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Structure of 5509-65-9 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Canadian Journal of Chemistry, 2005, vol. 83, # 3, p. 213 - 219
3
[ 5509-65-9 ]
[ 19064-24-5 ]
Yield
Reaction Conditions
Operation in experiment
52%
With sodium perborate In acetic acid at 80 - 90℃; for 1 h;
Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80° C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10percent THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52percent). MS (ESI) m/z 160 ([M+H]+).
52%
With sodium perborate In acetic acid at 80 - 90℃; for 1 h;
Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80° C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90° C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10percent THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52percent). MS (ESI) m/z 160 ([M+H]+).
Reference：
[1] Patent: US2005/222148, 2005, A1, . Location in patent: Page/Page column 58
[2] Patent: US2008/153873, 2008, A1, . Location in patent: Page/Page column 20
[3] Journal of Organic Chemistry, 1992, vol. 57, # 21, p. 5577 - 5585
[4] European Journal of Organic Chemistry, 2006, # 5, p. 1109 - 1112
[5] Patent: US2006/9509, 2006, A1, . Location in patent: Page/Page column 8
4
[ 5509-65-9 ]
[ 74087-85-7 ]
[ 19064-24-5 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 24, p. 5783 - 5788
5
[ 5509-65-9 ]
[ 13697-89-7 ]
Reference：
[1] Canadian Journal of Chemistry, 2005, vol. 83, # 3, p. 213 - 219
6
[ 87-61-6 ]
[ 4519-40-8 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
[2] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
7
[ 1435-43-4 ]
[ 367-25-9 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 52, # 3, p. 307 - 316
8
[ 87-61-6 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
[2] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
9
[ 38361-37-4 ]
[ 367-11-3 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
10
[ 372-39-4 ]
[ 5509-65-9 ]
Reference：
[1] Patent: US5294742, 1994, A,
11
[ 102284-85-5 ]
[ 108-88-3 ]
[ 5509-65-9 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, p. 8307 - 8309
12
[ 385-00-2 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1968, vol. 11, # 4, p. 814 - 819
13
[ 87-61-6 ]
[ 4519-40-8 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
[2] Journal of Fluorine Chemistry, 1991, vol. 53, # 3, p. 379 - 386
14
[ 108-70-3 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 52, # 3, p. 307 - 316
15
[ 372-18-9 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1968, vol. 11, # 4, p. 814 - 819
16
[ 1435-43-4 ]
[ 367-25-9 ]
[ 5509-65-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1991, vol. 52, # 3, p. 307 - 316
17
[ 5509-65-9 ]
[ 25892-08-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 10, p. 2215 - 2234
18
[ 5509-65-9 ]
[ 147808-42-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 107, p. 97 - 108
19
[ 5509-65-9 ]
[ 67567-26-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With bromine; acetic acid In water at 20℃; for 0.25 h; Stage #2: With sodium carbonate In water
b) Preparation of intermediate 2; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Bromine (1.2 ml) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgSC>4 and was evaporated. Yield : 92percent of intermediate 2.
91.7%
With bromine In ice-water; acetic acid
1a) 507.5 g of 2,6-difluoroaniline are added to 2500 ml of acetic acid, the mixture is cooled to 10° C., and a solution of 195 ml of bromine in 250 ml of acetic acid is added dropwise at 10-15° C. over the course of 3 hours. The mixture is subsequently stirred at room temperature for a further 1 hour and poured into 5000 ml of ice-water, the precipitated crystals are filtered off with suction and washed a number of times with a total of 3000 ml of ice-water, and the crystals are dried over Al2O3 under reduced pressure, giving 4-bromo-2,6-difluoroaniline, yield 91.7percent, GC 99.6percent.
84%
at 20℃; for 2 h; Cooling with ice
2,6-Difluoroaniline (20.0 g, 0.15 mol, 1.0 eq) was dissolved in of glacial acetic acid (70 mL). The mixture was cooled with an ice bath and bromine (27.6 g, 0.16 mol, 1.1 eq) dissolved in acetic acid (10 mL) was added dropwise. During the addition the product precipitated. After stirring for 2 h at room temperature Na2SO3-solution (1.3 g Na2SO3 in 400 mL water) was added. The product was filtered off, washed with water and dried to afford a colorless solid (27.7 g, 84percent). TLC [Silica, DCM]: Rf = 0.71. 1H NMR (300 MHz, CDCl3): δ = 7.08-6.89 (m, 2H), 3.73 (s, 2H). 13C NMR (75 MHz, CDCl3): δ = 151.9 (dd, J = 244.1, 8.6 Hz), 123.6 (t, J = 16.2 Hz), 115.1-114.6 (m), 107.2 (t, J = 11.7 Hz). 19F NMR (282 MHz, CDCl3): δ = 131.1 (d, J = 7.1 Hz). LRMS (ESI): m/z 207.9 (calcd. 208.0 for C6H579BrF2N [M+H]+).
80.7%
With N-Bromosuccinimide In dichloromethane at 20℃; for 3 h;
To a solution of 2,6-difluoroaniline (1 g, 7.75 mmol) in 20 mL of dry DCM was added NBS (1.96 g, 9.29mmol). The mixture was stirred at room temperature for 3 hours. The mixture was filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 50/1 to 20/1) to afford the title compound (1.61 g, 80.7percent yield) as a yellow solid. LCMS (ESI) calc’d for C6H4BrF2N [M+H]: 208, found: 208.
62%
With N-Bromosuccinimide In <i>N</i>-methyl-acetamide
(i) Preparation of 1-(4'-amino-3',5'-difluorobenzyl)imidazole-2-thiol-4-bromo-2,6-difluoroaniline Fifty grams (0.39 mole) of 2,6-difluoroaniline was treated with 71.0 g (0.39 mole) of N-bromosuccinimide in 250 ml of dimethylformamide by the procedure of Mitchell, Lai and Williams, J. Org. Chem., 44, 4733 (1979) to give a total yield of 50.2 g (62percent) of 4-bromo-2,6-difluoroaniline, m.p.: 64°-66° C.
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 4, p. 1544 - 1547[2] Angew. Chem., 2016, vol. 128, # 4, p. 1569 - 1573,5
[3] Journal of Materials Chemistry C, 2016, vol. 4, # 23, p. 5326 - 5333
[4] Patent: WO2006/15985, 2006, A1, . Location in patent: Page/Page column 54
[5] Patent: US6716491, 2004, B2,
[6] Agricultural and Biological Chemistry, 1984, vol. 48, # 11, p. 2883 - 2888
[7] European Journal of Medicinal Chemistry, 2016, vol. 107, p. 97 - 108
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 3, p. 751 - 764
[9] Journal of the American Chemical Society, 2012, vol. 134, # 51, p. 20597 - 20600
[10] Patent: WO2014/28589, 2014, A2, . Location in patent: Page/Page column 79
[11] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190
[12] Journal of Chemical Research, 2004, # 10, p. 699 - 701
[13] Patent: US5354502, 1994, A,
[14] Patent: US5030382, 1991, A,
[15] Patent: US4719223, 1988, A,
[16] Patent: US4883609, 1989, A,
[17] Journal of Chemical Research, 2011, vol. 35, # 3, p. 151 - 153
[18] Patent: WO2012/97682, 2012, A1, . Location in patent: Page/Page column 107
[19] Patent: WO2012/97684, 2012, A1, . Location in patent: Page/Page column 70-71
[20] Angewandte Chemie - International Edition, 2017, vol. 56, # 12, p. 3349 - 3353[21] Angew. Chem., 2017, vol. 129, p. 3397 - 3401,5
20
[ 289-95-2 ]
[ 5509-65-9 ]
[ 67567-26-4 ]
Reference：
[1] Patent: US5200110, 1993, A,
21
[ 5509-65-9 ]
[ 123843-67-4 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190
22
[ 147150-78-5 ]
[ 5509-65-9 ]
[ 145701-23-1 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 40℃; for 1.5 h;
B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40°C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table.
84.6%
at 25 - 45℃; for 5.5 - 8 h;
A jacketed 250 mL (milliliter) round bottom flask equipped with a stirrer, condenser, and nitrogen inlet and outlet was loaded with 49.1 g (grams), 0.38 mol (mole) of 2,6-difluoroaniline and 25 g of 1,2-propanediol. The mixture was warmed to 35°C by heating the jacket fluid and a solution of 30.3 g of 93 percent purity (0.10 mol) of 2-chlorosulfonyl-8-fluoro-5-methoxy-[1,2,4]triazolo[1,5-c]pyrimidine in 30.2 g of dichloromethane was added portionwise with stirring under a nitrogen blanket over 3.5 hours. A solid began to form in about one hour and all of the chlorosulfonyl starting material was consumed in 5.5 hours. The resulting mixture was cooled to 20°C and filtered, collecting the solids. The solids were washed 2x40 mL with methanol and then with 112 g of water. The white solid obtained after drying was found to be the title compound with a purity of greater than 99 percent and to amount to 34.2 g (88.9 percent of theory); The preparation of the title compound was carried out as in Example 1 except that some of the parameters were varied. When the reaction was carried out at 25, 35, and 45°C, the time to complete disappearance of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine and the recovered yield of title compound were 6.5 hours/86.5 percent of theory, 5.5 hours/87.9 percent of theory, and 4.9 hours/84.6 percent of theory, respectively. When the amount of 1,2-propanediol was 1.88, 0.95, and 0.48 grams per gram of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]-pyrimidine, the time to complete disappearance of the latter was 3, 5, and 8 hours, respectively.
83%
at 40℃; for 1.5 h;
B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40°C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table.
82%
at 45℃; for 2 h;
A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5°C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below.
68%
at 40℃; for 2.5 h;
A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5°C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below.
68%
at 40℃; for 3 h;
B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40°C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table.
67%
at 30℃; for 3 h;
A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5°C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below.
General procedure: GP3-1: A solution of 2-halo substituted aniline (1.0 eq), potassium ethyl xanthate (1.2 eq or 2.2 eq,typically 2.2 eq) in 10 volume of anhydrous DMF was heated at 100 0Cor 120 0C for 4 hours under nitrogen. TLC monitored the progress ofreaction. After completion, the reaction mixture was cooled to room temperature,diluted with water (10 volume) and neutralized by 1 M HCl solution to pH 5. Theformed precipitate was collected by filtration, rinsed with water, firstlydried by rotavapor, and then dried by oil pump to afford 2-mercaptobenzothiazole.GP3-2: 2-mercaptobenzothiazole in 10 volume ofanhydrous DCM, was added by sulfuryl chloride (SO2Cl2, 1volume) under ice-cooled condition. The mixture was stirred at rt for 1 hour,which was monitored by TLC. After consumption of starting material, the mixturewas diluted by 30 volume of ether, following quenching carefully by addingwater. Stirring was kept for 1 hour to make sure the SO2Cl2was totally consumed and product was released. Organic layer was collected,neutralized by saturated NaHCO3, dried over Na2SO4and purified by silica gel chromatograph to give the pure product, which wasfinally characterized by LC-MS and NMR.
Reference：
[1] Synthetic Communications, 2007, vol. 37, # 3, p. 369 - 376
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7661 - 7670
[3] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
[4] Journal of the American Chemical Society, 2013, vol. 135, # 41, p. 15579 - 15584
26
[ 5509-65-9 ]
[ 140-89-6 ]
[ 67-68-5 ]
[ 154327-24-9 ]
Reference：
[1] Patent: US5356864, 1994, A,
27
[ 5509-65-9 ]
[ 141743-49-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With Iodine monochloride In acetic acid at 20℃; for 0.25 h;
2, 6-Difluorobenzenamine (3. 0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Iodine monochloride (3.581g, 22.56 mmoles) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgS04 and was evaporated. Yield: 95percent of intermediate 33.
95%
Stage #1: With Iodine monochloride; acetic acid In water at 20℃; for 0.25 h; Stage #2: With sodium carbonate In water
Example A1; a) Preparation of intermediate 1; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml).Iodine monochloride (3.58lg, 22.56 mmoles) was added to the solution. The mixturewas stirred for 15 minutes at room temperature. After evaporation of the solvent, theresidue was treated with an aqueous solution of sodium carbonate. The aqueoussolution was extracted with dichloromethane. The organic extract was dried overMgSCU and was evaporated. Yield : 95percent of intermediate 1.
51%
With silver(I) nitrite; iodine In dichloromethane at 0 - 20℃; for 1 h;
Step 1: 4-Amino-3,5-difluoro-benzonitrile; To a suspension of iodine (5.59g, 22.0mmol) and AgNO2 (6.85g, 22.0mmol) in EPO <DP n="79"/>methylene chloride was added a solution of 2,6-difluoroaniline (2.58g, 20.0mmol) in methylene chloride at O0C, and the mixture was stirred for 30min at O0C and 30min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate = 15/1) to yield a yellow solid (2.57mg, 51percent).
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 51, p. 20597 - 20600
[2] Patent: WO2004/74266, 2004, A1, . Location in patent: Page 54
[3] Patent: WO2006/15985, 2006, A1, . Location in patent: Page/Page column 54
[4] Journal of Organic Chemistry, 2009, vol. 74, # 19, p. 7370 - 7382
[5] European Journal of Organic Chemistry, 2010, # 16, p. 3049 - 3067
[6] Patent: WO2006/98554, 2006, A1, . Location in patent: Page/Page column 77
[7] Angewandte Chemie - International Edition, 2017, vol. 56, # 12, p. 3349 - 3353[8] Angew. Chem., 2017, vol. 129, p. 3397 - 3401,5
[9] Patent: US5314640, 1994, A,
[10] Patent: US5356558, 1994, A,
28
[ 5509-65-9 ]
[ 182344-56-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7661 - 7670
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h;
96
1,3-Difluoro-2-isothiocyanato-benzene was synthesized as follows, according to scheme 1. A solution of 2,6-difluoro aniline (0.13 g, 1.01 mmol) in dichloromethane (10.00 ml) was treated with thiophosgene (0.12 g, 1.06 mmol) and diisopropylethylamine (0.26 g, 2.01 mmol). The mixture was stirred for 1 h at room temperature. The solvent was then evaporated, leaving 1,3-difluoro-2-isothiocyanato-benzene (0.17 g, 99%) as a light brown gum, which was used crude.
78%
With hydrogenchloride In dichloromethane for 3h; Ambient temperature;
In hydrogenchloride; dichloromethane
9 Preparation of 2,6-difluorophenylisothiocyanate
EXAMPLE 9 Preparation of 2,6-difluorophenylisothiocyanate A suspension of 11.0 g. of 2,6-difluoroaniline in 100 ml. of 1N hydrochloric acid and 50 ml. of methylene chloride was stirred mechanically as 6.8 ml. of thiophosgene was added. After remaining for three hours at room temperature, the layers were separated, and the aqueous phase was extracted 2 * 100 ml. of methylene chloride. The combined organic layers were washed 1 * 50 ml. of water, dried over magnesium sulfate and evaporated. The resulting oil was distilled, and the fraction boiling 160°-165°, 100 mm was collected, and yielded 11.1 g. (78%) of 2,6-difluorophenylisothiocyanate.
With N-ethylmorpholine;; copper; copper(I) bromide; In methanol; for 16h;Reflux;
To a solution of <strong>[573-54-6]2-bromo-3-nitrobenzoic acid</strong> (6, 1.01 g, 4.06 mmol) and 2,6-difluoroaniline (34, 1.05 g, 6.10 mmol) in methanol (50 mL) was added copper powder (13.0 mg, 0.20 mmol), copper (I) bromide (58.3 mg, 0.41 mmol) and N-ethyl morpholine (1.00 mL, 8.12 mmol). The reaction mixture was heated at reflux for 16 h, diluted with aqueous ammonium hydroxide (0.1 N, 12 mL) and filtered over celite. The solvent concentrated to half its volume under vacuum and then acidified to pH 2 using hydrochloric acid (1 N). The formed yellow precipitate was filtered, and dried under vacuum to afford 2-((2,6-difluorophenyl)amino)-3-nitrobenzoic acid as yellow solid (800 mg, 60%). To a solution of 2-((2,6-difluorophenyl)amino)-3-nitrobenzoic acid (650 mg, 2.21 mmol) in aqueous sodium hydroxide (2 N, 50 mL) was added sodium borohydride (336 mg, 8.84 mmol), and the reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, and acidified to pH 2 using hydrochloric acid (1 N). The formed precipitated was filtered, washed with water (2 x 20 mL) and dried under vacuum to afford 9-fluorophenazine-1-carboxylic acid 35, as yellow solid (224 mg, 31%); mp: 233-235 C. IR (KBr) 3047, 1728, 1515, 1458, 1246, 894, 763 cm-1; 1H NMR (500 MHz, CDCl3): delta 15.17 (s, 1 H), 9.02 (d, J = 7.0 Hz, 1 H), 8.54 (d, J = 9.0 Hz, 1 H), 8.16 (d, J = 9.0 Hz, 1 H), 8.09 (t, J = 9 Hz, 1 H), 7.95-7.91 (m, 1 H), 7.69 (t, J = 8.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3): 165.4, 144.4, 143.8, 138.1, 135.0, 131.2, 130.8, 130.8, 125.9, 125.8, 125.3, 115.5, 115.3; 19F NMR (470 MHz, CDCl3): delta -123.7; HRESIMS calcd for C13H7N2O2F 242.0492 (MH+), found 242.9999 (MH+).
With sodium perborate; In acetic acid; at 80 - 90℃; for 1h;
Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80 C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10% THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m/z 160 ([M+H]+).
52%
With sodium perborate; In acetic acid; at 80 - 90℃; for 1h;
Step 1: A mixture of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) was stirred at 80 C. 2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to the mixture. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layers were washed with a dilute solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified via Biotage chromatography (FlasH90i, silica, 10% THF/hexane) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) (52%). MS (ESI) m/z 160 ([M+H]+).
With sodium perborate; acetic acid; at 80 - 90℃; for 1h;
2,6-Difluoroaniline (11.0 g, 85 mmol) in glacial acetic acid (50 mL) was added slowly to a stirred suspension of sodium perborate tetrahydrate (65 g, 422 mmol) in glacial acetic acid (250 mL) at 80 C. The temperature was maintained between 80-90 C. for 1 hour. The cooled reaction mixture was poured into water and extracted twice with diethylether and the combined organic layers were washed with a dilute solution of sodium bicarbonate, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (Hexane:THF, 9:1) and the product washed with hexane to afford 2,6-difluoronitrobenzene (7.0 g) which was used without further examination.
b) Preparation of intermediate 2; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Bromine (1.2 ml) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgSC>4 and was evaporated. Yield : 92% of intermediate 2.
91.7%
With bromine; In ice-water; acetic acid;
1a) 507.5 g of 2,6-difluoroaniline are added to 2500 ml of acetic acid, the mixture is cooled to 10 C., and a solution of 195 ml of bromine in 250 ml of acetic acid is added dropwise at 10-15 C. over the course of 3 hours. The mixture is subsequently stirred at room temperature for a further 1 hour and poured into 5000 ml of ice-water, the precipitated crystals are filtered off with suction and washed a number of times with a total of 3000 ml of ice-water, and the crystals are dried over Al2O3 under reduced pressure, giving 4-bromo-2,6-difluoroaniline, yield 91.7%, GC 99.6%.
84%
With bromine; acetic acid; at 20℃; for 2h;Cooling with ice;
2,6-Difluoroaniline (20.0 g, 0.15 mol, 1.0 eq) was dissolved in of glacial acetic acid (70 mL). The mixture was cooled with an ice bath and bromine (27.6 g, 0.16 mol, 1.1 eq) dissolved in acetic acid (10 mL) was added dropwise. During the addition the product precipitated. After stirring for 2 h at room temperature Na2SO3-solution (1.3 g Na2SO3 in 400 mL water) was added. The product was filtered off, washed with water and dried to afford a colorless solid (27.7 g, 84%). TLC [Silica, DCM]: Rf = 0.71. 1H NMR (300 MHz, CDCl3): delta = 7.08-6.89 (m, 2H), 3.73 (s, 2H). 13C NMR (75 MHz, CDCl3): delta = 151.9 (dd, J = 244.1, 8.6 Hz), 123.6 (t, J = 16.2 Hz), 115.1-114.6 (m), 107.2 (t, J = 11.7 Hz). 19F NMR (282 MHz, CDCl3): delta = 131.1 (d, J = 7.1 Hz). LRMS (ESI): m/z 207.9 (calcd. 208.0 for C6H579BrF2N [M+H]+).
81.7%
With hydrogen bromide; dihydrogen peroxide; at 10 - 40℃; for 6h;
General procedure: Take 207 g of 47% hydrobromic acid and add it to a 1 L reaction bottle.The ice water bath is cooled to 10-15 C.Take 2,6-difluoroaniline129.1 g was slowly added dropwise to the reaction solution to maintain an internal temperature of 40 C or lower.After the drop, re-cool down to 10 C.Take 136 g of 30% hydrogen peroxide, slowly add dropwise to the reaction solution, and maintain the internal temperature below 30 C.After the completion of the dropwise addition, the temperature was kept at 20-30 C for 4 hours.The reaction solution was added to 2 L of water.The pH was adjusted to 9-10 with saturated sodium carbonate, extracted with methyl tert-ether (500 ml x 2), and the organic phases were combined. Wash once with 1 L of brine and dry over anhydrous sodium sulfate.Concentrate under reduced pressure at 45-55 C. The residue was beaten with 300 ml of petroleum ether for 30 min., filtered, and the filter cake was rinsed once with 50 ml of petroleum ether.The product is blast dried at 45-55 C.Yellowish compound 165.4g,The liquid phase purity was 98% or more, and the yield was 79.8.0%.
80.7%
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 3h;
To a solution of 2,6-difluoroaniline (1 g, 7.75 mmol) in 20 mL of dry DCM was added NBS (1.96 g, 9.29mmol). The mixture was stirred at room temperature for 3 hours. The mixture was filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE/EA = 50/1 to 20/1) to afford the title compound (1.61 g, 80.7% yield) as a yellow solid. LCMS (ESI) calc?d for C6H4BrF2N [M+H]: 208, found: 208.
With pyridine; bromine; In chloroform;
Step 2-1. 252 g (1.95 mol) of 2,6-difluoroaniline and 170 g (2.15 mol) of anhydrous pyridine were dissolved in 780 cm3 of chloroform, and a solution of 328 g (2.05 mol) of bromine dissolved in 390 cm3 of chloroform was added dropwise for 2 hours on an ice water bath while stirring, after which it was stirred for 2 hours at room temperature. After washing the reaction solution with water, the chloroform was removed, the residue was distilled under reduced pressure (b. p. 100 C./30 mmHg), and the crystals obtained were recrystallized from hexane to obtain 340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline.
With potassium hydroxide; bromine; In chloroform; water;
Step 1 300 g of bromine was added drop-wise to 231 g of 2,6-difluoroaniline dissolved in 400 ml of chloroform. The mixture was refluxed for one hour and the reaction solution was poured into an aqueous 10% solution of potassium hydroxide. The potassium hydroxide was extracted with chloroform and the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water. The chloroform was distilled off and the residue was distilled under reduced pressure (bp: 70-80 C./4 mmHg) and recrystallized from hexane, to yield 292 g of 4-bromo-2,6-difluoroaniline.
50.2 g (62%)
With N-Bromosuccinimide; In N-methyl-acetamide;
(i) Preparation of 1-(4'-amino-3',5'-difluorobenzyl)imidazole-2-thiol-4-bromo-2,6-difluoroaniline Fifty grams (0.39 mole) of 2,6-difluoroaniline was treated with 71.0 g (0.39 mole) of N-bromosuccinimide in 250 ml of dimethylformamide by the procedure of Mitchell, Lai and Williams, J. Org. Chem., 44, 4733 (1979) to give a total yield of 50.2 g (62%) of 4-bromo-2,6-difluoroaniline, m.p.: 64-66 C.
With potassium hydroxide; bromine; In chloroform; water;
Step 2 100 g of 2,6-difluoroaniline was dissolved in 180 ml of chloroform and 140 g of bromine was added dropwise. After one hour of reflux, the resulting solution was poured into a solution of 10% potassium hydroxide. The mixture was extracted with chloroform and the organic layer was washed with a solution of 10% potassium hydroxide in water. After the chloroform was removed by distillation, the residue was distilled under reduced pressure (bp 70 to 80 C. at 4 mmHg) and recrystallized with hexane to yield 127 g of 4-bromo-2,6-difluoroaniline.
EXAMPLE 42 7-(2,6-dichlorobenzyl)-5-{ [2,6-difluoro-4-( iperazin-l-yl)phenyl]amino}pyrido[3,4- d]pyridazin-4(3H)-one EXAMPLE 42A 4-bromo-2,6-difluorobenzenamine 2,6-Difluorobenzeneamine (6.0 g, 45 mmol) was dissolved in acetic acid (20 mL) and bromine (2.4 mL, 50 mmol) was added and the mixture was stirred at ambient temperature for 15 minutes. After concentration, the residue was treated with aqueous sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 25/1 petroleum ether/ethyl acetate to give the title compound. MS: 208 (M+H+).
Example 16 5-(2,6-dichlorobenzyl)-7-{ [2,6-difluoro-4-(piperazin- l -yl)phenyl]amino} [1.2,4]triazolo[4,3- c]pynmidine-8-carboxarnide Example 1 A 4-bromo-2,6-difluorobenzenamine 2,6-Difluorobenzeneamine (6.0 g, 45 mmol) was dissolved in acetic acid (20 mL) and bromine (2.4 mL, 50 mmol) was added and the mixture was stirred at ambient temperature for 15 minutes. After concentration, the residue was treated with aqueous sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 25/1 petroleum ether/ethyl acetate to give the title compound. MS: 208 (M+H .
5-methyl-1-(3-trifluoromethyl-phenyl)-1<i>H</i>-pyrazole-3-carboxylic acid (2,6-difluoro-phenyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane
With triethylamine; In chloroform; for 24h;Heating / reflux;
4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde To a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (11.1 g, 50 mmol) in CHCl3 (100 ML) was added 2,6-difluoroaniline (8.07 ML, 75 mmol, 1.5 eq) followed by Et3N (10.43 ML, 75 mmol, 1.5 eq).The reaction mixture turned yellow and was heated to reflux for 24 h, H2O (50 ML) was added and the layers were separated.The organic layer was evaporated and the crude product was recrystallized from 200 ML of a methanol: H2O mixture (2:1) to give 12.03 g (76%) of pure 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: delta 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m, 1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
76%
With triethylamine; In chloroform; for 24h;Heating / reflux;
EXAMPLE 1 4-Chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pirimidinecarbaldehyde To a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (11.1 grams(hereinafter "g"), 50 millimoles (hereinafter "mmol")) in CHCl3 (100 milliliters (hereinafter "mL")) was added 2,6-difluoroaniline (8.07 mL, 75 mmol, 1.5 equivalents (hereinafter "eq")) followed by Et3N (10.43 mL, 75 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to reflux for 24 h, H2O (50 mL) was added and the layers were separated. The organic layer was evaporated and the crude product was recrystallized from 200 mL of a methanol: H2O mixture (2:1) to give 12.03 g (76%) of pure 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: delta 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m, 1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
70%
With triethylamine; In tetrahydrofuran; at 55℃; for 22h;
To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in THF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 550C for about 22 h before concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 %) of pure 4-chloro-6-[(2,6-difluorophenyl)amino]-2- (methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.
70%
With triethylamine; In tetrahydrofuran; at 55℃; for 22h;
To the solution of phosphorus oxy chloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)- pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 eta), 10.4 (s, 1 eta).To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in TetaF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 550C for about 22 h before <n="109"/>concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 %) of pure 4- chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (16O0C) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc / Hexane, 1 : 5) provided the title compound (109 mg, 51%): LC-MS m/z 340 (M+H)+.
With sodium hydroxide In diethyl ether; water at 20℃; for 0.833333h;
1
Into a mixture of 1 M aqueous NaOH (98 mL) and 2,6-difluoroaniline (12.9 g, 0.1 mol) in 100 mL OfEt2O was added dropwise a solution of 2-chloroacetyl chloride (13.3 g, 1 17 mmol) in 100 mL Of Et2O over 20 minutes at room temperature. The mixture was stirred for 30 minutes at room temperature and the reaction was cooled to O0C. The white precipitate was collected by filtration to give the first portion of product 73a (12 g). The organic layer of the filtrate was separated and washed with saturated NaHCO3 and brine, dried and concentrated. The residue was recrystallized from EtOAc to give the second portion of 73a (7.5 g) as a white solid. MS (ESI) [M+H+]: 206.
With triethylamine In acetone at 0 - 20℃;
With NEt3/C
With sodium hydrogencarbonate In acetone at 20℃; for 1h;
With Iodine monochloride; In acetic acid; at 20℃; for 0.25h;
2, 6-Difluorobenzenamine (3. 0g, 22.56 mmoles) was dissolved in acetic acid (10 ml). Iodine monochloride (3.581g, 22.56 mmoles) was added to the solution. The mixture was stirred for 15 minutes at room temperature. After evaporation of the solvent, the residue was treated with an aqueous solution of sodium carbonate. The aqueous solution was extracted with dichloromethane. The organic extract was dried over MgS04 and was evaporated. Yield: 95% of intermediate 33.
95%
Example A1; a) Preparation of intermediate 1; 2,6-difluorobenzeneamine (3.0g, 22.56 mmoles) was dissolved in acetic acid (10 ml).Iodine monochloride (3.58lg, 22.56 mmoles) was added to the solution. The mixturewas stirred for 15 minutes at room temperature. After evaporation of the solvent, theresidue was treated with an aqueous solution of sodium carbonate. The aqueoussolution was extracted with dichloromethane. The organic extract was dried overMgSCU and was evaporated. Yield : 95% of intermediate 1.
51%
With silver(I) nitrite; iodine; In dichloromethane; at 0 - 20℃; for 1h;
Step 1: 4-Amino-3,5-difluoro-benzonitrile; To a suspension of iodine (5.59g, 22.0mmol) and AgNO2 (6.85g, 22.0mmol) in EPO <DP n="79"/>methylene chloride was added a solution of 2,6-difluoroaniline (2.58g, 20.0mmol) in methylene chloride at O0C, and the mixture was stirred for 30min at O0C and 30min at ambient temperature. The reaction was quenched with Na2S2O3. The reaction solution was extracted with methylenechloride, washed with water and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (hexane/ethylacetate = 15/1) to yield a yellow solid (2.57mg, 51%).
With Iodine monochloride; In acetic acid;
Step 3: 60 g of 2,6-difluoroaniline was dissolved in 180 ml of acetic acid. A solution containing 75 g of iodine chloride dissolved in 48 ml of acetic acid was added dropwise therein, and then agitated at 80 C. for 2 hours. The reaction solution was poured into water, and the resulting deposited crystals were filtrated and washed with water. The crystals were recrystallized with methanol, vacuum distilled (125 C./22 mmHg), and recrystallized again with methanol to obtain 57 g of 2,6-difluoro-4-iodoaniline.
With pyridine; Iodine monochloride; In chloroform; water; acetic acid;
Step 3: 2,6-Difluoroaniline (38 g) was dissolved in acetic acid (120 ml), and then pyridine (25 g) was added thereto, followed by stirring. Then, a mixture of iodine monochloride (50 g) with acetic acid (30 ml) was added dropwise thereto. After stirring at room temperature for 1 hour, the reaction solution was further stirred at 70 to 80 C. for 2 hours. Then, the reaction solution was poured into water, and the precipitated crystals were filtered, followed by washing with water. The resulting crystals were dissolved in chloroform, and then washed with water twice, further with 10% potassium hydroxide aqueous solution twice, and furthermore with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 120 to 130 C./20 mmHg), and then recrystallized from methanol to give 4-iodo-2,6-difluoroaniline (44 g).
Under nitrogen protection,Add to a 500mL four-neck reaction flask100mL of acetonitrile and 12.9g (0.1moL) of 2,6-difluoroaniline,Stir down to -20 C,A drop of dimethyl sulfide 3.1g (0.05moL),After dripping, stir for 30min.Then slowly dropwise add 26.67 g of N-chlorosuccinimide in acetonitrile solution.(Contains 6.67 g of N-chlorosuccinimide, 0.05 moL),After dropping, continue to react for 1 ~ 2h,Then slowly add 27.9g (0.3moL) of 3-methylpyridine,After stirring for 1h,56.6g of2-chlorosulfonyl-8-fluoro-5-methoxy [1,2,4] triazole[1,5-c] pyrimidine in acetonitrile(Containing 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4] triazole [1,5-c] pyrimidine26.6g, 0.1moL) slowly added to the above reaction solution,Finished in 1h, then,Stir at room temperature for 1h,The temperature was increased to 40 C, and the reaction was performed for 3 to 4 hours.HPLC traced the 2,6-difluoroaniline content to <0.5% to end the reaction.After the reaction is over,Reduce the temperature of the reaction solution to below 0 C,Add 250 g of dilute acid water (containing 41.7 g of 35% by weight hydrochloric acid),Acidified to pH <2,Precipitation of a large amount of solids,Stir for 1h, suction filter,Filter cake washedRinse with a small amount of methanol, dry,33.8 g of diflusulfuron was obtained as a white powder,The yield was 94.2% and the purity was 98.5% (HPLC).
88%
In propylene glycol; at 40℃; for 1.5h;Product distribution / selectivity;
B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table.
84.6 - 88.9%
In propylene glycol; dichloromethane; at 25 - 45℃; for 5.5 - 8h;Product distribution / selectivity;
A jacketed 250 mL (milliliter) round bottom flask equipped with a stirrer, condenser, and nitrogen inlet and outlet was loaded with 49.1 g (grams), 0.38 mol (mole) of 2,6-difluoroaniline and 25 g of 1,2-propanediol. The mixture was warmed to 35C by heating the jacket fluid and a solution of 30.3 g of 93 percent purity (0.10 mol) of 2-chlorosulfonyl-8-fluoro-5-methoxy-[1,2,4]triazolo[1,5-c]pyrimidine in 30.2 g of dichloromethane was added portionwise with stirring under a nitrogen blanket over 3.5 hours. A solid began to form in about one hour and all of the chlorosulfonyl starting material was consumed in 5.5 hours. The resulting mixture was cooled to 20C and filtered, collecting the solids. The solids were washed 2x40 mL with methanol and then with 112 g of water. The white solid obtained after drying was found to be the title compound with a purity of greater than 99 percent and to amount to 34.2 g (88.9 percent of theory); The preparation of the title compound was carried out as in Example 1 except that some of the parameters were varied. When the reaction was carried out at 25, 35, and 45C, the time to complete disappearance of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine and the recovered yield of title compound were 6.5 hours/86.5 percent of theory, 5.5 hours/87.9 percent of theory, and 4.9 hours/84.6 percent of theory, respectively. When the amount of 1,2-propanediol was 1.88, 0.95, and 0.48 grams per gram of 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]-pyrimidine, the time to complete disappearance of the latter was 3, 5, and 8 hours, respectively.
83%
In ethylene glycol; at 40℃; for 1.5h;Product distribution / selectivity;
B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table.
82%
In 1,1,1-trichloroethanol; at 45℃; for 2h;Product distribution / selectivity;
A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below.
79%
To a solution of 3.87 grams (0.03 mol) of 2,6-difluoroaniline in 5.4 grams of propylene glycol was added a solution of 5.73 grams (0.02 mol) of 8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonyl chloride (SC) in 7 grams of methylene chloride over 1 hour. The SC solution was added in about 0.5 mL portions every 5-10 minutes. The temperature of the resulting mixture was maintained at less than 25 C. during the addition of the SC. After stirring the reaction mixture for another 1 hour at room temperature, 2.20 grams (0.02 mol) of triethylamine was added over 2.45 hours using a syringe pump. The reaction mixture was stirred at room temperature overnight and then was diluted with 5 g of water over 15 minutes. The resulting mixture was cooled to about 5 C. with an ice bath and then filtered. The collected white solid was rinsed with 15 mL of 7:3 (v/v) methanol-water and then dried at 50 C. to provide 5.44 g (74%) of florasulam (97.7 wt %). An additional 5% yield (total yield 79%) of florasulam was detected in the aqueous filtrate.
68%
In 2,2,2-trifluoroethanol; at 40℃; for 2.5h;Product distribution / selectivity;
A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below.
68%
In 2-methoxy-ethanol; at 40℃; for 3h;Product distribution / selectivity;
B. A solution of 5.1 g (40 mmol) of 2,6-difluoroaniline, 10 mL of alcohol solvent and a few crystals of naphthalene (liquid chromatography internal standard) was placed in a 50 mL flask and heated to 40C. Solid 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo-[1,5-c]pyrimidine (2.67 g, 10 mmol) was added with stirring under nitrogen and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. The mixture was cooled to ambient temperature and the solids were recovered by filtration, washed with 10 mL of 2-propanol and then water, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 4 to 6 in the following table.
67%
In 2-methoxy-ethanol; at 30℃; for 3h;Product distribution / selectivity;
A. A 4.8 g (18 mmol) sample of 2-chlorosulfonyl-8-- fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine was placed in a 50 mL round bottom flask and then the following were added with stirring under nitrogen: 10 mL of an alcohol solvent, 12.9 g (100 mmol) of 2,6-difluoroaniline, and a few crystals of naphthalene (liquid chromatography internal standard). The mixture was heated to the desired temperature and the disappearance of the chlorosulfonyl starting material was monitored by high pressure liquid chromatography. When the reaction was complete, the mixture was cooled to 0 to 5C over a 30-min period and the solids were recovered by filtration, washed with cold solvent, washed with 0.5 N aqueous hydrochloric acid, and dried. The recovered title compound product was over 99 percent pure. The results are given as Runs 1 to 3 in the table below.
Synthesis Example 33 Synthesis of 2,6-Difluorobenzenesulfonamide [Compound (III-14)] Using 2,6-difluoroaniline [Compound (XXV-14)] (5 g, 0.0387 mol), 8.2 g (percent yield: theoretic) of <strong>[60230-36-6]2,6-difluorobenzenesulfonyl chloride</strong> [Compound (XXII-14)] was synthesised according to the process of Synthesis Example 31 (3). Thereafter, the Compound (III-14) was synthesised using 8.2 g (0.0387 mol) of the Compound (XXII-14) according to Synthesis Example 31 (3). White solid, m.p.: 184-5° C., yield: 2.79 g, percent yield: 37.4percent. IR KBr cm-1: 3370, 3262, 1620, 1593, 1473, 1356, 1170, 789. 1H-NMR (60 MHz, d6-DMSO, delta): 6.9-7.7 (3H, m, aromatic ring H), 7.7-7.9 (2H, bs, NH2).
4-Chloro-2,6-difluoroaniline 35.5 g of 2,6-difluoroaniline were mixed with 200 ml of concentrated acetic acid, and the mixture was heated to 80 C. 42.4 g of sulfuryl chloride were mixed with approximately the same amount of concentrated acetic acid, and the mixture was added dropwise to the heated solution. The mixture was then heated at reflux for six hours. After cooling, the solution was concentrated under reduced pressure and the residue was stirred with water and pentane. The solid residue was filtered off and washed with water. The resulting solid was admixed with 200 ml of concentrated hydrochloric acid and heated at reflux for two hours.
3.7 Step 7
Step 7 328 g (2.05 mol) of bromine was dissolved in 390 cm3 of chloroform and added drop-wise, while stirring, to a solution of 252 g (1.95 mol) of 2,6-difluoroaniline and 170 g (2.15 mol) of anhydrous pyrimidine dissolved in 780 cm3 of chloroform, over 2 hours. The solution was stirred at room temperature for 2 hours and washed with water. The chloroform was distilled off and the residue was distilled under reduced pressure (110° C./30 mmHg). The crystals formed were recrystallized from hexane to yield 340 g (1.63 mol) of 4-bromo-2,6-difluoroaniline.
To the solution of <strong>[33097-13-1]4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile</strong> (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 : 1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
90%
In N,N-dimethyl-formamide; at 50℃; for 1h;
To the solution of <strong>[33097-13-1]4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile</strong> (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 : 1) to give 4-chloro-6- [(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
90%
In N,N-dimethyl-formamide; at 50℃; for 1h;
To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum.The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H- NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H). To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- <n="80"/>pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residue SOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) delta 2.64(3 H).To the solution of <strong>[33097-13-1]4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile</strong> (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
90%
In N,N-dimethyl-formamide; at 50℃; for 1h;
To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4, 6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H- NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H). <n="103"/>To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 rnL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residueSOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) delta 2.64(3 H). To the solution of <strong>[33097-13-1]4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile</strong> (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
Stage #1: benzene 1,3-dicarboxylic acid monomethyl ester With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃;
Stage #2: 2,6-difluoroaniline With pyridine; dmap In dichloromethane
1.A
3-[(Methyloxy)carbonyl]benzoic acid (11.0 g, 61.1 mmol) was dissolved in 600 mL of dichloromethane with stirring. Oxalyl chloride (16.3 mL, 183.2 mmol) was added dropwise by addition funnel as a solution in 100 mL of DCM. DMF (3.0 mL) was added via syringe. The reaction was stirred overnight at rt and then concentrated in vacuo.The resultant solid was further dried under high vacuum pressure. The solid was dissolved in 600 mL of DCM with stirring. Pyridine (24.5 mL, 305.3 mmol), (4-dimethylamino)-pyridine (3.7 g, 30.5 mmol), and 2,6-difluoroaniline (19.7 mL, 183.2 mmol) were added to the solution. The reaction was stirred overnight and poured into 1N HCl. The layers were separated, and the aqueous layer was washed twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 14.87 g (84%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ10.40 (s, 1H), 8.58 (s, 1H), 8.24 (m, 1H), 8.18 (m, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.25-7.18 (m, 2H), 3.89 (s, 3H).
2-(Methyloxy)-5-[(methyloxy)carbonyl]benzoic acid (1.96 g, 9.33 mmol) was suspended in 60 mL of DCM with stirring. DMF (0.036 mL, 0.46 mmol) was added via syringe. Oxalyl chloride (7.0 mL, 2.0M in dichloromethane, 14 mmol) was added dropwise via addition funnel. The addition funnel was rinsed with 10 mL of DCM. The reaction was stirred for 2 hours and concentrated in vacuo. The resultant solid was further dried under high vacuum pressure. The solid was dissolved in 60 mL of DCM with stirring. Pyridine (3.8 mL, 47 mmol), (4-dimethylamino)pyridine (0.0570 g, 0.467 mmol), and 2,6-difluoroaniline (3.0 mL, 28 mmol) were added to the solution. The reaction was stirred for 18 hours and poured into 1N HCl. The layers were separated, and the aqueous layer was washed once with DCM and once with diethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 1.56 g (52%) of the desired product. 1H NMR (400 MHz, DMSO-d6): delta 9.81 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.10 (dd, J=8.8, 2.0 Hz, 1H), 7.38 (m, 1H), 7.31 (d, J=88 Hz, 1H), 7.22-7.13 (m, 2H), 3.97 (s, 3H), 3.82 (s, 3H).
tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; at 80℃; for 4h;
3.86g of the 2,6-difluoro-bromobenzene(20mM) in a nitrogen filled glove box was added to 2.6g (2OmM) 2,6-difluoroaniline and all stirred into 5OmL dry toluene. 0.21 g Pd2DBA3 (0.2I mM), 0.09g P(t-Bu)3 (0.42mM) and 2.Og t-BuONa (21 mM) were added. Upon addition of these catalyst materials, there is a sharp exotherm. The dark yellow brown mixture was then heated in the glove box at 8OC for 4 hrs.C6H5F2N CgH3BrF2 Exact Mass: 129.04 Exact Mass: 191.94MoI. Wt: 129.11 MoI. Wt.: 192.99 C, 55.82; H, 3.90; F, 29.43; N, 10.85 C, 37.34; H, 1.57; Br, 41 .40; F, 19.69C12H7F4N Exact Mass 241 05MoI Wt 241 18 C, 59 76, H, 2 93, F, 31 51 , N, 5 81The reaction mixture was then cooled and removed from the glove box to work up by silica chromatography using methylene chloride eluent to generate the desired secondary amine as a dark green/brown oil with structure confirmed by nmr. Yield -60%.
(60a) [2-(2,6-Difluorophenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester 17.0 g of sodium triacetoxyborohydride (80.0 mmol) was added to a solution of 15.0 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (80.0 mmol), 5.16 g of 2,6-difluoroaniline (40.0 mmol) and 2.09 ml of acetic acid (40.0 mmol) in methylene chloride (400 ml) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 20/1 - 10/1) to obtain 3.68 g of the title compound (yield: 31%). Colorless solid. 1H NMR spectrum (CDCl3, 400 MHz), delta: 6.81-6.77 (m, 2H), 6.67-6.60 (m, 1H), 4.56 (br s, 1H), 3.82 (br s, 1H), 3.47 (br d, 2H, J = 6.7 Hz), 1.43 (s, 9H), 1.32 (s, 6H).
Intermediate 22: Lambda/-(2,6-difluorophenyl)-1H-1 ,2,3-triazole-4-carboxamide; 1.6 M butyllithium in hexanes, (62.8 ml, 100 mmol) was added dropwise to a solution of 2,6-difluoroaniline, (10.8 ml, 100 mmol, Fluorochem) in dry tetrahydrofuran (90 ml) at -78 0C under nitrogen. The resulting suspension was stirred at -78 0C for 15 min and then allowed to warm to 0 0C to give a clear solution. A solution of ethyl 1 H-1 ,2,3-triazole-4-carboxylate,(4.726 g, 33.5 mmol, Chemgenx) in dry tetrahydrofuran(40 ml) was added to the reaction mixture at 0 0C and the resulting mixture was allowed to warm to room temperature. After 2 h at room temperature, ethanol (5 ml) was carefully added under nitrogen, and the reaction mixture was evaporated to dryness to give an oily residue. This residue was treated with water (30 ml) and the pH was adjusted to approximately 8 with 2 M hydrochloric acid. The resulting solution was extracted with chloroform :ethanol (5:1 , 4 x 120 ml). The aqueous solution from the extraction (approximately 70 ml total volume which contains inorganic impurities) was purified in 5 ml aliquots by passage through 6 g Oasis cartridges (four cartridges with 5 ml of aqueous solution per cartridge were run in parallel). Each cartridge was first washed with ethanol (2 column volumes) followed by water (2 column volumes). The aqueous solution (5 ml) was then applied and the cartridge was eluted with water (1.5 column volumes) followed by ethanol (2 column volumes). Fractions containing the required product (as judged by the UV absorption at 254 nM) were combined and evaporated to give the title compound as a white solid (5.34 g); LCMS: (System 3) MH+= 225, tRET = 0.61 min.
6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example II(1) N6-(trans-4-aminocyclohexyl)-N8-(2,6-difluorophenyl)imidazo[1,2-b]pyridazine-6,8-diamine (1a) To 60% NaH (22.5 mg, 0.563 mmol) in DMF (400 mul) was added 2,6-difluoroaniline (24 mg, 0.186 mmol). After stirring at RT for 5 minutes THF (1000 mul) was added followed by <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (50 mg, 0.186 mmol, prepared as described in Example 1, step (1b). The reaction was heated at 50 C. for 3 hours. The reaction was quenched with a few drops of water and methanol. The solution was then concentrated in vacuo to give crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine.
4,6-Dich.loro-2-(methylthio)pyrimidin.e-5-carboxaldehyde (40kg) was dissolved in anhydrous THF (200L) at room temperature. Triethylamine (20kg) was added followed by 2,6-difluoroan.iline (26kg) and the reaction mixture was heated at 60-650C for 12h. The mixture was cooled to room temperature. To the mixture was added water (160L) followed by triethylamine (25.6kg), 4-fluoro-2-mcthylbcnzcncboronic acid (33.2kg), palladium acetate (0.8kg, 2mol%) and. triphenylphosphine (1.88kg, 4mol%). The reaction mixture was heated to 65C and stirred vigorously at this temperature for 3h. The mixture was cooled to 55-600C and THF (160L) was added. The bottom aqueous phase was separated at 55-600C. The organic phase was concentrated to200L, methanol (400L) was added and the THF was removed (until <3mol% THF by NMR) by atmospheric distillation, keeping the volume of the solution at ca.600L by adding methanol (600- 800L). The solution was cooled to 55-6O0C and seeded with the title compound (0.16kg). The slurry was stirred at 55C for at least 30 min and then cooled to 2O0C over Ih. The slurry was stirred at 2O0C for at least 2h and filtered. The cake was washed with methanol (160L) followed by MeOH:water (4: 1,120L) and dried in vacuo at 60-650C <n="87"/>overnight to give the title compound (43.8kg) 400MHzNMR in CDCb. Tetramethylsilane as reference at 0.00 ppm. delta(ppm): 2.29 (3 H) s, 2.33 (3 H) s, 6.97 - 7.05 (4 H) m, 7.24 - 7.32 (3 H) m, 9.64 (1 H) s, 10.38 (1 H) s.
With tris-(dibenzylideneacetone)dipalladium(0); 2,2?-bis(diphenylphosphino)-1,1?-binaphthalene.; sodium t-butanolate; In toluene; at 70℃; for 7h;Inert atmosphere;
Example 1 W-(5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(3-{6-[1 -(2,6-difluoro-phenyl)- ureido]-pyridin-2-yl}-phenyl)-acetamidea. (6-Chloro-pyridin-2-yl)-(2,6-difluoro-phenyl)-amineA solution of <strong>[5140-72-7]2-<strong>[5140-72-7]bromo-6-chloro-pyridine</strong></strong> (3.0 g, 15.6 mmol), 2,6- difluoroaniline (1.76 ml_, 16.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (285 mg, 0.31 mmol), BINAP (388 mg, 0.62 mmol) and sodium fe/f-butoxide (2.1 g, 21.83 mmol) in toluene (50 ml_) was purged with argon, stirred at 700C for 7 h then allowed to cool down to RT. The reaction mixture was partitioned between diethyl ether and water. The aqueous layer was extracted twice with diethyl ether, the combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo and purified twice by chromatography (0 to 10% ethyl acetate in cyclohexane then 0 to 30% DCM in cyclohexane) to give the title compound as a white solid (1.78 g, 47%). LCMS (Method 1 ): Rt 4.55 min, m/z 241/243 [MH+]. 1H NMR (400 MHz, DMSO-d6): 8.90 (1 H, s), 7.57 (1 H, dd, J 8.2, 7.5), 7.34-7.25 (1 H, m), 7.21-7.13 (2 H, m), 6.77 (1 H, dd, J 7.5, 0.6), 6.63 (1 H, d, J 8.2).
General procedure: To a stirred solution of 3,5-dichlorosalicylaldehyde (2.00 g,10.47 mmol) in ethanol (20 mL) was slowly added 2,6-difluoroaniline (1.37 g, 10.47 mmol) at room temperature in the presence of trace amount of formic acid as a catalyst. The reaction mixture was stirred at room temperature for 3 h. Orange crystals were formed and then filtered. The product was obtained in 64%yield (2.74 g). 1H NMR data (500.13 MHz, CDCl3, 298 K): δ 13.77(s, 1H, OH), 8.87 (s, 1H, NCH), 7.48 (d, 4JHH 2.5, 1H, salicyl-H), 7.31(d, 4JHH 2.5, 1H, salicyl-H), 7.23e7.16 (m, 1H, aniline-H), 7.06e6.98(m, 2H, aniline-H). 13C NMR data (125.77 MHz, CDCl3, 298 K):δ 166.50 (HCN), 157.61 (d, CF), 156.22 (COH), 155.57 (d, CF), 133.61(salicyl-CH), 130.50 (salicyl-CH), 128.15 (t, aniline-CN), 124.14(t, CCHN), 123.90 (CCl), 123.35 (CCl), 120.68 (aniline-CH), 112.64(d, aniline-CH). Elemental analysis for C13H7Cl2F2NO: C, 51.68; H,2.34; N, 4.64%. Found C, 51.89; H, 2.31; N, 4.66%.
Example 121 Step-1 : 5-Chloro-N-(2,6-difluorophenyl)pyrazine-2-carboxamide: A mixture of 5- hydroxypyrazine-2-carboxylic acid (500 mg, 3.57 mmol, 1.0 eq), thionyl chloride (5 mL) and DMF (0.3 mL) was refluxed for 15 h. The excess of thionyl chloride was removed under vacuum and the residue was taken in THF (5 mL). The resulting mixture was cooled to 0 C and a solution of 2,6-difluoroaniline (0.58 mL, 5.35 mmol, 1.5 eq) was added to the above mixture followed by triethyl amine (0.75 mL, 5.35 mmol, 1.5 eq). After stirring for 3 h at room temperature, the reaction was diluted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), 2N HC1 (10 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum. The crude product was purified with flash column chromatography (silica gel, ethyl acetate and hexane system as eluent) to afford 500 mg of the title product as a white solid. 1HNMR (400 MHz, DMSO-c¾) delta 10.67 (s, 1H, D20 exchangeable), 9.1 1 (s, 1H), 9.98 (s, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 2H); ESI-MS (m/z) 270, 272 [(MH)+, CI 35> 37]
Step-1 :- Preparation of 4-chloro-2,6-difluoro-phenylamine:-To a solution of 2,6-difiuoro aniline (1.0 g, 7.75 mmol) in acetic acid (5 mL) was drop wise added solution of sulfuryl chloride (1.19 g, 8.82 mmol) in acetic acid at 80C. The reaction mass was refluxed for 1-2 hours. The reaction mass was quenched in water and neutralized with potassium carbonate and the reaction mass was filtered. Filtrate was extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.700 g of desired product. 'HNMR (DMSO- 6): delta 5.38 (s, 2H), 6.85-7.16 (s, 2H).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
5-bromonicotinic acid (2.0 g, 10 mmol) was dissolved in DCM (5 mL), then SOCl2 (1 mL) was added dropwise to this mixture. The reaction mixture was heated to reflux and allowed to stir at this temperature for 2 hours. The reaction mixture was concentrated in vacuo, then DCM (2 mL) was added and the resulting solution was concentrated in vacuo again. The resulting residue was diluted with DCM (30 mL) and the resulting solution was added to a solution of 2,6-difluoro aniline (1.05 g, 9.48 mmol) and TEA (1.05 g, 10.34 mmol) in DCM (20 mL) at 0 C dropwise. The mixture was allowed to stir at room temperature for 2 hours, and then diluted with DCM. The diluted mixture was washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using columnchromatography (eluted with PE : EtOAc = 10 : 1) to provide 2-bromo-N-2,6- difiuorophenyl)isonicotinamide (1.4 g, yield: 64.0%) as a white solid. 1H-NMR (CDC13, 400 MHz) delta 9.07 (s, 1H), 8.89 (s, 1H), 8.80-8.84 (m, 1H), 8.40-8.42 (m, 1H), 7.62-7.64 (m, 2H), 7.02-7.06 (m, 1H). MS (M+H)+: 313 / 315.
64%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
5-bromonicotinic acid (2.0 g, 10 mmol) was dissolved in DCM (5 mL), then SOCl2 (1 mL) was added dropwise to this mixture. The reaction mixture was heated to reflux and allowed to stir at this temperature for 2 hours. The reaction mixture was concentrated in vacuo, then DCM (2 mL) was added and the resulting solution was concentrated in vacuo again. The resulting residue was diluted with DCM (30 mL) and the resulting solution was added to a solution of 2,6-difluoro aniline (1.05 g, 9.48 mmol) and TEA (1.05 g, 10.34 mmol) in DCM (20 mL) at 0 C dropwise. The mixture was allowed to stir at room temperature for 2 hours, and then diluted with DCM. The diluted mixture was washed with water and brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using columnchromatography (eluted with PE : EtOAc = 10 : 1) to provide 2-bromo-N-2,6- difiuorophenyl)isonicotinamide (1.4 g, yield: 64.0%) as a white solid. 1H-NMR (CDC13, 400 MHz) delta 9.07 (s, 1H), 8.89 (s, 1H), 8.80-8.84 (m, 1H), 8.40-8.42 (m, 1H), 7.62-7.64 (m, 2H), 7.02-7.06 (m, 1H). MS (M+H)+: 313 / 315.
With pyridine; trichlorophosphate at 0 - 20℃; for 2h;
3.1 Example 3 (S)-2-[(S)-2-Cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-l, 2,3,4- tetrahydro-isoquinoline-l-carboxylic acid (2,6-difiuoro-phenyl)-amide hydrochloride Step 1 :
To the solution of (S)-3,4-dihydro-lH-isoquinoline-l,2-dicarboxylic acid 2- tert-butyl ester (500 mg, 1.8 mmol, Eq: 1.00) and 2,6-difiuoroaniline (279 mg, 2.16 mmol, Eq: 1.2) in pyridine (10.0 mL) at 0 °C was added POCl3 (415 mg, 252 μ,, 2.7 mmol, Eq: 1.5). The mixture was warmed to RT and stirred for 2 h. The solvent was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSC>4 and concentrated in vacuo. The crude material was purified by flash chomatography to give (S)-l-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro- lH-isoquinoline-2-carboxylic acid tert-butyl ester (380 mg) as a white foam.
With pyridine; trichlorophosphate; at 0 - 20℃; for 2h;
To a solution of 2-(tert-butoxycarbonyl)isoindoline-l-carboxylic acid (500 mg, 1.9 mmol, Eq: 1.00) and 2,6-difluoroaniline (294 mg, 2.28 mmol, Eq: 1.2) in pyridine (10 mL) at 0 C was added POCI3 (437 mg, 266 mu, 2.85 mmol, Eq: 1.5). The reaction was warmed to RT and stirred for 2 h. The mixture was evaporated and water was added and the resulting mixture was extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSC>4 and concentrated in vacuo. The crude material was purified by flash chomatography to give l-(2,6-difluoro-phenylcarbamoyl)-l,3-dihydro-isoindole-2- carboxylic acid tert-butyl ester (462 mg) as a light yellow foam.
N-(3-allylsalicylidene)-2,6-difluoroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With formic acid; In ethanol; at 80℃;
General procedure: The preparation of phenoxy-imine ligands 1-3 (ligand 1 and 2 are novel ligands,ligand 3 has been synthesized as the literature20 reported) by the Schiff Base condensation reaction was modified compared to the literature20: to a single neck, round bottomed flask equipped with a stir bar and condenser, a mixture of <strong>[24019-66-7]3-allylsalicylaldehyde</strong> (4.96 g,30 mmol), fluorinated aniline (3.95 g 2,6-difluoroaniline, 5.05 g 2,3,5,6-tetrafluoroaniline, 5.60 g 2,3,4,5,6-perfluoroaniline, 30 mmol), anhydrous ethanol (30 mL), and formic acid (1.41 g, 30 mmol) was heated in an oil bath at 80 C for 3-4 h. Then, the mixture was cooled at 0 C to obtain crystals to afford the corresponding phenoxy-imine ligands in 59-87% yield. The data for the ligands are listed below:
2-bromo-N-(2,6-difluorophenyl)thiazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
To a stirred solution of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (2.0 g, 9.61 mmol) in DMF (20 mL) was added HATU (5.48 g, 14.4 mmol) followed by DIPEA (5.0 mL, 28.8 mmol) and the resulting mixture was stirred at room temperature for 15 min. Then 2,6-difluoroaniline (1.2 mL, 9.61 mmol) was added to the above stirring mixture and the resulting mixture was continued to stir for another 16 h at room temperature. The reaction mass was then poured into ice-water (50 mL). Solid product precipitated out was filtered off and dried to afford 2.0 g (96%) of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) delta 8.55 (brs, 1H, D2O exchangeable), 8.22 (s, 1H), 7.32-7.22 (m, 1H), 7.03 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 319, 321 [(MH)+, Br79, 81].
With dodecyl-N,N-dimethylamine N-oxide; potassium carbonate; potassium iodide In acetonitrile at 20℃; for 4h;
Preparation of N-geranyl-substituted anilines (7a-7t).
General procedure: Yields: 39-83%. Take N-geranyl-aniline (7a) for example. To a mixture of aniline (1.12g, 12 mmol), KI (0.08g, 0.4 mmol), K2CO3(0.56g, 4 mmol), DDAO (9.16g, 12 mmol), and CH3CN (20 mL), the solution of geranyl chloride (0.70g, 4 mmol) in CH3CN was gently added in 20min. The resulting mixture was stirred 4h under room temperature. Then poured into 30 mL water and extracted with dichloromethane (2×30 mL), organic layer was combined and dried over anhydrous MgSO4and concentrated in vacuo. The resulting residue was purified by column chromatography on silica-gel column (petroleum ether: ethyl acetate = 4:1, v/v) to obtain the product 7a, yellow liquid, yield 75%.
2,6,2’,6’-tetrafluoro-(4-hydroxy)azobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
In the first step, ortho-fluorinated benzene-azophenol (FA-OH) was synthesized by a diazonium reaction. 2,6-Difluoro aniline (0.387 g, 3 mmol, 1 eq) and 1.0 mL of concentrated hydrochloric acid were dissolved in 7.5 mL of water. This solution was cooled to 0 C and stirred. To this stirred solution was added a solution of sodium nitrite (0.249 g, 3.3 mmol, 1.1 eq) in water (4.5 mL) dropwise. The temperature was controlled between 0 C and 5 C during the addition. The resulting suspension was added to an ice bath-cooled solution of <strong>[2713-34-0]3,5-difluorophenol</strong> (0.429 g, 3.3 mmol, 1.1 eq) and sodium hydroxide (0.400 g, 10 mmol, 3.3 eq) in water, dropwise. The suspension was acidified with 1 M HCl to pH = 2, and extracted with dichloromethane. The organic layer was collected and dried over MgSO4. Then the dichloromethane was evaporated, the mixture was purified by column chromatography, and 0.432 g of 15 product was isolated as a dark red solid, yield= 53%. 1H NMR in CD3CN: delta=7.49 (1H, m), 7.19 (2H, t. J=8.8 Hz), 6.69 (2H, dd, J1=11.2 Hz, J2=2.8 Hz) (Fig.S1).
1-(4-amino-3,5-difluorophenyl)-2-fluoroethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.7%
With trifluorormethanesulfonic acid In dichloromethane at 50℃;
II Embodiment II [Preparation of Raw Material III]
Add 2,6-difluoroaniline (2.6 g, 20 mmol) and fluorineacetonitrile/dichlormethane solution (1M, 40 mL) into the reaction flask, and add trifluoromethanesulfonic acid (15 g, 100 mmol) while stirring, raise the temperature to 50° C., and conduct stirring operations for 12-15 hours, and detect the end of reactions with TLC. Pour in ice water to quench the reaction, and make three times of extractions with dichlormethane, and as for the organic phase, use water, 10% sodium bicarbonate solution and saturated salt solution respectively, and use anhydrous sodium sulfate for dry and concentration, and there will be solid precipitation, and recrystallize the obtained crude products with n-hexane and ethyl acetate (5:2, V/V), dry it by vacuum to obtain the off-white solid, 1-(4-amidogen-2,6-difluoro-phenyl)-2-fluoro-ethanone (III) 3.2 g, the yield rate is 84.7%; mass spectrum (EI): m/z190 (M+H).
Stage #1: 4,4'-Dichlorobenzophenone With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 20℃; for 0.166667h;
Stage #2: 2,6-difluoroaniline In toluene at 80℃; for 2h;
1.1 Synthesis Example 1
A solution of 4,4'-dichlorobenzophenone (10g, 39.8mmol), Pd2 (dba) 3 (220mg, 0.002mol%), XPhos (230mg, 0.005mol%) and sodium t-butoxide (11.48g, 119.5 mmol) were added to a round-bottomed flask, and 50 g of toluene was added thereto. The mixture was stirred at room temperature for 10 minutes, and then 2,6-difluoroaniline (10.3 g, 79.6 mmol) was added thereto. The temperature of the reaction is stirred for 2 hours while slowly rising to 80°C. When the reaction is completed, the temperature of the reaction product is lowered to room temperature, and 50 g of isopropanol is added thereto, followed by stirring. The precipitate was filtered using a filter, washed with water, added to acetonitrile, and stirred at 80 ° C for 30 minutes. After lowering the temperature to room temperature, the precipitate was filtered and dried to synthesize a compound represented by the following formula (S-1) (15 g, 86%).
tert-butyl 4-((2.6-difluorophenyl)carbamoyl)-4-methylpiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
Preparation of teit-butyl 4-((2.6-difluorophenvOcarbamovO-4- methylpiperidine- 1 -carboxylate. To a solution of 2,6-difluoroaniline (226.2 mu^, 2.24 mmol) in toluene (9.0 mL) was treated with trimethylaluminum (1.1 mL, 2.24 mmol) was stirred for 15 min at ambient temperature. Then the solution was treated with ethyl N-Boc-4- methylpiperidine-4-carboxylate (506 mg, 1.86 mmol) and then stirred for 16 h at 70C. The reaction was cooled to ambient temperature and treated with 0.5 M NaK Tartrate and diluted with EtOAc. The organic solution was washed with water and brine. The organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (5-75% EtOAc in Hexanes as the gradient eluent) to cleanly provide the title compound (21 1 mg, 32% yield) MS (apci) m/z= 343.2 (M-H).
N-(2,6-difluorophenyl)pyrimidine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Pyrimidine-4-carboxylic acid (500mg, 4.03 mmol) was slurried in N,N- dimethylformamide (dry) (4 ml), DIPEA (0.842 ml, 4.83 mmol) was added followed by HATU (1685 mg, 4.43 mmol). After 15 mins 2,6-difluoroaniline (572 mg, 4.43 mmol) was added to the brown suspension and the resulting reaction mixture stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness. This mixture was added to a cold water/ sat. sodium bicarbonate mixture (2:1, 20 ml) and DCM 20 mL. The product was extracted and the layers were separated over a phase separator. The product was purified by reveleris 12 g column using heptane-EtOAc gradient (0 to 30%). Appropriate fractions were combined and solvents removed in vacuo to give the product as a white solid. Used as such.
With sodium hypochlorite; sodium hydroxide; In water; at -5℃; for 2h;Large scale; Green chemistry;
First, 14.4 L of the prepared 30% aqueous sodium hydroxide solution and 19.0 L of sodium hypochlorite aqueous solution were added to the reaction vessel, and the mixture was cooled to -5 C.Add <strong>[18063-03-1]2,6-difluorobenzamide</strong> to a total of 4.0 kg (25 mol) with stirring. After the addition,Stirring reaction was continued for 2 h. Then, add 2.1 kg of sodium bisulfate at room temperature.After stirring for 10 min, steam distillation was carried out, and the mixture was separated and distilled under reduced pressure.The light red product 2,6-difluoroaniline was obtained and weighed 3.0 kg (23 mol).The purity was 98.3% and the yield was 92.0%.
89.6%
With sodium hypochlorite; sodium hydroxide; at -5℃; for 1.5h;Large scale;
First, 28.8 L of prepared 30% sodium hydroxide solution and 38.0 L of sodium hypochlorite solution were added to the reaction kettle, it was cooled to -5 C, a total of 8.0 kg (50 mol) of <strong>[18063-03-1]2,6-difluorobenzamide</strong> was added in portions with stirring, it was ensured that the last addition of <strong>[18063-03-1]2,6-difluorobenzamide</strong> was completely dissolved before each addition, and after the addition, continued to stir for 1.5 h. 4.1 kg of sodium bisulfate was added at room temperature, stirred for 15 min, the solution was orange, and steam distillation was carried out. The obtained distillate was separated, and the lower organic layer was separated and distilled under reduced pressure to give an Tangerine product 2,6-difluoroaniline. The weighing was 5.9 kg (46 mol), the purity was 96.5%, and the yield was 89.6%.
N-(2,6-difluorophenyl)-4-hydroxy-2-(methylthio)pyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With phosphorus trichloride; In toluene; at 100.0℃; for 72h;
To a stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-(methylthio)pyrimidine-5-carboxylic acid</strong> (5 g, 26.88 mmol, 1.0 eq) in 100 mL of 24 Toluene was added 394 2,6-difluoroaniline (3.81 g, 29.55 mmol, 1.1 eq) and 91 PCl3 (25 mL). Reaction was allowed to stir at 100 C. for 72 h. Progress of reaction was monitored by LCMS. After consumption of starting material, solvent was removed under reduced pressure, residue was diluted with diethyl ether (100 mL) and 10 mL of MeOH. Solid was filtered out and dried under vacuum to obtain 7 g (88%) of 393 N-(2,6-difluorophenyl)-4-hydroxy-2-(methylthio)pyrimidine-5-carboxamide. (0473) LCMS: 298 [M+1]+
With triethylamine In tetrahydrofuran at 0 - 20℃; for 24h;
1 Example 1: [00231] Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3):
Example 1: [00231] Ethyl 2-((2,6-difluorophenyl)amino)-2-oxoacetate (3): Triethylamine (27.2 mL, 193.8 mmol, 1 equiv.) was added to a solution of 2,6-difluoroaniline (25.0 g, 193.8 mmol, 1 equiv.) in THF (1 L) at 0-5°C. Ethyl oxalyl chloride (21.6 mL, 193.8 mmol, 1 equiv.) was added dropwise over 60 minutes, while maintaining the temperature <5°C. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was filtered through celite, the celite was washed with methyl /-butyl ether (500 mL) and the combined organic layers were washed with a IN HCI (2 x 200 mL) and water (400 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired product as a beige oil (44.8 g, quantitative yield).
With triethylamine In tetrahydrofuran at 0℃; for 16h; Inert atmosphere;
N-(2,6-difluorophenyl)-3-hydroxynaphthalene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With phosphorus trichloride In chlorobenzene at 100 - 130℃; for 0.75h; Microwave irradiation;
General Procedure for the Synthesis of N-(Disubstituted phenyl)-3-hydroxynaphthalene-2-carboxamides 1-24
General procedure: 3-Hydroxynaphthalene-2-carboxylic acid (0.5 g, 2.65 mM) was suspended in drychlorobenzene (20 mL) at ambient temperature and phosphorus trichloride (0.12 mL,1.35 mM), and the corresponding substituted aniline (2.65 mM) was added dropwise.The reaction mixture was transferred to the microwave reactor, where the synthesis wasperformed (1st phase: 10 min, 100 C; 2nd phase: 15 min, 120 C; 3rd phase: 20 min, 130 C;max 500 W). The mixture was then cooled to 60 C, and the solvent was removed underreduced pressure. The residue was washed sequentially with hydrochloric acid and water,and the crude product was recrystallized from EtOH. All the compounds are presented inTable 1.
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