-78 °C. Stirring was continued at-78 °C for 2 h. 4- Pyridine CARBOXALDEHYDE (3.55 g, 0.033 mol) dissolved in dry THF (10 ml) was added slowly. The reaction mixture was warmed to room temperature and stirred over night. The reaction mixture was then quenched with water and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Compound was purified by column chromatography to yield carbinol (2.6 g, 65%). [00150] To carbinol (2.6 g, 0.0031 mol) in 17.3 mi of pyridine was added a suspension of chromium trioxide (0.705 g, 0.007 mol) in pyridine (6.0 ml) under a nitrogen atmosphere. The resulting mixture was allowed to stir at RT over night. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with brine, dried over sodium sulfate and concentrated. The compound was purified by column chromatography to yield the protected precursor to the title compound (1.7 g, 65.8%). [00151] To this pivaloyl protected amino ketone (1.7 g, 0.0053 mol) was added 70 % sulfuric acid (14.6 ml) and the reaction mixture heated to 95-100 °C overnight. The reaction mixture was basified by using 10 % sodium hydroxide and extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The product obtained was purified by column chromatography to yield title compound (0.58 g, 46.4%).
With TEA In dichloromethane at 0 - 25℃; for 3h;
With triethylamine In dichloromethane at 0 - 20℃; for 1h;
6
N-(3 ,4-DifluorophenylV2.2-dimethylpropanamide (6-2)To a 0 0C solution of 5.250 g (40.663 mmol) 3,4-difluoroanailine in 75 ml dichloromethane was added 5.487 mL (44.729mmol) pivaloyl chloride and 6.8 mL (48.796mmol) triethylamine. After stirring 1 h from 0 0C to room temperature, the reaction mixture was diluted with CH2Cl2, washed with water and brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo to afforded N-(3,4-difluorophenyl)-2,2-dimethylpropanamide. 1H NMR (CDCI3, EPO 400 MHz) δ 7.68 - 7.63 (m, IH, ArH); 7.09 - 7.06 (m, 2H, ArH); 1.31 (s, 9H, O=C(CH3)3). ES MS+1 =214.1. f6-amino-23-difluorophenyl)f4-fluorophenyl)methanone (6-4)To a -78 0C solution of 2.5 g (11.724 mtnol) N-(3,4-difluorophenyl)-2,2- dimethylpropanamide in 39 ml anhydrous THF was added drop wise over 15 mins 18mL (28.136 mmol) n-BuLi (1.6M solution in cyclohexanes). After lhr at -78°C, 4mL (26.966mmol) ethyl 4-fluorobenzoate was added dropwise and the reaction mixture stirred from -78°C to rt. After 45mins, the reaction mixture was cooled to OC and quenched with saturated ammonium chloride and poured into a 1:1 mixture of etheϖwater and warmed to room temperature. The organic phase was isolated, washed with brine, dried over MgSθ4, filtered, and concentrated in vacuo to yield Ν-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide (6-3). A solution of 3.5 g (10.706 mmol)
Ip: 3-Chloro-N-(3,4-difluoro-phenyl)-propionamide 3,4-Difluoro-phenylamine (250 mmol) was dissolved in ethyl acetate (500 mL) and triethyl amine (300 mmol) was added. 3-Chloropropionyl chloride (275 mmol) was added drop wise while maintaining the temperature below 30 °C. Stirred at room temperature for Ih, then H2O (250 mL) was added. The phases were separated and the organic phase was washed with brine, dried on MgSO4, and filtered. The solvent was evaporated to yield the product, which was used without further purification. Yield = 73%
Stage #1: carbon disulfide; 3,4-difluoroaniline With triethylamine In methanol at 0 - 5℃;
Stage #2: With bis(trichloromethyl) carbonate In chloroform at 0℃; for 4h; Further stages.;
74.5%
Stage #1: carbon disulfide; 3,4-difluoroaniline With 1,4-diaza-bicyclo[2.2.2]octane In toluene at 20℃; for 8h;
Stage #2: With bis(trichloromethyl) carbonate In dichloromethane at -5℃; Reflux;
5.3.12. 2,4-Dichloro-1-isothiocyanatobenzene (8a)
General procedure: To a solution of 2,4-dichloroaniline (2.51 g, 15.5 mmol) and triethylenediamine (2.08 g, 18.6 mmol) in 40 mL toluene, CS2 (3.5 g, 46.5 mmol) was added slowly. The resulting mixture was stirred at room temperature for 8 h. After filtration, the filter cake was washed with toluene and dried. Obtained 7a was suspended in 40 mL DCM. Then, a 25 mL DCM solution of BTC (5.0 g, 17.0 mmol) was added slowly under -5-0 °C. The mixture was stirred for 2 h at room temperature, and then was refluxed for 1.5-2 h. After filtration, the filtrate was concentrated in vacuo. The crude product was purified by chromatography (ethyl acetate/petroleum ether = 1:1) on silica gel to give 0.19 g white solid (60%).
Stage #1: carbon disulfide; 3,4-difluoroaniline With sodium hydroxide for 24h; Heating;
Stage #2: With chloroformic acid ethyl ester In water at 35 - 40℃;
Stage #1: carbon disulfide; 3,4-difluoroaniline With sodium hydroxide for 24h; Heating;
Stage #2: With chloroformic acid ethyl ester at 35 - 40℃; for 0.666667h;
Stage #1: carbon disulfide; 3,4-difluoroaniline With 1,4-diaza-bicyclo[2.2.2]octane In toluene
Stage #2: With benzene-1,3,5-tricarboxylic acid In chloroform
Stage #1: carbon disulfide; 3,4-difluoroaniline With 1,4-diaza-bicyclo[2.2.2]octane In toluene at 0 - 5℃;
Stage #2: With bis(trichloromethyl) carbonate In dichloromethane Reflux;
With iodine; sodium hydrogencarbonate; In water; at 20℃; for 0.5h;
3,4-Difluoroaniline (645mg, 5mmol) was suspended in water (25 mL). Sodium bicarbonate (630 mg, 7.5 mmol) was added and then iodine (1.65 g, 6.5 mmol). The reaction mixture was stirred vigorously at ambient temperature for 30min and then poured into saturated sodium thiosulphate solution (50 mL) and extracted with ethyl acetate (2x25 mL). The combined extracts were washed with sodium thiosulphate (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to give the title compound as a dark oil. (1.24g, 97%).
69%
With N-iodo-succinimide; In dichloromethane; at 20℃;Inert atmosphere;
At room temperature, a solution of 3,4-difluoroaniline (100 muL, 1 mmol) and N-iodosuccinimide (225 mg, 1 mmol) in anhydrous dichloromethane (4 mL) was stirred overnight under argon atmosphere. Then an aqueous solution of sodium sulfite was added and the reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 1/0 to 8/2) to afford 4,5-difluoro-2-iodoaniline (175 mg, 69%) as a red oil. ESI-MS m/z 255.9 (M+H)+.
12 g
With iodine; sodium hydrogencarbonate; In water; at 20℃; for 1h;
Reference Example 3a 2-methyl-5,6-fluoro-2,3-dihydro-1H-indole Step 1a:4,5-Difluoro-2-iodoaniline 16.5 g of iodine and 6.3 g of sodium bicarbonate are added, at ambient temperature, to a suspension of 6.45 g of 3,4-difluoroaniline in 250 ml of water. The reaction medium is stirred at ambient temperature for 1 hour.A saturated sodium thiosulfate solution is added and then the resulting mixture is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give 12 g of 4,5-difluoro-2-iodoainiline, the characteristics of which are the following:Mass spectrometry: method ARetention time Tr (min)=0.90; [M+H]+: m/z 256; base peak: m/z 297
(3,4-difluorophenyl)phenylhydrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: 3,4-difluoroaniline With hydrogenchloride; acetic acid; sodium nitrite In water at 0℃; for 1h;
Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0℃;
1 General procedure for the synthesis of phenylhydrazines
General procedure: A solution of the respective aniline (8.01-10.0 mmol) in glacial acetic acid (5.0 mL) was treated with concentrated hydrochloric acid (20-50 mL, 36%) at room temperature and cooled to 0 C. Subsequentlya pre-cooled solution of sodium nitrite (11.0-12.0 mmol) in water (3.0 mL) was added slowly and the mixture was stirred for 1 h at 0 C. The chilled solution was filtered andthen a solution of tin(II)-chloride dihydrate (20.0-22.0 mmol) inconcentrated hydrochloric acid (10 mL) was added dropwise at0 C. The precipitate was filtered off and washed with a saturated aqueous solution of sodium chloride (30 mL). Due to stability reasons hydrazines which were not used immediately, were dried and stored as hydrochlorides. They were later extracted under basic conditions directly before using them in a reaction. Therefore the solid hydrochloride (1.00 mmol) was dissolved in a saturated aqueous solution of sodium carbonate (40.0 mL) and then extracted with diethyl ether (4 x 50 mL). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (20 mL) and dried over sodium sulfate. After filtration the solvent was removed under reduced pressure. The phenylhydrazine could be used without further purification Compound 15a was prepared from 3,4-difluoroaniline (1.03 g, 8.01 mmol), sodium nitrite (0.83 g 12.0 mmol) and tin(II)-chloride dihydrate (4.51 g, 20.0 mmol) in hydrochloric acid (20 mL). Hydrochloride 15a (1.15 g, 6.36 mmol, 79%) was obtained as a white solid. 1H NMR (600 MHz, CDCl3 as free base) δ 3.57 (br s, 2H), 5.16 (br s, 1H), 6.48 (dtd, J = 1.6 Hz, J = 3.2 Hz, J = 7.9 Hz, 1H), 6.70 (ddd, J = 2.8 Hz, J = 6.7 Hz, J = 12.0 Hz, 1H), 7.00 (td, J = 8.6 Hz, J = 10.0 Hz, 1H); 19F NMR (339 MHz, HCl salt, D2O) δ -138.0 (m, 1F), -146.8 (m, 1F), (the analytical data obtained is in agreement with those reported in literature). 37
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water
Stage #2: With tin(ll) chloride In water
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With sodium hydrogensulfite In water for 3h; Reflux;
General procedure for preparation intermediates of Phenylhydrazine hydrochloride (9a-h)
General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 15% HCl (60 mL), NaNO2 (5 g, 0.072 mol) in H2O (200 mL) was added drop-wise at 0 °C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min. and then was dropped into the mixture of saturated solution of sodium hydrogen sulfite (22.5 g, 0.216 mol), keeping the reaction below 20 °C. Upon completing the addition, the reaction was heated under refluxed for 3 h and cooled to room temperature. The solid is filtered and washed with ethyl acetate and the cake was dried to give white solid 9a-h yielded 90%.
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: With sodium hydrogensulfite In water at 20℃; for 3h;
6.2.1. General procedure for preparation intermediates ofPhenylhydrazine hydrochloride (9a-h)
General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 15%HCl (60 mL), NaNO2 (5 g, 0.072 mol) in H2O (200 mL) was addeddrop-wise at 0 C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min. and then wasdropped into the mixture of saturated solution of sodium hydrogen sulfite (22.5 g, 0.216 mol), keeping the reaction below 20 C. Upon completing the addition, the reaction was heated under refluxed for 3 h and cooled to room temperature. The solid is filtered and washed with ethyl acetate and the cake was dried to give white solid 9a-h yielded 90%.
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 1.16667h;
Stage #2: With tin(ll) chloride In water at 0℃;
5.1
Step 1: To a solution of 3,4-difluoroaniline (Int-18a, 25.8 g, 0.2 mol) in concentrated HCl (100 mL) was cooled to 0 °C and a solution of sodium nitrite (13.8 g, 0.2 mol) in 4OmL water was added dropwise with stirring over 10 min. Stirring was continued for Ih at 0 °C. To the resulting mixture a solution of SnCl2 (152 g, 0.8 mol) in concentrated HCl (150 mL) was added dropwise. The mixture was kept at 0 °C for 3 hrs. The solid was filtered and dissolved in water (300 mL) and subsequently basified with a 2N NaOH, and extracted with ethyl acetate. The ethyl acetate solution was bubbled with HCl gas, and obtained Int-18b as a pink solid (20.7 g, yield 57.5%).
Stage #1: 3,4-difluoroaniline With hydrogenchloride In methanol
Stage #2: With sodium nitrite In methanol; water at 0℃; for 0.333333h;
Stage #3: With hydrogenchloride; tin(ll) chloride In methanol; water at 4℃; for 6h; Further stages.;
Stage #1: 3,4-difluoroaniline With hydrogen bromide; sodium nitrite In water at -10 - -5℃; for 1h; Inert atmosphere;
Stage #2: With tin(ll) chloride In water at -10 - -5℃; for 2h; Inert atmosphere;
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In dichloromethane; water at 0 - 20℃; for 1.5h;
Stage #2: With tin(ll) chloride In dichloromethane; water at 0℃; for 6h;
4.1.1 General procedure for the synthesis of substituted phenylhydrazine (2a-2d)
General procedure: 2.7g (24.29mmol) of substituted phenylamine was suspended in 10mL of 37% aqueous HCl at 0°C and was carefully treated with 1.7g (2.75mmol, 1.05 equivalent) of sodium nitrite dissolved in 20mL of ice-cold water. The solution was stirred for 1h at 0°C and 30min at rt. Then, 27g (0.12mol, 5 equivalent) of tin (II) chloride in 30mL HCl were dropped carefully into the cooled solution (0°C) and stirred for 6h. The reaction was neutralized and basified with aqueous NaOH (pH 14). The aqueous phase was extracted three times with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The product obtained was used for the next reaction step without purification.
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at -10℃; for 0.666667h;
Stage #2: With tin dichloride hydrochloride In water at -10℃;
4.4.1. General procedure for the synthesis of building blocks for moieties I (Ib-h)
General procedure: Aniline (1.0 equiv) was dissolved in conc. HCl and cooled to 10 ,then an aqueous sodium nitrite solution (1.5 equiv) was added andstirred cold for 40 min. The newly prepared tin dichloride (3.0 equiv)hydrochloric acid solution was added to the reaction solution slowly andstired at 10 for 2-3 h [34]. At the end of the reaction, the precipitateis formed and filtered, washed with water and ethyl acetate, then driedin a vacuum, and used for the next step without further purification.
With hydrogenchloride; chloranil In 2-methyl-propan-1-ol at 100 - 110℃; for 4h; Acidic conditions; Heating / reflux;
1.3 Step 3 : 6, 7-difluoro-2-methylquinoline
Step 3 : 6, 7-difluoro-2-methylquinoline 25.0 G of 3, 4-difluoroaniline are dissolved in 120 of 2-butanol. 50 ml of a saturated solution of hydrogen chloride in 2-butanol are added slowly and afterwards 47.6 G (0.1936 mol) of P-CHLORANIL are also added. With a good stirring and at reflux temperature (100-110°C) a solution of 19. 4 ml (0.236 mol) of crotonaldehyde in 45 ml of butanol is dropped slowly (ca. 2 hr). The whole is refluxed for two additional hours and then evaporated to dryness. The residue is taken with excess THF and is filtered and washed thoroughly with THF until the filtering appears to be uncoloured. The solid thus obtained is solved in water, filtered from some solid impurities and washed with ethyl ether. The aqueous layer is made slightly alkaline with 2N NaOH solution and then extracted with diethyl ether. The ethereal layer is dried and treated with a little decolourising charcoal. After evaporation a white solid is obtained (22.7 G, 65 %).
328.08 g (57%)
With HCl conc.; chloranil In tetrahydrofuran; aq. K2 CO3; ethyl acetate; toluene; iso-butanol
2.A.B.A Step A
Step A 6,7-Difluoro-2-methylquinoline Crotonaldehyde (226.34 g, 3.23 mol) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 mol), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at ca. 60° C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent or until a very pasty solid formed. THF (2 L) was added and the mixture heated 30 min. after which it was cooled to 0° C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2 CO3 /EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2*) and the organic phases combined, dried over MgSO4 and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of the title compound. 1 H NMR (CD3 COCD3): δ 8.19 (1H, d), 7.75 (2H, m), 7.4 (1H, d), 2.64 (3H, s).
328.08 g (57%)
With HCl conc.; chloranil In tetrahydrofuran; aq. K2 CO3; ethyl acetate; toluene; iso-butanol
168.1 Step 1
Step 1 6,7-Difluoro-2-methylquinoline Crotonaldehyde (226.34 g, 3.23 mol) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 mol), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at ca. 60° C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2 L) was added and the mixture heated 30 min. after which it was cooled to 0° C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2 CO3 /EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2*) and the organic phases combined, dried over MgSO4 and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of the title compound. 1 H NMR (CD3 COCD3): δ 8.19 (1H, d), 7.75 (2H, m), 7.4 (1H, d), 2.64 (3H, s).
328.08 g (57%)
With HCl conc.; chloranil In tetrahydrofuran; aq. K2 CO3; ethyl acetate; toluene; iso-butanol
2.1 6,7-Difluoro-2-methylquinoline
Step 1 6,7-Difluoro-2-methylquinoline Crotonaldehyde (226.34 g, 3.23 tool) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 tool), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at ca. 60° C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2L) was added and the mixture heated 30 min. after which it was cooled to 0° C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2 CO3 /EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2X) and the organic phases combined, dried over MgSO4, and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of the title compound. 1 H NMR (CD3 COCD3): δ 8.19 (1H, d), 7.75 (2H, m), 7.4 (1H, d), 2.64 (3H, s).
Stage #1: 3,4-difluoroaniline With hydrogenchloride In water; toluene at 110℃; for 1h; Inert atmosphere;
Stage #2: trans-Crotonaldehyde In water; toluene at 110℃; for 15h; Inert atmosphere;
75 6, 7-dijluoro-2-methyl-quinoline:
To a mixture of 3,4-difluoroaniline (5 g, 38.7 mmol) in toluene (25 mL) was added HC1 (6 M, 25 mL) at 20 °C under N2. The mixture was stirred at 110 °C. After lh, E-but-2-enal (4.07 g, 58.1 mmol) was added and the reaction mixture was further stirred at 110 °C for 15 h. The reaction mixture was poured into NaOH (6 M, 25 mL) and adjusted to pH = 11. The aqueous phase was extracted with EtOAc (3 x 50 mL), washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the title compound. LC-MS: m/z: 180.3 [M+Hj.
With potassium <i>tert</i>-butylate In 1,4-dioxane at 120℃; for 15h;
3 Example 3; N, N'-Bis (3, 4-difluorophenyl)-4, 4'-bipyridine-2, 2'-diamine
2, 2'-DICHLORO- (4, 4') -bipyridine (50 mg, 0.22 mmol), palladium acetate (5.6 mg, 0.022 mmol), bis [tri- (tert-butyl) phosphine] palladium (12.5 mg, 0.022 mmol), sodium tert- butoxide (60 mg, 0.61 mmol) and 3,4-difluoroaniline (0.5 ML, 4.0 mmol) were flushed in a Schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with toluene (5 X 10 NIL), water (3 X 5 ML) and dichloromethane (5 x 2 mL). The resulting powder was dried under vacuum to yield 35 mg (66%) of the title compound as a slightly brown SOLID. 1H NMR (DMSO-d6) : 8 9.71 (s, 2H), 8.29 (d, J = 5.3 Hz, 2H), 8.07 (ddd, J = 7. 8/6. 4/1.9 Hz, 2H), 7.38-7. 28 (m, 4H), 7.12 (s, 2H), 7.06 (d, J = 5.4 Hz, 2H). 19F NMR (DMSO-d6) : 5-138. 17 (m, 2F), -149. 26 (m, 2F). MS (TSP) m/z 411 (M+1).
With sodium chloride; acetic anhydride; sodium hydrogencarbonate; triethylamine; In dichloromethane; pentane;
Stage 95a: N-(3,4-difluorophenyl)acetamide A mixture of 3,4-difluoroaniline (50 ml; 500 mmol) and triethylamine (70 ml; 500 mmol) in dichloromethane (1.5l) is cooled down using an ice bath. Acetic anhydride (71.5 ml; 750 mmol) is added dropwise and the reaction mixture is agitated for 1 hour at ambient temperature. The mixture obtained is then washed sequentially with water, with a solution of sodium bicarbonate at 10%, and with a saturated solution of sodium chloride. The organic fraction, dried over sodium sulphate, is concentrated under reduced pressure. The residue is suspended in pentane, filtered and dried under reduced pressure in order to produce the expected anilide, a beige solid (m.p.: 126-127.5 C.). NMR 1H (DMSO-d6, δ): 2.15 (s, 3H); 7,10-7.65 (m, 2H); 7,65-8.10 (m, 1H); 10.30 (broad peak, 1H).
With acetic anhydride;
REFERENCE EXAMPLE 1 N-(3,4-difluorophenyl)acetamide To 3,4-difluoroaniline (28.2 g) was added acetic anhydride (30 ml) slowly. After allowed to stand for 30 minutes, the reaction mixture was poured into ice water (100 ml). The resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (34.7 g) as colorless needles, mp 127-127.5 C. Analysis (%) for C8 H7 F2 NO, Calcd. (Found): C, 56.14 (56.15); H, 4.12 (4.06); N, 8.18 (8.00).
With sodium chloride; acetic anhydride; sodium hydrogencarbonate; triethylamine; In dichloromethane; pentane;
Stage 95a: N-(3,4-difluorophenyl)acetamide A mixture of 3,4-difluoroaniline (50 ml; 500 mmol) and triethylamine (70 ml; 500 mmol) in dichloromethane (1.5l) is cooled down using an ice bath. Acetic anhydride (71.5 ml; 750 mmol) is added dropwise and the reaction mixture is agitated for 1 hour at ambient temperature. The mixture obtained is then washed sequentially with water, with a solution of sodium bicarbonate at 10%, and with a saturated solution of sodium chloride. The organic fraction, dried over sodium sulphate, is concentrated under reduced pressure. The residue is suspended in pentane, filtered and dried under reduced pressure in order to produce the expected anilide, a beige solid (m.p.: 126-127.5 C.). NMR 1H (DMSO-d6, δ): 2.15 (s, 3H); 7,10-7.65 (m, 2H); 7,65-8.10 (m, 1H); 10.30 (broad peak, 1H).
With acetic anhydride; sodium hydrogencarbonate; triethylamine; In dichloromethane; pentane;
81.a. N-(3,4-difluorophenyl)acetamide A mixture of 3,4-difluoroaniline (50 ml; 0.5 mole) and triethylamine (70 ml; 0.5 mol) in dichloromethane (1.5 l) is cooled down using an ice bath. Acetic anhydride (71.5 ml; 0.75 mol) is added dropwise and the reaction mixture is then agitated for 1 hour at ambient temperatue. The mixture obtained is then washed successively with water, a 10% solution of sodium bicarbonate and saturated salt water. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is suspended in pentane, filtered and dried under reduced pressure in order to produce the product in the title (78 g; 91% yield) in the form of a whitish solid (M.p. 126-127.5 C.). NMR 1H (DMSO): 2.15 (s, 3H); 7.10-7.65 (m, 2H); 7.65-8.10 (m, 1H); 10.30 (wide peak, 1H).
91%
With acetic anhydride; sodium hydrogencarbonate; triethylamine; In dichloromethane; pentane;
81.a. N-(3,4-difluorophenyl)acetamide A mixture of 3,4-difluoroaniline (50 ml; 0.5 mole) and triethylamine (70 ml; 0.5 mol) in dichloromethane (1.5 l) is cooled down using an ice bath. Acetic anhydride (71.5 ml; 0.75 mol) is added dropwise and the reaction mixture is then agitated for 1 hour at ambient temperature. The mixture obtained is then washed successively with water, a 10% solution of sodium bicarbonate and saturated salt water. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is suspended in pentane, filtered and dried under reduced pressure in order to produce the product in the title (78 g; 91% yield) in the form of a whitish solid (M.p. 126-127.5 C.). NMR 1H (DMSO): 2.15 (s, 3H); 7.10-7.65 (m, 2H); 7.65-8.10 (m, 1H); 10.30 (wide peak, 1H).
4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine hydrochloride hydrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; LiAlH4; benzenesulfonic acid; In tetrahydrofuran; methanol; nitrogen;
EXAMPLE 31 4-[[(3,4-Difluorophenyl)amino](4-fluorophenyl)methyl]piperidine hydrochloride hydrate (1:2:1) A mixture of 50.7 g (0.21 mol) of <strong>[25519-78-2]4-(4-fluorobenzoyl)piperidine hydrochloride</strong>, 40.0 g (0.31 mol) of 3,4-difluoroaniline and 0.80 g (0.0051 mol) of benzenesulfonic acid in 1 L of xylenes was heated at reflux for 4 days with water being removed with Dean-Stark trap. The mixture was cooled to room temperature and 500 mL of dry THF was added. The mixture was cooled in an ice bath and was swept with a stream of nitrogen. To this mixture was slowly added 40.0 g (1.1 mol) of LiAlH4, and the mixture was stirred mechanically at room temperature overnight. Dilute NaOH was added slowly over 1 h, and the resulting mixture was filtered through a pad of Celite. The solvent was removed from the filtrate in vacuo, and the residue was partitioned between CH2 Cl2 and water. The CH2 Cl2 solution was dried (Na2 SO4), and the solvent was removed in vacuo. The residue was dissolved in CH3 OH, an excess of ethereal HCl was added, and anhydrous ether was added until the solution became cloudy. The solution stood at room temperature overnight and 28.72 g (33.3%) of product was collected. The filtrate yielded an additional 4.51 g (5.2%) of product. A small portion of this was reccrystallized from CH3 OH/ether to give an analytically pure sample of the title compound as a white crystalline solid, mp 210-213 C. Analysis calculated for: C18 H19 N2 F3.2HCl.H2 O: C, 52.57; H, 5.64; N, 6.81. Found: C, 52.93; H, 5.61; N, 6.83.
Referential Example 32 Synthesis of 4-Fluoro-3-methoxyaniline 3,4-Difluoroaniline (2.6 g) was added to a 28% methanol solution of sodium methoxide, and the mixture was heated for 2 days at about 60 C. and for 4 days at 110 C. After distilled water (50 ml) was added to the reaction mixture, it was extracted with chloroform (50 ml). A chloroform layer was washed with distilled water (20 ml) and then dried over anhydrous magnesium sulfate. The dry chloroform layer was concentrated under reduced pressure to obtain the title compound (2.8 g) as a dark brown oil. 1 H-NMR (CDCl3) delta: 3.54(br,2H), 3.84(s,3H), 6.17(dt,J=8 Hz,3 Hz,1H), 6.31(dd,J=3 Hz,7 Hz,1H), 6.86(dd,J=8 Hz,11 Hz,1H).
To this product, 70 g of 36% hydrochloric acid was added to convert it into its salt. Under stirring, 18 g of a 25% NaNO2 aqueous solution was added at 0 C. to obtain a diazonium salt. The diazonium salt was dropwise added to a hydrochloric acid solution of cupric chloride heated to 120 C., for thermal decomposition. The diazotization yield was 84%. 3,4-Difluorochlorobenzene was obtained in an overall yield of 72%.
With hydrogenchloride; N-chloro-succinimide; trifluoroborane diethyl ether; triethylamine; In tetrahydrofuran; diethyl ether; dichloromethane; chloroform; water;
EXAMPLE 1 Preparation of 5,6-difluoroisatin and 4,5-difluoroisatin STR9 To a solution of 3,4-difluoroaniline (12.98 g, 0.100 mol) in 325 mL of methylene chloride at -65 C. was added a solution of t-butylhypochlorite (10.86 g, 0.100 mol) in 52 mL of methylene chloride. The mixture was stirred for 10 min. A solution of ethyl thiomethylacetate (13.49 g, 0.100 mol) in 65 mL of methylene chloride was added dropwise to the mixture and stirred at -65 C. for 1 h. Triethylamine (10.17 g, 0.100 mol) in 65 mL of methylene chloride was added and the reaction mixture was warmed to room temperature and stirred for 3 h. Water was added and the methylene chloride layer was separated and concentrated under reduced pressure to yield an oil. The resulting oil was diluted with 300 mL of diethyl ether and 80 mL of 2N HCl, and stirred for 24 h. A precipitate was formed, filtered and washed with 50 mL of diethyl ether to give a mixture of 5,6- and 4,5-difluoro-3-thiomethyloxindoles in 70% yield. The crude oxindoles (11.64 g, 0.054 mol) were reacted with N-chlorosuccinimide (7.26 g, 0.05 mol) in 500 mL of chloroform at room temperature for 1 h. The reaction mixture was concentrated and the resulting residue was dissolved in 70 mL of THF. To this solution was added red mercury (II) oxide (11.78 g, 0.054 mol), boron trifluoride etherate (7.72 g, 0.05 mol), and 400 mL of aqueous 20% THF. The slurry was stirred for 3 h, diluted with 1000 mL of chloroform and filtered through celite. The resulting solids were washed with chloroform and the chloroform layer was separated and concentrated. Chromatography on silica gel eluding with 1% isopropyl alcohol:chloroform gave 5,6-difluoroisatin (Saul Kadin, U.S. Pat. No. 4,721,712) and 4,5-difluoroisatin in 31% and 4% yield, respectively. 4,5-Difluoroisatin: mp 140 C. (dec); 1 H NMR (300 MHz, DMSO-d6) delta 11.25 (s, 1H), 7.7 (dd, 1H), 6.7 (dd, 1H).
4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride salt[ No CAS ]
[ 184475-78-3 ]
[ 179688-53-0 ]
[ 3863-11-4 ]
6-acetoxy-4-(3',4'-difluoroanilino)-7-methoxyquinazoline hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In isopropyl alcohol;
The 4-(3',4'-difluoroanilino)-6-hydroxy-7-methoxyquinazoline used as a starting material was obtained as follows: A mixture of 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride ›obtained from <strong>[179688-53-0]6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one</strong> (6 g) and thionyl chloride (87[ml)], 3,4-difluoroaniline (2.9 ml) and isopropanol (170 ml) was stirred and heated to reflux for 4 hours. The precipitate was isolated, washed with isopropanol and dried. There was thus obtained 6-acetoxy-4-(3',4'-difluoroanilino)-7-methoxyquinazoline hydrochloride (7.5 g); NMR Spectrum: 2.4 (s, 3H), 4.0 (s, 3H), 7.45-7.6 (m, 3H), 7.95 (m, 1H), 8.8 (s, 1H), 8.95 (s, 1H), 11.5 (broad s, 1H).
PREPARATION 3 Ethyl 6,7-Difluoro-3,4-dihydro-3-oxo-2-quinoxaline Carboxylate. About 25 ml. of acetic anhydride were added cautiously to 25.8 g. of 3,4-difluoroaniline. The mixture was stirred for 1 hour after the addition was complete and was then poured over ice. The resulting white precipitate comprising 3,4-difluoroacetanilide was separated by filtration, and dried. Recrystallization from a benzene-acetone solvent mixture yielded 30 g. of 3,4-difluoroacetanilide melting at 125-6 C. Analysis Calc.; C, 56.14; H, 4.12; N, 8.12. Found: C, 56.28; H, 4.22; N, 8.16.
With acetic anhydride;
EXAMPLE 3 Preparation of Ethyl 6,7-Difluoro-3,4-dihydro-3-oxo-2-quinoxaline Carboxylate About 25 ml. of acetic anhydride were added cautiously to 25.8 g. of 3,4-difluoroaniline. The mixture was stirred for 1 hour after the addition was complete and was then poured over ice. The resulting white precipitate comprising 3,4-difluoroacetanilide was separated by filtration, and dried. Recrystallization from a benzene-acetone solvent mixture yielded 30 g. of 3,4-difluoroacetanilide melting at 125-6 C. Analysis Calc.: C, 56.14; H, 4.12; N, 8.12. Found: C, 56.28; H, 4.22; N, 8.16.
<strong>[38186-88-8]2-Chloro-5-fluoronicotinic acid</strong> (5.0 g, 28.5 mmol), K2CO3 (4.7 g, 34.2 mmol) was added to dry DMF (10 ml) in argon atmosphere. Copper (0.11 g, 1.71 mmol), methanol washed and dried copper (I) bromide (0.16 g, 1.14 mmol) and 3,4-difluoroaniline (4.8 ml, 48.4 mmol) were added and the mixture was stirred in 15O0C oil bath. Product was formed after 1.5 h according to LC-MS. The mixture was poured into 1 M HCl whereupon the precipitate was filtered, washed with 1 M HCl, dissolved in saturated Na2CO3 solution and extracted with ethyl acetate. The organic phase was dried with Mg2SO4 and evaporated to obtain the title compound (5.3 g, 69 percent). APCI-MS m/z: 269 [MH+].
With sodium t-butanolate In toluene at 20 - 120℃; Inert atmosphere;
4.1
Example 4; [4-1] Synthesis of 3,4-difluorophenylphenylamine; [Show Image] In a 300-mL three-neck flask were placed 200 mL of toluene, 0.21 g (0.96 mmol) of palladium acetate, and an ellipsoidal stirring chip. The two outer necks were closed with septum caps and the center neck was provided with a reflux coiled condenser. To the top of the condenser was attached a three-way stopcock, to which is attached a balloon filled with nitrogen gas. The atmosphere in the flask was replaced three times by nitrogen gas supplied from the balloon with the help of a vacuum pump. Into the flask was injected 3.8 g (18.9 mmol) of tris-t-butylphosphine by means of a syringe, followed by stirring for five to ten minutes at room temperature. The flask was further charged with 10 g (63.7 mmol) of 4-bromobenzene, 4.11 g (31.8 mmol) of 3,4-difluoroaniline, and 6.1 g (63.7 mmol) of sodium t-butoxide. With the flask placed on an oil bath, the solution therein was gradually heated to 120°C with stirring. After 20 hours, the flask was dismounted from the oil bath so as to terminate reaction, and the solution was allowed to cool to room temperature in an atmosphere of nitrogen. The reaction solution was transferred to a separatory funnel and was given 70 mL of diethyl ether. It was washed several times with 100 mL of saturated aqueous solution of sodium chloride. The organic layer was separated and dried with anhydrous magnesium sulfate. With the anhydrous magnesium sulfate filtered out, the organic layer was freed of solvent by means of an evaporator. Thus there was obtained a crude product, which was subsequently purified by means of a silica gel column (hexane:chloroform = 2:1) (Yields: 92%). 1H-NMR;δ 5.8 (-NH, 1H, s), 6.9-7.8 (Ar, 8H, m) ppm
With hydrogenchloride; In 1,4-dioxane; at 100℃; for 16h;
Method for svnthesising A. Ic; A.1c; Carboxylic acid ester B.5a (200 mg, 0.635 mmol) and aniline B.6a (119 mg, 0.925 mmol) are taken up in 1 mL dioxane and combined with dioxanic HCl (476 muL, 4 mmol/mL). The reaction mixture is stirred for 16 h at 1000C and then the solvent is eliminated in vacuo. The residue is purified by RP chromatography (method prep. HPLCl; 5 % acetonitrile to 50 % in 10 min) and the free acid A.lc (HPLC-MS: tRet. = 1.27 min; MS(M+H)+ = 251; method FECB4) is obtained.
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 100℃; for 20h; Inert atmosphere;
XI (0.660 g, 1.523 mmol), 3,4-difluoroaniline (0.236 g, 1.83 mmol), Cs2CO3 (0.695 g, 2.132 mmol), Pd(OAc)2 (17.06 mg, 0.076 mmol), and rac-BINAP (71 mg, 0.114 mmol) were dissolved in toluene and heated at 100° C. under stirring and inert atmosphere for 20 h. After cooling of the reaction mixture, filtration through celite, washing of the precipitate with EtOAc, the crude was isolated after concentration of the filtrate. Recrystallisation (CH2Cl2) afforded XII, (399 mg, 63%).
a) (Z)-phenyl N'-cyano-N-(3,4-difluorophenyl)carbamimidate; To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.19 g, 5.00 mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86percent).MS ISP (m/e): 274.1 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): 6(ppm)=10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H).
86%
In isopropyl alcohol; at 20℃;
To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.19 g, 5.00 mmol) and the suspension was stirred at room temperature over nigth. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86percent).MS ISP (m e): 274.1 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): 5(ppm) = 10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H).
86%
In isopropyl alcohol; at 20℃;
To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.19 g, 5 mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86percent).MS ISP (m/e): 274.1 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): 5(ppm) = 10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H).
79%
In isopropyl alcohol; at 20 - 25℃;
3,4-Difluoroaniline (3.00 g, 23.20 mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (5.53 g, 23.20 mmol) were dissolved in 2-propanol (64.00 mL). The reaction mixture was stirred at RT overnight. The crude was evaporated in vacuo and purified by column chromatography (Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenyl N-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g, 79percent). MS (ES+) m/z: 274.1 [M+Hj.
79%
In isopropyl alcohol; at 20 - 25℃;
3,4-Difluoroaniline (3.00 g, 23.20 mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (5.53 g, 23.20 mmol) were dissolved in 2-propanol (64.00 mL). The reaction mixture was stirred at RT overnight. The crude was evaporated in vacuo and purified by column chromatography (Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenyl N'-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g, 79percent). MS (ES+) m/z: 214.1 [M+H]+.
With potassium carbonate In <i>tert</i>-butyl alcohol at 110℃; for 3h; Inert atmosphere;
145.A
Step A; Tert-butanol (2 mL) was degassed by sonication for 1 min while a stream of argon was passed through the solution. To the degassed tert-butanol (1 mL) was added palladium(ll) acetate (0.003 g, 0.0127 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.018 g, 0.038 mmol). This mixture was heated at -100 °C in a sand-bath for 1 min to generate the catalyst. To the faint red catalyst solution was then added a solution of the title compound from Preparative Example 1 , Step D (0.045 g, 0.127 mmol) and commercially available 3,4-difluoro aniline (0.019 g, 0.15 mmol) in degassed tert-butanol (1 mL). After the addition of potassium carbonate (0.039 g, 0.28 mmol), the mixture was heated in a sand-bath at ~1 10 °C for 3 h. The mixture was diluted with ethyl acetate (30 mL), water (10 mL) and brine (10 mL). The organic phase was separated, dried over Ν32304, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethyl acetate/n-heptane (20/80) to afford the title compound as an off-white solid (0.045 g, 87 %)."-NMR (400 MHz, CDCI3): δ = 1.12-1.16 (m, 18H), 1.80-1.90 (m, 3H), 6.22 (br-s, 1 H), 6.47 (d, 1 H), 6.53 (d, 1 H), 6.90-6.94 (m, 1 H), 7.06 (t, 1 H), 7.10 (d, 1 H), 7.60-7.67 (m, 1 H), 7.75 (d, 1 H)
87%
With potassium carbonate; XPhos In <i>tert</i>-butyl alcohol at 110℃; for 3h; Inert atmosphere;
145.A
Tert-butanol (2 mL) was degassed by sonication for 1 min while a stream of argon was passed through the solution. To the degassed tert-butanol (1 mL) was added palladium(II) acetate (0.003 g, 0.0127 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.018 g, 0.038 mmol). This mixture was heated at 100° C. in a sand-bath for 1 min to generate the catalyst. To the faint red catalyst solution was then added a solution of the title compound from Preparative Example 1, Step D (0.045 g, 0.127 mmol) and commercially available 3,4-difluoro aniline (0.019 g, 0.15 mmol) in degassed tert-butanol (1 mL). After the addition of potassium carbonate (0.039 g, 0.28 mmol), the mixture was heated in a sand-bath at 110° C. for 3 h. The mixture was diluted with ethyl acetate (30 mL), water (10 mL) and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethyl acetate/n-heptane (20/80) to afford the title compound as an off-white solid (0.045 g, 87%).1H-NMR (400 MHz, CDCl3): δ=1.12-1.16 (m, 18H), 1.80-1.90 (m, 3H), 6.22 (br-s, 1H), 6.47 (d, 1H), 6.53 (d, 1H), 6.90-6.94 (m, 1H), 7.06 (t, 1H), 7.10 (d, 1H), 7.60-7.67 (m, 1H), 7.75 (d, 1H)
87%
With palladium diacetate; potassium carbonate; XPhos In <i>tert</i>-butyl alcohol at 110℃; for 3h;
N-(3,4-difluorophenyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-6-amine (34a)
Tert-butanol (2 mL) was degassed by sonication for 1 min while a stream of argon was passed through the solution. To the degassed tert-butanol (1 mL) was added palladium(II) acetate (3 mg, 0.0127 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 18 mg, 0.038 mmol). This mixture was heated at ~100 °C in a sand-bath for 1 min to generate the catalyst. To the faint red catalyst solution was then added a solution of the bromo derivative 8 (45 mg, 0.127 mmol) and commercially available 3,4-difluoro aniline (19.8 mg, 0.15 mmol) in degassed tert-butanol (1 mL). After the addition of potassium carbonate (39 mg, 0.28 mmol), the mixture was heated in a sand-bath at ~110 °C for 3 h. The mixture was diluted with ethyl acetate (30 mL), water (10 mL) and brine (10 mL). The organic phase was separated, dried over Na2SO4, filtered and the solvents were removed. The residue was purified by chromatography on silica using ethyl acetate/n-heptane (20/80) to afford the title compound as an off-white solid 34a (44.9 mg, 87 %). 1H-NMR (400 MHz, CDCl3): δ = 7.75 (d, 1H), 7.67-7.60 (m, 1H), 7.10 (d, 1H), 7.06 (t, 1H), 6.94-6.90 (m, 1H), 6.53 (d, 1H), 6.47 (d, 1H), 6.22 (br-s, 1H), 1.93-1.85 (m, 3H), 1.16-1.12 (m, 18H). 13C NMR (101 MHz, DMSO) δ 157.19, 154.85, 151.40, 146.35, 138.94, 138.92, 130.01, 121.35, 118.60, 118.52, 114.99, 114.77, 112.00, 104.73, 100.13
With triphenyl phosphite In toluene for 8h; Reflux;
4.1.1.1. N-Phenyl-2-hydroxy-5-nitrobenzamide (3a)
General procedure: A mixture containing 2-hydroxy-5-nitrobenzoic acid (1.83 g, 10 mmol), aniline (1.21 g, 13 mmol), triphenyl phosphite (3.6 mL) and toluene (30 mL) was strirred under refluxing for 8 h, cooled to room temperature. The resulted solid was collected by filtration under reduced pressure, washed with cooled dichlormethane (5 mL × 2), crystallized from ethanol (20 mL) to produce 2.17 g of 3a as a yellow solid. Yield 84%.
Stage #1: 5-chloro-2-hydroxybenzoic acid; 3,4-difluoroaniline In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 0.5h;
Stage #2: With phosphorus trichloride In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 3h;
General procedure for the synthesis of compounds 3-25
General procedure: To a mixture of 5-chlorosalicylic acid (1a-d, 1 mmol) andaniline derivative (2a-k, 1 mmol) in a round bottom flasadded 10 mL xylenes mixture (mixture of o-, m-, and pxylenes)and heated to 120 °C for 30 min.PCl3(0.4 mmol)was added dropwise for 5 min, then the reaction contentsstirred at 120 °C for 3-4 h. The reaction progress wasmonitored by TLC carried out on Merck silica-gel plates(0.25 mm thick, 60F254) in ethylacetate-hexanes (1:3) andvisualized by UV (254 nm) light. After complete consumptionof starting materials (observed by TLC), thecontents were brought to 70 °C, and then quenched withwater. The resulting white precipitate was filtered and washed with water (20 mL, 70 °C), obtained desired salicylanilidewith >96% purity. Further washing with 10%ethanol in water (20 mL) removed trace amount (3-4%) ofunreacted aniline derivative. The wet white solid was driedunder reduced pressure for 3-4 h, resulted desired compounds(3-25) with >98% purity.
25%
With pyridine; phosphorus trichloride In toluene for 12h; Inert atmosphere; Reflux;
73 4.1.1 Procedure A
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley’s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With ionic liquid immobilized on γ-Fe2O3(at)SiO2 nanoparticles In water at 100℃; for 1.16667h;
General procedure for synthesis of N-substituted pyrroles
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and γ-Fe2O3(at)SiO2-Sb-IL (0.08 g). The reaction mixture was stirred at 100 °C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product. 1-(3,4-Difluorophenyl)-1H-pyrrole (3p). IR (KBr): 3134, 3078, 1614, 1521, 1485, 1444, 1350, 1271, 1262, 1124, 1066, 1022, 954, 890, 729 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 6.35 (t, J = 2.0 Hz, 2H), 7.0 (t, J = 2.0 Hz, 2H), 7.10-7.13 (m, 1H), 7.19-7.25 (m, 2H) ppm; 13C NMR (CDCl3, 125 MHz) (: 110.1 (d, JFC = 20.3 Hz), 111.1, 116.2 (dd, JFC = 6.1, 3.6 Hz), 118.0 (d, JFC = 18.0 Hz), 119.5, 137.4 (dd, JFC = 8.0, 3.0 Hz), 148.3 (dd, JFC = 245.4, 12.6 Hz), 150.6 (dd, JFC = 247.9, 13.5 Hz) ppm; ESI-MS: m/z = 180 (M + 1)+; Anal. Calcd. for C10H7F2N: C, 67.04; H, 3.94; N, 7.82. Found: C, 66.95; H, 4.12; N, 8.01.
77%
With acetic acid In water; 1,2-dichloro-ethane at 20℃; Inert atmosphere;
76%
With 4-chlorpyridine hydrochloride In 1,4-dioxane for 4h; Reflux; Inert atmosphere;
4.1.1 1-(3,4-Difluorophenyl)-1H-pyrrole (1)
A mixture of 3,4-fluoroaniline (129mg, 1mmol), 2,5-dimethoxytetrahydrofuran (213mg, 1.61mmol) and 4-chloropyridine hydrochloride (236mg, 1.57mmol) in 1,4-dioxane (17mL) was refluxed under a nitrogen atmosphere for 4h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was then diluted in CH2Cl2, sonicated for 15min, and filtered. The procedure was repeated one more time and the organic extracts were concentrated under reduced pressure. The residue was flash chromatographed with petroleum ether to provide the title compound (136mg, 76%). An analytical sample was obtained by recrystallization from petroleum ether (bp 80-100°C). Mp 62-64°C [lit.63 62-63°C]; IR (KBr) 1614 (C=C) cm-1; 1H NMR (CDCl3) δ 6.33-6.40 (m, 2H, pyrrolyl H-3, H-4), 6.98-7.05 (m, 2H, pyrrolyl H-2, H-5), 7.10-7.17 (m, 1H, phenyl H-5), 7.18-7.27 (m, 2H, phenyl H-2, H-6). Anal. Calcd for C10H7F2N: C, 67.04; H, 3.94; N, 7.82. Found: C, 66.80; H, 3.97; N, 7.74.
General procedure: To a mixture of substituted phenyl amine (0.06 mol) and 20% HCl (50 mL), NaNO2 (0.123 mol) in H2O (200 mL) was added drop-wise at 0 C. After the completion of addition, the reaction mixture was stirred at this temperature for 30 min, and then it is dropped into the mixture of appropriate intermediate (10a or 10b) (0.047 mol), sodium acetate anhydrous (10.2 g, 0.124 mol), EtOH (200 mL) at 0 C. Upon completing the addition, the mixture was filtered and the cake was dried to give light yellow to white solid (11a-t, 12a and 12b) yielded 75-80%.
Stage #1: 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid With thionyl chloride In tetrahydrofuran for 8h; Reflux; Inert atmosphere;
Stage #2: 3,4-difluoroaniline In tetrahydrofuran for 14h;
3 N-(3,4-difluorophenyl)-2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxamide (compound 3)
Thionyl chloride (1 mL, 14 mmol) was added to disfunisal (0.9 g, 4 mmol) in anhydrous tetrahydrofuran (30 mL), and the mixture was refluxed under nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was steamed to give the intermediate by Dean-Stark apparatus, which residue was used directly in the next step. Freshly prepared intermediate was directly reacted with 3,4-difluoroaniline (0.4 mL, 4 mmol) in anhydrous tetrahydrofuran (30 mL) for 14 h. After removal of tetrahydrofuran, the reaction mixture was washed with ethyl acetate/hexane and the crude product was extracted in ethyl acetate. The organic layer was collect and dried over anhydrous Na2SO4, and then the solvent was evaporated. The crude product was washed and purified by crystallization from hot ethanol to afford compound 3. Yield: 61%. Mp: 231-232° C. (EtOH). 1H-NMR (300 MHz, DMSO-d6): δ ppm 7.09 (d, J=8.7 Hz, 1H, Ar-H5), 7.20 (td, J=8.4, 3 Hz, 1H, Ar-H6'), 7.45-7.49 (m, 3H, Ar-H3',5,6"), 7.56-7.64 (m, 2H, Ar-H6,5"), 7.87-7.93 (m, 1H, Ar-H6"), 8.01 (t, J=0.9 Hz, 1H, Ar-H2), 10.55 (s, 1H, NH), 11.70 (s, 1H, OH). HRMS (EI) m/z: calcd [M]+, 361.0726 (C19H11F4NO2+). found, 361.0724.
With N-ethyl-N,N-diisopropylamine; In toluene; at 90.0℃; for 24.0h;
General procedure: A mixture of asubstituted aniline (33aem) (5.5 mmol), N-ethyldiisopropylamineand alkyl halide (34aec) or ethyl sulfate (34d) in the molar ratio of1:1:1 in toluene (21 ml) was stirred and heated at 90?C for 18 h. Inthe cases listed below it was necessary to vary the conditions of reaction as summarized in Table 1.The resulting suspension was taken up with ethyl acetate. The organic phase was washed with water then dried over anhydrous sodium sulfate. On evaporation of the solvent, in most cases a solidor an oily residuewas obtained. Purification was performed by flash chromatography on a silica gel column eluting with the following mixture of solvents: ethyl acetate/petrol ether 40-60?, in the ratio of 6:4 (35, 42); 7:3 (52); 8:2 (41, 43, 48, 51, 53, 62, 65); 9:1 (38, 39,45, 46, 47, 50); 95:5 (36, 37, 44, 55, 56, 57, 58, 59, 60, 61); 98:2 (64);petrol ether 40-60?/diethyl ether 9:1 (49); toluene/ethyl acetate 95:5 (63); chloroform/methanol 95:5 (54), chloroform/methanol 98:2 (66).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 20h;
Example 85 5-(5,6-Dihydro-4H-pyr -3-yl)-lH-indole-2-carboxylic acid (3,4-difluoro-phenyl)-amide a) 5-Bromo-lH-indole-2-carboxylic acid (3,4-difluoro-phenyl)-amid A mixture of <strong>[7254-19-5]5-bromoindole-2-carboxylic acid</strong> (2 g), 3,4-difluoroaniline (1.63 g), EDC*HC1 (2.44 g), 1-hydroxybenzotriazole (1.49 g) and N,N-diisopropylethylamine (3.64 mL) in tetrahydrofuran (60 mL) was stirred at room temperature for 20 hours. The reaction was diluted with ethyl acetate, washed water and brine. The combined organic layers were dried over magnesium sulfate. The concentrated filtered solution was purified by flash chromatography using heptane / ethyl acetate (95:5 to 0: 100) as eluent to yield the title compound as a light yellow solid (1.8 g, 62 %).
62%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 20h;
A mixture of <strong>[7254-19-5]5-bromoindole-2-carboxylic acid</strong> (2 g), 3,4-difluoroaniline (1.63 g), EDC*HCl (2.44 g), 1-hydroxybenzotriazole (1.49 g) and N,N-diisopropylethylamine (3.64 mL) in tetrahydrofuran (60 mL) was stirred at room temperature for 20 hours. The reaction was diluted with ethyl acetate, washed water and brine. The combined organic layers were dried over magnesium sulfate. The concentrated filtered solution was purified by flash chromatography using heptane / ethyl acetate (95:5 to 0:100) as eluent to yield the title compound as a light yellow solid (1.8 g, 62 %).
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: ethyl acetoacetate With sodium acetate In ethanol; water at 0℃;
General procedure for preparation intermediates of 3-oxo-2-(2-arylhydrazono)butanoic acid ethyl ester (9a-i)
General procedure: To a mixture of substituted phenyl amine (0.06mol) and 15% HCl (60mL), NaNO2 (5g, 0.072mol) in H2O (200mL) was added drop-wise at 0°C. After the completion of addition, the reaction mixture was stirred at this temperature for 30min, and then added into a mixture of ethyl acetylacetate (8.2g, 0.063mol), anhydrous sodium acetate (14.76g, 0.18mol), and EtOH (200mL) at 0°C. Then, the mixture was filtered, and the residue was dried to afford light yellow solids (9a-i) in 90-95% yields.
Stage #1: 3,4-difluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.0833333h;
Stage #2: ethyl acetoacetate With ammonium acetate In ethanol; water at 0℃; for 0.5h;
5.2. General procedure for preparation of compounds 10a-h
General procedure: Appropriate substituted anilines 8a-h (0.101mol) was added to the mixture solution of hydrogen chloride/water (1:1, 10ml), sodium nitrite (0.1mol) and stirred for 5min at 0°C, respectively. Then the mixture was added to the ethanol solution which ammonium acetate (1mol) and ethyl acetoacetate (0.1mol) were dissolved in. The reaction was monitored by TLC until completed. Finally the solution was filtered and washed with a plenty of water to give a yellow solid.
N<SUP>1</SUP>-(3,4-difluorophenyl)-3-iodo-N<SUP>2</SUP>-(2-methyl-1-(methylthio)propan-2-yl)phthalamide[ No CAS ]
N<SUP>2</SUP>-(3,4-difluorophenyl)-3-iodo-N<SUP>1</SUP>-(2-methyl-1-(methylthio)propan-2-yl)phthalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 83%
2: 18%
Stage #1: 3-iodophthalic anhydride; 2-methyl-1-methylthio-2-propylamine With triethylamine In dichloromethane at 20℃;
Stage #2: With methanesulfonyl chloride; triethylamine In dichloromethane at -10℃;
Stage #3: 3,4-difluoroaniline In dichloromethane at -10 - 20℃;
1-methyl-N-3',4'-difluorobenzyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.2%
With potassium carbonate In tetrahydrofuran at 5 - 20℃;
3.5. General Procedure for the Preparation of 7aa-bk
General procedure: Pyrazole acid chlorides 6a-b were prepared by refluxing 4a-b in thionyl chloride for 8 h. Pyrazole acid chlorides 6a-b (12 mmol) in anhydrous tetrahydrofuran (THF; 30 mL) were slowly added to a solution of amine derivatives or 5-methylisoxazol-3-ol (10 mmol) and K2CO3 (1.38 g, 10 mmol) in anhydrous THF (30 mL) at a controlled temperature of 5 °C. The reaction proceeded at room temperature until 6a-b was no longer tested by TLC. The reaction solution was then filtered and the solvent distilled. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and recrystallized to generate the target pyrazole carboxamides and isoxazolol pyrazole carboxylates (7aa-bk). The product yields ranged from 40% to 80%. All 20 compounds were novel, and the physical and spectral data for these compounds are listed below.
63.2%
With potassium carbonate In benzene at 55℃; for 6h;
10
Is provided with a thermometer and the agitator in 100 ml of the three-port bottle by adding 0.01 molar anhydrous K 2 CO 3 powder, 0.01 mol 3-methylaniline, 30 ml of acetonitrile, at room temperature under (25 ±5 °C) slowly dropping 0.01 mol 1-methyl-3-trifluoromethyl-4-pyrazole formyl chloride dissolved in 20 ml of acetonitrile into a solution of the, completion of the dropping, the reaction continue to stir at room temperature for 10 hours. Filter the reaction mixture under reduced pressure, the resulting filtrate exsolution, compounds prepared Q120209 crude product, using ethanol-toluene (volume ratio of 1:1) the compound Q120209 crude product recrystallized, obtain white flaky crystal compound Q120209, yield 64.2%. Using 3,4-difluoroaniline instead of 3-methylaniline; A The reaction of benzene as solvent; reaction temperature is 55 ± 5 ° C; the reaction time was 6 hours; recrystallization from toluene
With Sodium hydrogenocarbonate In tetrahydrofuran at 0 - 20℃;
7.3 General procedure for the synthesis of 8
General procedure: To a 100ml three neck flask equipped with thermometer was added naphthalen-2-amine (2g, 13.97mmol, 1 eq.), THF (20ml), NaHCO3 (1.41g, 14.67mmol, 1.2 eq.) and cooled to 0°C. Then a solution of phenyl chloroformate (1.84g, 14.67mmol, 1.05 eq.) in THF (10ml) was added dropwise under 5°C. The reaction was monitored by TLC. After completion of the reaction, THF was removed by evaporation under reduced pressure. The aqueous phase was extracted with ethyl acetate (50+25ml). The combined organic layers were washed with brine (20ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give 3.5g brown solid, which was subjected to crystallization in EA:PE (1:2/v:v, 45ml) to give 3g off-white solid (yield 81.5%).
With potassium carbonate In acetone at 0 - 20℃; for 3h;
4
General procedure: To the mixture of variant amines (50.0 mmol) and K2CO3(13.8 g, 0.100 mol) in dry acetone (50 mL), phenyl chloroformate(75.0 mmol) was added dropwisely while maintaining the temperaturebetween 0 and 5 C. After the addition was completed, the mixture was warmed to room temperature for another 3 h, and thesolvent was evaporated under reduced pressure. The residue waswashed with water 50 mL for thrice, filtered, and dried undervacuum to afford corresponding carbamates 29a-d.
With potassium carbonate In acetone at 0 - 20℃;
With Sodium hydrogenocarbonate In water monomer; ethyl acetate
General procedure: 2,4-difluorobenzylamine (378 mg, 2.64 mmol), EDC·HCl(557 mg, 2.91 mmol), HOBt·H2O (444 mg, 2.91 mmol), andexcess triethylamine was added to Boc-beta-Ala-OH(500 mg, 2.64 mmol) in 10 mL DCM. The reaction wasstirred overnight. After diluting with EtOAc, the reactionmixture was washed with saturated aqueous NH4Cl andbrine. The organic phase was dissolved in 1:1 MeOH to 4M HCl in dioxane for several hours and then dried overnighton high vacuum. Then, it was refluxed in acetonitrileat 50 °C overnight with paraformaldehyde (1.2 eq.) andcyanuric chloride (0.1 eq.). The reaction was concentrateddown and purified with HPLC to afford the cyclized intermediate,3-(2,4-difluorobenzyl)tetrahydropyrimidin-4(1H)-one. 3-(difluoromethyl)-4-fluoroaniline was reacted with 1.2eq of phenyl chloroformate in 1:1 EtOAc to saturate aqueousNaHCO3 overnight. The organic phase was concentrateddown and reacted with 3-(2,4-difluorobenzyl)tetrahydropyrimidin-4(1H)-one with excess DIPEA inDCM overnight. The desired product 34 was obtained afterHPLC separation.
0.18 g
With Sodium hydrogenocarbonate In tetrahydrofuran; water monomer at 0 - 20℃; for 2h;
16 (3,4-difluorophenyl) phenyl carbamate
With a thermometer in a 100ml three-necked flask with 3,4-difluoroaniline (2g, 15.5mmol, 1eq.), THF (20ml), water (20ml), sodium hydrogen carbonate (1.56g, 18.6mmol, 1.2eq.) was cooled to 0°C in an ice-water bath, and a solution of phenyl chloroformate (2.55g, 16.3mmol, 1.05eq.) in THF (10ml) was added dropwise at 5°C. After adding, remove the ice water bath and stir. TLC (EA:PE=1:4) showed that the reaction was complete after 2h. The THF was evaporated under reduced pressure and extracted with ethyl acetate (40+30ml). The organic phases were combined, washed with saturated sodium chloride (20 ml), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was evaporated under reduced pressure to obtain 4.3 g of brownish yellow solid. Ethyl acetate: petroleum ether (1:6, 10.5ml) crystallized to obtain 3.18g of off-white solid. The mother liquor was crystallized with ethyl acetate: petroleum ether (1:6, 2.5 ml) to obtain 0.18 g of off-white solid, with a combined yield of 87%.
With potassium carbonate In acetone at 0 - 20℃; for 3h;
Synthesis of variant carbamate (B)
General procedure: To the mixture of variant amines (50.0 mmol) and K2CO3 (13.8 g, 0.100 mol) in acetone (50 mL), phenyl chloroformate (75.0 mmol) was added dropwisely while maintaining the temperature between 0 and 5°C. After the addition was completed, the mixture was warmed to room temperature for another 3 h, and the solvent was evaporated under reduced pressure. The residue was washed with water 50 mL for thrice, filtered and dried under vacuum to afford corresponding carbamates B.
N-(3,4-difluorophenyl)-2-phenoxyacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72h;
General Procedure for the Preparation of Compounds
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N’-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
N-(3,4-difluorophenyl)-5-methoxyquinolin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In neat (no solvent); at 160℃;
General procedure: A mixture of compound 3 (0.2 g, 1.03 mmol) and the appropriate aniline (1.03 mmol) were reacted neat at 160 C for 10-120 minutes. The reaction mixture was cooled, dissolved in DCM and concentrated under reduced pressure to afford the desired product, which was used directly in the next step without further purification.
4-[(3,4-difluorophenyl)amino]-6-chloro-7-bromo-quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: 4-hydroxy-6-chloro-7-bromo-quinazoline With triethylamine; trichlorophosphate In acetonitrile at 50 - 80℃; for 5h;
Stage #2: 3,4-difluoroaniline In 1,4-dioxane; acetonitrile at 20℃; for 1h;
Intermediate 1: 4-[(3,4-difluorophenyl)amino]-6-chloro-7-bromo-quinazoline
Intermediate 1: 4-[(3,4-difluorophenyl)amino]-6-chloro-7-bromo-quinazoline 10g4- hydroxy-6-chloro-7-bromo-quinazoline was suspended in 40ml of acetonitrile, 9g dropwise phosphorus oxychloride. Control temperature is less than 50°C, triethylamine was slowly added to 6g, the addition was completed was heated to an internal temperature of 80°C, the reaction was stirred. After 5hr, TLC detection, detection reaction. 7g 3,4-difluoroaniline was dissolved in 50ml of dioxane, was added dropwise to the above reaction, the reaction 1 hour the reaction monitored by TLC. The reaction was cooled to room temperature, 40ml of water was slowly added, aqueous potassium hydroxide solution was slowly adjusted to pH 8-9, the solid precipitated. Filter, the resulting solid was washed with water, ethanol wash, 50°C vacuum drying, Intermediate 1 was obtained, yield 91% .
91%
Stage #1: 4-hydroxy-6-chloro-7-bromo-quinazoline With triethylamine; trichlorophosphate In acetonitrile at 80℃; for 5h;
Stage #2: 3,4-difluoroaniline In 1,3-dioxane; acetonitrile for 1h;
int-1 intermediate 1
10g 4- hydroxy-6-chloro-7-bromo-quinazoline was suspended in 40ml of acetonitrile was added dropwise phosphorus oxychloride 9g. Control temperature is less than 50 ° C, was slowly added 6g triethylamine addition was completed was heated to an internal temperature of 80 ° C, the reaction was stirred. After 5hr, TLC detection, detection reaction. 7g 3,4- difluoroaniline was dissolved in 50ml of dioxane, was added dropwise to the above reaction, the reaction 1 hour the reaction monitored by TLC. The reaction was cooled to room temperature, was slowly added 40ml of water, aqueous potassium hydroxide solution was slowly adjusted to PH 8-9, a solid precipitated. Filtered and the resulting solid was washed with water, washed with ethanol, 50 ° C and dried under vacuum to give intermediate 1, yield 91%
91%
Stage #1: 4-hydroxy-6-chloro-7-bromo-quinazoline With triethylamine; trichlorophosphate In acetonitrile at 50 - 80℃; for 5h;
Stage #2: 3,4-difluoroaniline In 1,4-dioxane at 20℃; for 1h;
1 Intermediate 1: 4 - [(3,4-difluorophenyl) amino] -6-chloro-7-bromo-quinazoline
10g4- hydroxy-6-chloro-7-bromo-quinazoline was suspended in 40ml of acetonitrile was added dropwise phosphorus oxychloride 9g.Controlling the temperature less than 50 , 6g triethylamine was slowly added, the addition was completed the temperature was raised to 80 deg.] C, the reaction was stirred.After 5hr, TLC detection, detection reaction.7g3,4- difluoroaniline was dissolved in 50ml of dioxane, was added dropwise to the above reaction, the reaction 1 hour the reaction monitored by TLC.The reaction was cooled to room temperature, was slowly added 40ml of water, aqueous potassium hydroxide solution was slowly adjusted to PH 8-9, a solid precipitated.Filtered and the resulting solid was washed with water, washed with ethanol, and dried 50 deg.] C under vacuum to give intermediate 1, a yield of 91%
General procedure: Prior synthesis of pyrido[3,2-d]pyrimidines utilized ethoxyethanol and aniline for substitution on 3 (Scheme 1) whereas for substituted anilines, strong bases such as LDA were used to facilitate the reaction. Both methods suffer from long durations and stringent reaction conditions, respectively. A simpler and versatile synthetic route to obtain 4-18 from 3 was envisioned using appropriate anilines at reflux in isopropanol at 120 C, a highly versatile reaction process that provided good yields (75-83%). Reduction of the nitro group was performed using iron in cone. HCl (Bechamp reduction) or using H2/Pd to give quantitative yields. Cyclization of the resultant intermediate with chlorformamidine in dimethylsulfone at 140 C provided the desired target compounds.
In isopropyl alcohol; at 130℃; for 8.5h;
General procedure: A solution of <strong>[93683-65-9]6-chloro-3-nitropicolinonitrile</strong> (25) (0.60 g, 2.7 mmol) and an appropriate aniline was heated at 130 C in isopropanol. After 3-16 h, the solution was concentrated under reduced pressure. The precipitate obtained was neutralized with solution of ammonia in methanol to afford 26-38 as a crude product. The next step was carried out without any purification. To a suspension of 26-38 in methanol (20 mL) and concentrated hydrochloric acid (36%, 2 - 4.0 mL) was added iron powder. The mixture was refluxed until all the starting material had reacted (monitored on TLC). The hot reaction mixture was poured into water (20 mL) and stirred for 5 min. The unreacted iron was removed using a stirring bar retriever, and the aqueous solution was neutralized with ammonium hydroxide to pH 4. The solution was then extracted with chloroform (3 × 20 mL), and the combined organic layer was washed with water (2 × 5.0 mL), sodium bicarbonate solution (5.0 mL), and brine (5.0 mL) and dried over anhydrous sodium sulfate. The product (39-52) was obtained as a gummy brown semi-solid. The next step was carried out without any purification and characterization. Mixture of 39-52, chloroformamidine hydrochloride (1 g), and dimethyl sulfone (4.0 g) was heated in an oil bath at 140 C under nitrogen for 15 min. The oil bath was removed, and water (10 mL) was added slowly to the hot reaction mixture. The aqueous solution was cooled to room temperature and extracted with chloroform (3 × 5 mL) to remove dimethyl sulfone. The aqueous phase was made basic to pH 10 with ammonium hydroxide, followed by removal of water under reduced pressure. The residue was dissolved in a mixture of 50:50 methanol-acetone (v/v), and silica gel was added (3.0 g). After the removal of solvent with a rotary evaporator, the silica gel plug was loaded onto a column and eluted with 1:5 MeOH-CHCl3 (v/v). The fractions containing the required compound were evaporated under reduced pressure to afford the targeted compounds.
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃;
2.1.1. General procedure and results for the preparation of the formamides
General procedure: Formamides were prepared based on the procedure from Wang et al.1 A reactor was charged with amine (1 equiv), methyl formate (1.2 equiv) and THF (0.55 M). A solution of NaHMDS 40 % THF (1.5 equiv) was added at 0 °C over 45 min. The internal temperature stays between 0 and 5°C. After addition, the mixture is warmed to rt and stirred for 24 h. The reaction mixture was quenched with a saturated solution of NH4Cl and THF was evaporated in vacuo (40 °C, 200 mbar). The mixture was then partitioned between EtOAc and H2O and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed twice with H2SO4 1 M (2 x 150 mL), then with H2O, finally with a NaHCO3 aq. solution 2 % (m/v) and concentrated to dryness.
5-(N-((1-Cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)sulfamoyl)-N-(3,4- difluorophenyl)-2-fluorobenzamide (13) 2-fluorobenzoic acid 9 (10.0 g, 71.4 mmol) was added to chlorosulfonic acid (50 mL) at 0 C and the mixture was stirred at 0 C for 1 h. The reaction mixture was then slowly poured onto ice. The precipitate formed was filtered, rinsed off with water (3 x 100 mL) and dried under vacuum overnight to yield 5-(chlorosulfonyl)-2- fluorobenzoic acid 10 as a brownish solid (10.5 g, 44.0 mmol). 5-(chlorosulfonyl)-2- fluorobenzoic acid 10 (10.0 g, 41.9 mmol) was added to 60 mL of SOCl2 at room temperature and the mixture was refluxed for 1.5 h. After removal of SOCl2 in vacuo, the residual oil was solubilized in toluene (150 mL) and 3,4-difluoroaniline (6.5 g, 50.3 mmol) was added. The mixture was stirred at 100 C for 4 h and then cooled down to room temperature. The solution was then poured into a saturated solution of ammonium chloride (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (Hexanes/EtOAc = 6:4 v/v) to yield 3- ((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1-sulfonyl chloride 11 (92%, 13.51 g, 38.6 mmol). To a solution of 3-((3,4-difluorophenyl)carbamoyl)-4-fluorobenzene-1- sulfonyl chloride 11 (10.0 g, 28.6 mmol) in CH2Cl2 (200 mL) at 0 C were added propargylamine hydrochloride (3.1 g, 34.3 mmol) and Et3N (7.8 mL, 57.2 mmol). The reaction mixture was stirred overnight at room temperature and then poured into a saturated solution of ammonium chloride (250 mL). After extraction with CH2Cl2 (3 x 100 mL), the combined organic layers were dried over sodium sulfate and finally concentrated in vacuo. The resulting solid was washed with diethyl ether (50 mL) and hexanes (50 mL) to yield N-(3,4-difluorophenyl)-2-fluoro-5-(N-(prop-2-yn-1- yl)sulfamoyl)benzamide 12 (74%, 7.8 g, 21.1 mmol) as a white powder. A solution of bromocyclopropane (0.6 mL, 4.9 mmol) and sodium azide (483 mg, 7.4 mmol) in water (1 mL) was heated under microwave irradiation for 30 minutes at 120 C. To this solution were added a solution of compound 12 (0.1 g, 0.3 mmol) in acetonitrile (1 mL), sodium ascorbate (10 mg, 0.05 mmol) and copper sulfate (20 mg, 0.12 mmol). (0096) The reaction mixture was then heated for 30 minutes at 80 C under microwave irradiation before being poured into a saturated solution of ammonium chloride (50 mL). After extraction with EtOAc (3 x 50 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (Hexanes:EtOAc = 6:4 v/v) giving compound 13 as a white powder (19%, 23 mg, 0.05 mmol). 1H NMR (400 MHz, Acetone-d6) delta 9.92 (s, 1H), 8.25 (dd, J = 6.6, 2.5 Hz, 1H), 8.06- 7.95 (m, 2H), 7.77 (s, 1H), 7.58- 7.52 (m, 1H), 7.48 (dd, J = 10.1, 8.7 Hz, 1H), 7.37 (dt, J = 10.6, 9.0 Hz, 1H), 7.21 (brs, 1H), 6.11- 5.94 (m, 1H), 5.32- 5.16 (m, 1H), 4.99 (dt, J = 6.0, 1.5 Hz, 2H), 4.32 (s, 2H). 13C NMR (101 MHz, Acetone-d6) delta 188.9, 167.9, 162.1, 150.2, 149.2 (d, J = 12.9 Hz), 146.8 (d, J = 13.0 Hz), 142.8, 137.9 (d, J = 5.9 Hz), 128.5, 124.6, 120.4- 118.2 (m), 117.5 (dd, J = 6.0, 3.6 Hz), 110.6 (d, J = 22.1 Hz), 81.5, 73.3, 33.2, 29.7, 12.8 (d, J = 9.6 Hz). 19F NMR (377 MHz, Acetone-d6) delta -110.6 (s), -139.6- - 139.7 (m), -146.1- -146.3 (m). HRMS (ESI): m/z [M+H]+ calcd for C19H17F3N5O3S: 452.1004, found: 452.0999.
2.87 g
A solution of 2 (3 g, 12.6 mmol) in SOCl2 (20 mL) was heated at80 C for 16 h. The mixture was concentrated under reducedpressure and co-evaporated with toluene. The crude residue wasdissolved in toluene (25 mL) and 3,4-difluoroaniline (1.24 mL, 12.6 mmol) was added. The mixture was heated at 110 C for 2 hand concentrated under reduced pressure. The residuewas purifiedby silica gel column chromatography using hexanes/EtOAc (8:2) toafford 3 (2.87 g, 65% over two steps). 1H NMR (400 MHz, Acetoned6) delta9.99 (s, 1H), 8.54 (dd, J = 6.1, 2.6 Hz, 1H), 8.43-8.32 (m, 1H),7.98-7.87 (m, 1H), 7.73 (dd, J = 9.7, 8.9 Hz, 1H), 7.54-7.45 (m, 1H),7.33 (dt, J = 10.5, 9.0 Hz, 1H). 13C NMR (101 MHz, Acetone-d6) delta163.4 (d, J = 262.3 Hz), 160.2, 149.6 (dd, J = 244.5, 13.3 Hz), 146.8(dd, J= 243.6, 12.8 Hz), 140.2 (d, J = 3.2 Hz), 135.3 (dd, J = 8.9,3.2 Hz), 132.2 (d, J = 11.2 Hz), 130.1 (d, J = 4.9 Hz), 125.9 (d,J = 16.7 Hz), 118.9 (d, J = 25.0 Hz), 117.3 (d, J = 18.3 Hz), 116.5 (dd,J = 6.1, 3.5 Hz), 109.6 (d, J = 22.1 Hz). 19F NMR (377 MHz, Acetoned6) delta-103.6, -139.3 to -139.4 (m), -145.6 to -145.7 (m).
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.
N-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 65℃;
2-(5-((3,4-difluorophenyl)carbamoyl)-1-methyl-1H-pyrrol-3-yl)-2-oxoacetic acid (24) To a solution of 1-methyl-1H-pyrrole-2-carboxylic acid (4 g, 32 mmol), 3,4- difluoroaniline (6.2 g, 48 mmol) and DIPEA (13 mL, 96 mmol) in DMF (150 mL) was added HATU (18.2 g, 48 mmol) at room temperature. The mixture was heated at 65 C overnight and poured into a saturated solution of ammonium chloride. After extraction with ethyl acetate (3 x 50 mL), the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting mixture was purified by flash chromatography (hexanes:EtOAc = 6:4 v/v), to give compound 22 as a white powder (82%, 6.2 g, 26.2 mmol). To a solution of N-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide 22 (3 g, 12.7 mmol) in CH2Cl2 (150 mL) was added dropwise, at 0 C, a solution of ethyl 2-chloro-2-oxo-acetate (2.12 mL, 19.1 mmol) in CH2Cl2 (20 mL), followed by AlCl3 (5.1 g, 38.1 mmol) portion wise. The resulting mixture was stirred overnight at room temperature and then poured onto crushed ice. After addition of water (300 mL), the mixture was filtered on Celite and the aqueous layer was extracted with CH2Cl2 (3 x 100mL). The combined organic layers were washed with a saturated solution of sodium carbonate (100 mL), a saturated solution of ammonium chloride (100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting oil was diluted in methanol/THF (v/v = 1/2, 30 mL) and a 5% solution of sodium hydroxide (30 mL) was added. After being stirred for 15 min at room temperature, the mixture was concentrated in vacuo. The mixture was washed with ethyl acetate (2 x 50 mL), acidified with a 1N HCl solution (pH = 1) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The resulting solid was washed with diethyl ether (20 mL) and hexanes (20 mL) to yield 2-(5-((3,4-difluorophenyl)carbamoyl)-1-methyl-1H-pyrrol-3-yl)-2- oxoacetic acid 24 (3.48 g, 11.3 mmol) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) delta 10.28 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.94- 7.81 (m, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.56- 7.47 (m, 1H), 7.44- 7.24 (m, 1H), 3.96 (s, 3H). 13C NMR (101 MHz, DMSO-d6) delta 181.1, 165.3, 159.5, 150.5 (d, J = 13.1 Hz), 148.0 (d, J = 13.1 Hz), 147.0 (d, J = 12.5 Hz), 144.6 (d, J = 12.6 Hz), 136.6, 136.4 (dd, J = 9.2, 2.8 Hz), 127.9, 119.0, 117.7 (d, J = 17.7 Hz), 116.8 (dd, J = 5.8, 3.2 Hz), 114.9, 109.4 (d, J = 21.7 Hz), 37.7.19F NMR (377 MHz, DMSO-d6) delta -138.0- -138.2 (m), -145.5- -145.6 (m).
<i>N</i>-(3,4-difluoro-phenyl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With allylchloro-[1,3-bis(diisopropylphenyl)-imidazole-2-ylidene]palladium(II); water; potassium carbonate In toluene at 110℃; for 16h; Inert atmosphere;
5-bromo-2,6-dichloro-N-(3,4-difluorophenyl)pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium acetate; In tetrahydrofuran; water; at 20 - 25℃; for 18h;
5-Bromo-2,4,6-trichloropyrimidine (3.00 g, 10.9 mmol) was dissolved in THF (18 mL) and water (9 mL), and sodium acetate (2.67 g, 32.6 mmol), followed by 3,4-difluoroaniline (1.43 g, 1.10 mL, 11.1 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 10:90) to afford, after drying in vacuo (40C, 5 mbar), the title compound as a light yellow solid (3.32 g, 86%). HPLC (method LCMS_fastgradient) tR = 1.37 min. 1H NMR (CDC13, 300 MHz): delta 7.17- 7.24 (m, 2 H), 7.43 (br s, 1 H), 7.59-7.68 (m, 1 H). MS (ES+) m/z 353.9, 355.9, 357.8 [M+H, Br & 2 CI isotopes] .
diphenyl (3,4-difluorophenyl)phosphoramidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With dmap; In dichloromethane; at 0 - 25℃;Inert atmosphere;
The synthesis of diphenyl (3,4-difluorophenyl)phosphoramidateconstitutes a nucleophilic substitution reaction where dichloromethane (dry DCM, 30 ml) is utilized as the reaction medium, (dimethylamino)pyridine (DMAP, 1.2 equiv.) acts asa weak base which extracts a proton from 3,4-difluoro substituted aniline (1.1 equiv.), which further acts as an ucleophile and attacks the electrophilic site of diphenylphosphoryl chloride (1.5 equiv.), substituting the chloride (Scheme 1). The addition of reactants was carried out at 0 C in a round-bottomed flask that was closed with a septum to ensure a dry atmosphere using a nitrogen balloon. The reaction mixture was stirred for 7-8 h at room temperature (22-25 C) and the completion of the reaction was monitored using thin-layer chromatography. The quenching of the reaction wascarried out using 5% hydrochloric acid. It was dried using sodium sulfate and finally purified by column chromatography, yielding the final product in abundant yield (88%). All chemicals were purchased from Sigma-Aldrich (analytical grade) and were used directly from the bottle.
N-(3,4-difluorophenyl)-4-fluoro-3-iodobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 g
HATU (1.7 g, 4.5 mmol) was added to a solution of <strong>[403-18-9]4-fluoro-3-iodobenzoic acid</strong> (1 g, 3.8 mmol) in DMF (10 mL) at rt. After 30 min, 3,4-dif uoroaniline (0.51 g, 3.9 mmol) and DIPEA (0.5 g, 3.8 mmol) in DMF (2 mL) were added dropwise to it. The resulting mixture was stirred at rt for 20 hrs. The reaction mixture was diluted with EtOAc, washed with water, and brine. The organic layer was dried over Na2S04, filtered, concentrated, and purified by flash chromatography on silica gel (EtO Ac/Hexanes 0 ~ 100%) to afford the product as white solid (1.0 g). ESI-MS, m/z 378 (MH)+.
2 Example 2: Preparation of intermediate 1-(3,4-difluoro)phenyl-3-cyanoguanidine
NaN(CN)2 (50g, 0.56mol) was dissolved in 430mL of water to prepare a solution, and 3,4-difluoroaniline solution was added at 80 ° C (38.7g, 0.3mol of 3,4-difluoroaniline was dissolved in water and concentrated HCl (132mL /23.5mL)), maintained at 80 ° C, and continued the reaction for about 1 hour, a solid gradually precipitated in the reaction solution, and the reaction solution was detected by TLC until it did not contain 3,4-difluoroaniline, that is, the reaction was completed.Filtration and vacuum drying yielded 1-(3,4-difluoro)phenyl-3-cyanoguanidine with a yield of 95.2%.
95.2%
With hydrogenchloride In water at 80℃; for 1h;
4.1.1. Method for synthesizing compounds 4,5 and 6
General procedure: NaN (CN) 2 (50 g, 0.56 mol) was dissolved in 430 ml of water to form a solution, and substituted anilines solution (45 g, 0.3 mol of substituted anilines dissolved in water and concentrated HCl (132 ml / 23.5 ml)) was added at 80 °C, and then maintaining the reaction at 80 °C for about 1 h. TLC detected the reaction solution until no substitutedanilines was present. Finally, the white powdery solids were filtered and dried in vacuum to obtain intermediate products.
2,6-dichloro-9-(cyclopropylmethyl)-9H-purine[ No CAS ]
[ 3863-11-4 ]
2-chloro-9-(cyclopropylmethyl)-N-(3,4-difluorophenyl)-9H-purin-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-ethyl-N,N-diisopropylamine In butan-1-ol at 110℃; for 12h;
4.2.2.1. General procedures for the synthesis compounds 3a-g
General procedure: To a solution of 2 (100 mg, 0.411 mmol), aniline (154 mg, 0.411 mmol) and DIPEA (0.15 mL, 0.822 mmol) in n-butanol (20 mL) were added, and the mixture was stirred at 110 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel chromatography using a polarity mobile phase (acetone/dichloromethane, 10:100) to give product 3a.
N-(3,4-difluorophenyl)-4-(3-(3-methoxyphenyl)-5-(1-methyl-1H-indol-5-yl)-4,5-dihydro-1H-pyrazol-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.7%
Stage #1: C26H23N3O3 With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h;
Stage #2: 3,4-difluoroaniline In dichloromethane at 20℃; for 5h;
General procedure: To a mixture of compounds 7-8 (1 mmol) in the dichloromethane(30 mL) was added EDC (1.6 mmol), and HOBt (0.6 mmol), then themixture was stirred at 0 °C for 30 min. Aniline derivatives (0.6 mmol)was added subsequently, and the reaction was transferred at roomtemperature and kept overnight. Reaction was quenched by 10% aqueoussolution of sodium bicarbonate and extracted with dichloromethane.The organic layer was washed with 10% aqueous solutionof sodium bicarbonate for three times, dried over anhydrousNa2SO4, filtered, and evaporated in vacuo. Crude products were purifiedby column chromatography using n-hexane/ethyl acetate (6:1 v:v)as eluent, to obtain the target compounds Q1-Q20.
With N-Bromosuccinimide In acetonitrile at 86℃; for 16h;
2,6-Dibromo-3,4-difluoroaniline
N-Bromosuccinimide [128-08-5] (16.2 g, 91.02 mmol) was added to a stirred solution of 3,4-difluoroaniline [3863-11-4] (3.84 mL, 38.73 mmol) in acetonitrile (100 mL). The mixture was stirred at 86 °C for 16 h. The mixture was concentrated in vacuo and the residue was residue was purified by flash column chromatography on silica gel, using as eluent a gradient EtO Ac/heptane, 5/95 to 20/80. The desired fractions were collected and concentrated in vacuo to afford 2,6-dibromo-3,4-difluoroaniline (9 g, 79%) as a brown solid
63%
With N-Bromosuccinimide In acetonitrile at 20℃; Inert atmosphere;
36.1 Example 36: (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide
Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed benzenamine, 3,4-difluoro- (1.0 g, 7.75 mmol, 1.0 equiv), CH3CN (30.0 mL), NBS (2.9 g, 16.27 mmol, 2.10 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 1.4 g (63%) of 2,6- dibromo-3,4-difluoroaniline as a dark brown solid.
63%
With N-Bromosuccinimide In acetonitrile at 20℃; Inert atmosphere;
36.1 Example 36: (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide
Step 1: Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed benzenamine, 3,4-difluoro- (1.0 g, 7.75 mmol, 1.0 equiv), CH3CN (30.0 mL), NBS (2.9 g, 16.27 mmol, 2.10 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF:PE (1:5-1:3). This resulted in 1.4 g (63%) of 2,6- dibromo-3,4-difluoroaniline as a dark brown solid.
49%
With N-Bromosuccinimide In acetonitrile at 85℃; for 16h;
1 Step 1 : 2,6-Dibromo-3,4-difluorobenzenamine
Into a 250-mL round-bottom flask, was placed 3,4-difluorobenzenamine (5 g, 38.7 mmol), ACN (100 mL), NBS (16.2 g, 91.0 mmol). The resulting solution was stirred for 16 h at 85°C and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :6 to 1 :4). This resulted in 5.49 g (49%) of the title compound as a yellow solid. MS-ESI: 287.9, 285.9, 289.9 (M+l).
3‑bromo‑4‑[(3,4‑difluorophenyl)amino]furan‑2(5H)‑one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol at 20℃; for 24h;
General procedure for the synthesis of furanones 5-11
General procedure: General procedure for the synthesis of furanones 5-11 wasconducted as previously reported with slight modifications[12] (Scheme 2). To a solution of 1.0 mmol of 4 in 10 cm3of dry methanol was added 2.0 mmol of an aromatic amine.The solution was left 24 h at room temperature. Afterward,the solvent was evaporated under reduced pressure, then20 cm3of CH2Cl2was added and washed with water (3 × 5cm3).The organic layer was dried over anhydrous Na2SO4,filtrated, and the solvent evaporated under reduced pressure.The crude residue was recrystallized from CHCl3/hexane,affording the respective solid furanones. Compounds7, 8, and 10 were purified by open column chromatographypacked with silica and eluted with hexane/EtOAc 7:3mixture.
[4-(2-benzyloxy-6-bromophenyl)-2,2-dimethylbut-3-ynoxy]-tert-butyl-dimethylsilane[ No CAS ]
[ 3863-11-4 ]
3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; Inert atmosphere;
1.A.3 Step 3. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l-ynyl]-N- ( 3, 4-difluorophenyl)aniline ( C23)
To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert- butyl-dimethyl-silane C22 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL) under nitrogen was added NaOtBu (6 g, 62.4 mmol) followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and sat aq. MLCl and extracted with EtOAc (x 2). The combined organics were concentrated to dryness and purified by silica gel chromatography (Column: 220g Silica. Gradient: 0-50% EtOAc in heptane) to afford the product as a yellow oil. 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l-ynyl]-N-(3,4- difluorophenyl)aniline (11.6 g, 96%). 'H NMR (400 MHz, Chloroform-r/) d 7.49 (ddt, J = 7.4, 1.3, 0.7 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.25 (m, 1H), 7.10 - 6.96 (m, 3H), 6.86 - 6.80 (m, 1H), 6.70 (dd, J = 8.3, 0.8 Hz, 1H), 6.43 - 6.39 (m, 2H), 5.11 (s, 2H), 3.53 (s, 2H), 1.28 (s, 6H), 0.84 (s, 9H), 0.00 (s, 6H). LCMS m/z 522.52 [M+l]+.
96%
With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; Inert atmosphere;
1.A.1 Step 1. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N- (3,4-difluorophenyl)aniline (C10)
To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert- butyl-dimethyl-silane C4 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL) under nitrogen was added NaOtBu (6 g, 62.4 mmol) followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and sat aq. NH4Cl and extracted with EtOAc (x 2). The combined organics were concentrated to dryness and purified by silica gel chromatography (Column: 220g Silica. Gradient: 0-50% EtOAc in heptane) to afford the product as a yellow oil (11.6 g, 96%).1H NMR (400 MHz, Chloroform-d) δ 7.49 (ddt, J = 7.4, 1.3, 0.7 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.25 (m, 1H), 7.10 - 6.96 (m, 3H), 6.86 - 6.80 (m, 1H), 6.70 (dd, J = 8.3, 0.8 Hz, 1H), 6.43 - 6.39 (m, 2H), 5.11 (s, 2H), 3.53 (s, 2H), 1.28 (s, 6H), 0.84 (s, 9H), 0.00 (s, 6H). LCMS m/z 522.52 [M+1]+.
96%
With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; sodium t-butanolate In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; Inert atmosphere;
1.A.3 Step 3. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l-ynyl]-N- ( 3, 4-difluorophenyl)aniline ( C23)
To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert- butyl-dimethyl-silane C22 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL) under nitrogen was added NaOtBu (6 g, 62.4 mmol) followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and sat aq. MLCl and extracted with EtOAc (x 2). The combined organics were concentrated to dryness and purified by silica gel chromatography (Column: 220g Silica. Gradient: 0-50% EtOAc in heptane) to afford the product as a yellow oil. 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l-ynyl]-N-(3,4- difluorophenyl)aniline (11.6 g, 96%). 'H NMR (400 MHz, Chloroform-r/) d 7.49 (ddt, J = 7.4, 1.3, 0.7 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.25 (m, 1H), 7.10 - 6.96 (m, 3H), 6.86 - 6.80 (m, 1H), 6.70 (dd, J = 8.3, 0.8 Hz, 1H), 6.43 - 6.39 (m, 2H), 5.11 (s, 2H), 3.53 (s, 2H), 1.28 (s, 6H), 0.84 (s, 9H), 0.00 (s, 6H). LCMS m/z 522.52 [M+l]+.
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