* 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.
A35-a intermediate 36: 2-Fluoro- -nitrobenzoic acidNitric acid (60percent solution, 5.0 mL) was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 °C. 2-f uorobenzoic acid (2.1 g, 15.0 mmol) was added by small portions while maintaining temperature between 15 and 25 °C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder. Yield: 93percent; mp 135-137 °C; 1H NMR (300 MHz, OMSO-d6): δ = 7.32 (t, 1 H, H3, 3 J H3_H4 = J H3-F= 9.2 Hz), 8.43 (dt, 1 H, H JH4.H3 = 9.2 Hz, JH4.F = JH4.H6 = 3.5 Hz), 8.89 (dd, 1H, 3/4,4JH6.F = 5.8 Hz, 4JH6.H4 = 3.0 Hz); 13C NMR (75 MHz, DMSO- d6): δ = 118.7 (d, Ci, 2JC-F = 10.9 Hz), 118.7 (d, C3, 2JC-F = 25.0 Hz), 128.9 (d, C6>3JC-F = 2.2 Hz), 130.6 (d, C4,3JC- = 10.9 Hz), 143.9 (C5), 165.7 (d, C2, 1JC.F = 272.0 Hz), 166.7 (d, COOH, 3Jc- = 3.8 Hz).
Reference：
[1] Patent: WO2012/85003, 2012, A1, . Location in patent: Page/Page column 83
[2] Journal of Organic Chemistry, 2008, vol. 73, # 2, p. 538 - 549
[3] Journal of Heterocyclic Chemistry, 1998, vol. 35, # 6, p. 1301 - 1304
[4] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1905 - 1917
[5] Australian Journal of Chemistry, 1981, vol. 34, # 5, p. 969 - 979
[6] Patent: US4565872, 1986, A,
[7] Patent: US4380543, 1983, A,
[8] Patent: US4400386, 1983, A,
2
[ 445-29-4 ]
[ 7304-32-7 ]
[ 317-46-4 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1930, vol. 39, p. 101
[2] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
3
[ 95-52-3 ]
[ 7304-32-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
[2] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
[3] Bulletin des Societes Chimiques Belges, 1930, vol. 39, p. 101
A35-b intermediate 37:Methyl 2-fluoro-5-nitrobenzoateIntermediate 36 ( 3.7 g, 20.0 mmol) was dissolved at 0 °C in MeOH (100 mL) and thionyl chloride (5.3 mL, 60.0 mmol) was added dropwise. The solution was heated under reflux for 24 h and concentrated in vacuo. The residue was dissolved in EtOAc and washed several times with 1.0 M NaOH. After drying over Na2S04, the solvent was evaporated in vacuo to yield intermediate 37 as a yellow oil, which crystallized upon standing as light yellow needles. Yield: 90percent; mp 47-49 °C; 1H NMR (300 MHz, CDC13) δ = 4.01 (s, 3 H, OCH3), 7.35 (t, 1H, H3, 3JH3.H4 = 3JH3.F= 9.2 Hz), 8.44 (dt, 1H, U43 JH4-H3 = 9.2 Hz, 4JH4.F = 4JH4-H6 = 3.5 Hz), 8.87 (dd, 1H, 3/4, 4JH6-F = 5.9 Hz, 4JH6-H4 = 2.7 Hz); 13C NMR (75 MHz, CDC13): 6 = 47.7 (OCH3), 113.2 (d, C3, 2JC-F = 25.1 Hz), 114.5 (d, Ci, 2JC-F = 12.0 Hz), 122.9 (d, C6>3JC-F = 3.3 Hz), 124.3 (d, C4>3JC-F = 10.9 Hz), 138.6 (C5), 157.4 (d, COOCH3, 3JC-F = 3.8 Hz), 159.8 (d, C2, 1JC-F = 269.0 Hz).
88%
for 16 h; Reflux
Sulfuric acid (5 mL, 93.80 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid (25.55 g, 138.03 mmol) in MeOH (250 mL) with stirring. The mixture was heated under reflux for 16 hr, concentrated under reduced pressure to a half volume, and ethyl acetate (about 300 mL) was added. The mixture was washed with water, aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate to give methyl 2-fluoro-5-nitrobenzoate (24.32 g, 122 mmol, 88percent) as a grayish white solid. 1H NMR (300 MHz, CDCl3): δ 4.00(3H,s), 7.33(1H,t,J=9.3 Hz), 8.38-8.45(1H,m), 8.86(1H,dd,J=6.2,2.8 Hz).
78%
for 16 h; Heating / reflux
Example 10: 17-Cyclohexyl- 18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin- 1 -yl)- benzyloxyl-phenyll-1.4J l-triaza-tricvclori l.5.2.016'19licosa-7J3(20).14J6(19)J7- pentaene-3,12-dione (11)Step A.To a solution of 2-fluoro-5-nitrobenzoic acid 10-1 (5.22 g, 28.2 mmol) in methanol (30 mL) was added chlorotrimethylsilane 10-2 (6.00 g, 1.96 eq.). The reaction mixture was stirred under reflux during 16h, then cooled down to room temperature, concentrated and the resulting precipitate was filtered off, washed with a small quantity of methanol, then heptane, to provide 4.36 g (78percent yield) of 2-fluoro-5-nitro-benzoic acid methyl ester 10-3 as a white powder; m/z = 200 (M+H)+.
With thionyl chloride; at 80℃; for 3.08333h;Cooling with ice;
General procedure: Compound 1a or 1b (10.8 mmol) was added to ethanol solution(15 ml), into which thionyl chloride (1.54 g, 12.9 mmol) was slowlydropped under ice-cooling and stirred for 5 min. Subsequently, thesolution was refluxed at 80 C for 3 h. The reaction was monitoredwith TLC until it completed. Then the reaction solution wasconcentrated by rotary evaporation and separated by silica gelcolumn (PE/EA system) to afford compound 2a or 2b with 98%yield.
With thionyl chloride; at 0 - 80℃; for 4h;
Reference Example 7 Production of ethyl 2-fluoro-5-nitrobenzoate Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added. This mixture was stirred at 80C for 4 hrs. and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.77 g) as a pale-yellow oil. 1H-NMR (CDCl3) δ: 1.43 (3H, t, J= 7.2 Hz), 4.46 (2H, q, J= 7.2 Hz), 7.32 (1H, t, J= 9.1 Hz), 8.41 (1H, ddd, J= 9.1, 4.3, 3.0 Hz), 8.85 (1H, dd, J= 6.1, 3.0 Hz).
With sulfuric acid; at 20℃; for 5h;Heating / reflux;
To a solution of 2-fluoro-5-nitro-benzoic acid (0.269g, 1.45mmol) in 3 mL ethanol, was added concentrated sulfuric acid (0.5 ml). The solution was refluxed under argon for 3 hours. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, concentrated in vacuo to give pure 2-fluoro-5-nitro-benzoic acid ethyl ester.
2.3 g
In ice bath conditions,1.54 g of thionyl chloride (1.5 eq) was slowly added dropwise to 15 ml of ethanol solution, and after stirring for 5 min,2 g of 2-fluoro-5-nitrobenzoic acid (1.0 eq) was added, the ice bath was removed, and refluxed at 80 C for 3 h.After the reaction was monitored by TLC,The reaction solution was sparged to give 2.3 g of an off-white solid.
With hydrogen;palladium(II) hydroxide/carbon; under 2585.81 Torr;
Into a Parr pressure reactor were added 3-fluoro-5-nitrobenzoic acid (667, 5.0 g, 0.027 mol), methanol (50.0 mL), 20% Pd(OH)2 on carbon (300 mg). The reaction was shaken under an atmosphere of hydrogen at 50 psi overnight. The reaction was filtered through celite and was concentrated to dryness to provide a white solid (668, 4.0 g, 95.0%).
palladium-carbon; In methanol;
(1) 2-Fluoro-5-nitrobenzoic acid (60 g) was suspended in 300 ml of methanol, 6.0 g of 5% palladium-carbon was added thereto and the mixture was reduced at 40 C. with hydrogen pressure of 6.5 atm. The catalyst was removed, the solvent was evaporated and the crystals separated out therefrom were filtered to give 42 g of 5-amino-2-fluorobenzoic acid, m.p. 189-192 C. NMR spectra (DMSO-d6) delta: 6.65-7.25 (3 H, m), 5.5-7.5 (3 H, broad).
With sulfuric acid; nitric acid; at 10 - 25℃; for 2h;
A35-a intermediate 36: 2-Fluoro- -nitrobenzoic acidNitric acid (60% solution, 5.0 mL) was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 C. 2-f uorobenzoic acid (2.1 g, 15.0 mmol) was added by small portions while maintaining temperature between 15 and 25 C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder. Yield: 93%; mp 135-137 C; 1H NMR (300 MHz, OMSO-d6): δ = 7.32 (t, 1 H, H3, 3 J H3_H4 = J H3-F = 9.2 Hz), 8.43 (dt, 1 H, H JH4.H3 = 9.2 Hz, JH4.F = JH4.H6 = 3.5 Hz), 8.89 (dd, 1H, ¾, 4JH6.F = 5.8 Hz, 4JH6.H4 = 3.0 Hz); 13C NMR (75 MHz, DMSO- d6): δ = 118.7 (d, Ci, 2JC-F = 10.9 Hz), 118.7 (d, C3, 2JC-F = 25.0 Hz), 128.9 (d, C6> 3JC-F = 2.2 Hz), 130.6 (d, C4, 3JC- = 10.9 Hz), 143.9 (C5), 165.7 (d, C2, 1JC.F = 272.0 Hz), 166.7 (d, COOH, 3Jc- = 3.8 Hz).
71.2%
With sulfuric acid; nitric acid; at 20℃; for 2h;
2-fluorobenzoic acid (5 g, 35.7 mmol) was dissolved in 11 mL of concentrated sulfuric acid.Slowly drip 11 mL of concentrated nitric acid in an ice bath and gradually increase to room temperature for 2 h.After the reaction was completed, the reaction solution was slowly dropped into ice water, and a large amount of white solid precipitated.Filtering and drying to obtain 4.7 g of 2-fluoro-5-nitrobenzoic acid, the yield is 71.2%;2-Fluoro-5-nitrobenzoic acid (500 mg, 2.7 mmol) was dissolved in 15 mL of dioxane.Add morpholine (1.2mL, 13.5mmol), react at room temperature for 2h, spin dry solvent and excess morpholine, dissolve in water, acidify with 10% dilute hydrochloric acid, and filter to give 2-morpholinyl-5-nitrobenzoic acid yellow 520 mg solid, 76.4% yield;2-morpholinyl-5-nitrobenzoic acid (80 mg, 0.32 mmol) was dissolved in 10 mL of DCM, and p-methoxybenzylamine (48 mg, 0.35 mmol), hydroxybenzotriazole (51 mg, 0.38 mmol) , EDCI (122 mg, 0.64 mmol), stirred at room temperature for 2 h, diluted with water, ethyl acetate (25 mL×3). : 1) A yellow solid 103 mg, a yield of 88.0%
71.2%
With sulfuric acid; nitric acid; at 0 - 20℃; for 2h;
To a solution of 2-fluorobenzoic acid (10) (5.0 g, 35.7 mmol) in10 mL concentrated H2SO4, 10 mL concentrated HNO3 was addeddropwise at 0 C. After stirring for 2 h at room temperature, themixture was slowly poured into ice water. The resulting precipitatewere collected by filtration, which werewashed bywater, and driedto give 4.7 g 2-fluoro-5-nitrobenzoic acid (11) as yellow solid, yield 71.2%; To the solution of 11 (500 mg, 2.7 mmol) in 10 mL dioxane,morpholine (1.2 mL, 13.5 mmol) was added in one potion. Afterstirring for 2 h at room temperature, the solvent and remainingmorpholine were removed in vacuo. Then, the residues were dissolvedinto water and neutralized by 10% HCl aqueous. Theresulting precipitate were collected, washed by water, and dried togive 520 mg 2- morpholine-5-nitrobenzoic acid (12) as yellowsolid, yield 76.4%. 1H NMR (300 MHz, DMSO-d6) d 8.40 (d, J 2.9 Hz,1H), 8.20 (dd, J 9.2, 2.9 Hz, 1H), 7.19 (d, J 9.2 Hz, 1H), 3.72 (d,J 4.8 Hz, 4H), 3.28 (d, J 4.7 Hz, 4H); 13C NMR (75 MHz, DMSO-d6)d 167.39, 155.09, 138.17, 127.42, 127.28, 120.86, 117.75, 65.70, 50.95;ESI-MS m/z 252.1 [M H]- 251.1.
54%
With sulfuric acid; nitric acid; at 15 - 25℃; for 1h;
To a mixture ofconc.sulfuricacid (10 mL) and conc.nitric acid (10 mL) was added 2-Fluorobenzoic acid (1.40 g,10 mmol).Thetemperature was maintained between 15-25C. The mixture was stirred for 1h after completion of theaddition,duringwhich time the temperature rose to 30C. The solution was decanted into 100 mL of ice water to provide 2-fluoro-4-nitrobenzoic acid (FBA) as a white solid (1.0 g, 54.0%).1H-NMR (400MHz,DMSO-d6,ppm):δ 8.594 (q,1H,J=3.2 Hz, 3.2 Hz, 2.8 Hz), 8.473 (m,1H,J=3.2 Hz, 0.8 Hz, 3.2 Hz, 2.0 Hz, 3.2 Hz, 0.8 Hz, 3.2 Hz), 7.610 (t,1H, 9.6 Hz, 9.6 Hz);13C-NMR (100MHz,DMSO-d6,ppm):δ 165.69, 163.16, 143.64, 129.80, 127.49, 120.42, 118.92; HRMS (ESI) m/zcalcdfor C7H4FNO4+H+: 186.01 [M+H]+;Found:186;m.p: 144-146C.
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Part A To a mixture of 225 ml (3.75 moles) of concentrated sulfuric acid and 225 ml (3.3 moles) of concentrated nitric acid was added 100 g (0.713 mole) of 2-fluorobenzoic acid. The temperature was maintained between 15 and 25 C. The mixture was stirred for an hour after completion of the addition, during which time the temperature rose to about 30 C. The solution was decanted into 4 liters of ice water to provide 111.1 g of white crystals of 2-fluoro-5-nitrobenzoic acid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Part A To a mixture of 225 ml (3.75 mole) of concentrated sulfuric acid and 225 ml (3.3 mole) of concentrated nitric acid was added 100 g (0.713 mole) of 2-fluorobenzoic acid. The temperature was maintained between 15 and 25 C. The mixture was stirred for an hour after completion of the addition. The temperature rose to about 30 C. The solution was decanted into 4 liters of ice water to provide 111.1 g of white crystals of 2-fluoro-5-nitrobenzoic acid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
With sulfuric acid; nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Part A To a mixture of 225 ml (3.75 mole) of concentrated sulfuric acid and 225 ml (3.3 mole) of concentrated nitric acid was added 100 g (0.713 mole) of 2-fluorobenzoic acid. The temperature was maintained between 15 and 25 C. The mixture was stirred for an hour after completion of the addition. The temperature rose to about 30 C. The solution was decanted into 4 liters of ice water to provide 111.1 g of white crystals of 2-fluoro-5-nitrobenzoic acid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
13-amino-10-isobutyl-7-methyl-2-nitro-7,8,10,11,14,15-hexahydro-6<i>H</i>,13<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecene-9,12,16-trione[ No CAS ]
13-amino-10-hydroxymethyl-7-methyl-2-nitro-7,8,10,11,14,15-hexahydro-6<i>H</i>,13<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecene-9,12,16-trione[ No CAS ]
((10S,13S)-13-Amino-10-isobutyl-7-methyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl)-urea[ No CAS ]
Pyrazine-2-carboxylic acid ((10S,13S)-13-amino-7-hydroxymethyl-10-isobutyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl)-amide[ No CAS ]
(10S,14S)-10-Isobutyl-7-methyl-9,12,16-trioxo-2-[(piperidine-4-carbonyl)-amino]-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecene-14-carboxylic acid[ No CAS ]
3-{(10S,13S)-13-Amino-7-methyl-9,12,16-trioxo-2-[(piperidine-4-carbonyl)-amino]-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-10-yl}-propionic acid[ No CAS ]
<i>N</i>-(13-amino-7-hydroxymethyl-10-isobutyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl)-2-(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetamide[ No CAS ]
Pyrazine-2-carboxylic acid [(10S,13S)-13-amino-7-(3-guanidino-propyl)-10-isobutyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
<i>N</i>-[13-amino-7-(4-amino-butyl)-10-isobutyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-2-(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetamide[ No CAS ]
<i>N</i>-[13-amino-10-(3-guanidino-propyl)-7-methyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-2-(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetamide[ No CAS ]
<i>N</i>-[13-amino-7-(3-guanidino-propyl)-10-hydroxymethyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-2-(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetamide[ No CAS ]
2-{13-amino-7-(4-hydroxy-benzyl)-2-[2-(5-methyl-2,4-dioxo-3,4-dihydro-2<i>H</i>-pyrimidin-1-yl)-acetylamino]-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6<i>H</i>-5-oxa-8,11,15-triaza-benzocyclotetradecen-10-yl}-acetamide[ No CAS ]
<i>N</i>-isopropyl-2-(8-nitro-6-oxo-2,3,3a,4-tetrahydro-1<i>H</i>,6<i>H</i>-benzo[<i>f</i>]pyrrolo[1,2-<i>a</i>][1,4]diazepin-5-yl)-4-phenyl-butyramide[ No CAS ]
1,4-dihydroquinoxaline-2,3-dione-6-carboxylic acid[ No CAS ]
2,3-Dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid [(7S,10S,13S)-13-amino-7-(4-amino-butyl)-10-benzyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
[(S)-4-({Amino-[(E)-2,2,5,7,8-pentamethyl-chroman-6-sulfonylimino]-methyl}-amino)-1-hydroxymethyl-butyl]-carbamic acid 9H-fluoren-9-ylmethyl ester[ No CAS ]
1,4-dihydroquinoxaline-2,3-dione-6-carboxylic acid[ No CAS ]
2,3-Dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid [(7S,10S,13S)-13-amino-7-(3-guanidino-propyl)-10-(4-hydroxy-benzyl)-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
N-α-(9-fluoromethoxycarbonyl)-L-4-tert-butoxycarbonylaminophenylalanine[ No CAS ]
[(S)-4-({Amino-[(E)-2,2,5,7,8-pentamethyl-chroman-6-sulfonylimino]-methyl}-amino)-1-hydroxymethyl-butyl]-carbamic acid 9H-fluoren-9-ylmethyl ester[ No CAS ]
1,4-dihydroquinoxaline-2,3-dione-6-carboxylic acid[ No CAS ]
2,3-Dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid [(7S,10S,13S)-13-amino-10-(4-amino-benzyl)-7-(3-guanidino-propyl)-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(3-pyridyl)propanoic acid[ No CAS ]
[(S)-4-({Amino-[(E)-2,2,5,7,8-pentamethyl-chroman-6-sulfonylimino]-methyl}-amino)-1-hydroxymethyl-butyl]-carbamic acid 9H-fluoren-9-ylmethyl ester[ No CAS ]
1,4-dihydroquinoxaline-2,3-dione-6-carboxylic acid[ No CAS ]
2,3-Dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid [(7S,10S,13S)-13-amino-7-(3-guanidino-propyl)-9,12,16-trioxo-10-pyridin-3-ylmethyl-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid[ No CAS ]
[(R)-4-({Amino-[(E)-2,2,5,7,8-pentamethyl-chroman-6-sulfonylimino]-methyl}-amino)-1-hydroxymethyl-butyl]-carbamic acid 9H-fluoren-9-ylmethyl ester[ No CAS ]
1,4-dihydroquinoxaline-2,3-dione-6-carboxylic acid[ No CAS ]
2,3-Dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid [(7R,10R,13S)-13-amino-7-(3-guanidino-propyl)-9,12,16-trioxo-10-pyridin-3-ylmethyl-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
Fmoc-D-α-amino-4-(protected)-aminobutyric acid[ No CAS ]
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [(7S,10R)-10-(2-amino-ethyl)-7-benzyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
Fmoc-D-α-amino-4-(protected)-aminobutyric acid[ No CAS ]
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [(7R,10R)-10-(2-amino-ethyl)-7-benzyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
Fmoc-L-α-amino-4-(protected)-aminobutyric acid[ No CAS ]
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [(7S,10S)-10-(2-amino-ethyl)-7-benzyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
Fmoc-L-α-amino-4-(protected)-aminobutyric acid[ No CAS ]
1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [(7R,10S)-10-(2-amino-ethyl)-7-benzyl-9,12,16-trioxo-7,8,9,10,11,12,13,14,15,16-decahydro-6H-5-oxa-8,11,15-triaza-benzocyclotetradecen-2-yl]-amide[ No CAS ]
5-amino-2-{2-benzyl-6-[6-(3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; trifluoroacetic acid;palladium-carbon; silica gel; In methanol; N,N-dimethyl-formamide;
A small amount of 4A flame dried molecular sieves (cooled down by a flow of argon) was added to a vial containing a portion of the product immediately above (0.131 g, 0.34 mmol). The mixture was capped with a rubber septum and cooled down to 0 C. To this mixture trifluoroacetic acid (2.5 mL) was added via syringe and the mixture stirred at this temperature for 15 min. Phenyl acetaldehyde dimethylacetal (0.230 ml, 4 eq.) was added dropwise and the mixture stirred at 0 C. for 2 h. One more equivalent of phenyl acetaldehyde dimethyl acetal was added and stirred an additional five hours. The volatiles were evaporated off and the residue was purified by flash chromatography (hexane:ethyl acetate, 8:2, 1% triethylamine) to give 0.095 g of product (60% yield) as a yellow solid. MW calculated for C25H24N6O5 (MH+) 489, found 489 by LCMS. A portion of this acetal product (0.068 g, 0.14 mmol) was dissolved in dry N,N-dimethyl formamide (2.5 mL) and potassium tert-butoxide (0.084 g, 5 eq) was added to give a yellow solution. To this mixture was added <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (0.046 g, 1.8 eq). After 2.5 h of stirring at room temperature the mixture was concentrated and purified by preparative HPLC to give the nucleoside analog as a white powder. MW calculated for C32H27N7O9 (MH+) 654, found 654 by LCMS. The nitro group of the product immediately above was reduced under a hydrogen atmosphere with a catalytic amount of 10% Pd/C in methanol during 6 h. Filtration through Celite followed by HPLC purification yielded 52 mg (62% yield) of the title compound as clear semisolid.
With benzotriazol-1-ol; diisopropyl-carbodiimide; In DMF (N,N-dimethyl-formamide); for 16h;
TentaGel resin was suspended in 1,2-dichloroethane, 1 equivalent of quinolinium toluenesulfonate was added, and the mixture was heated to reflux. 4 equivalents of 2-bromo-1,1-diethoxyethane were added, and the mixture was heated under reflux for 4 hours while distilling off ethanol. The resin was separated, washed with dimethylformamide and dioxane and lyophilized. The resin was shaken in dimethylsulfoxide with an excess of 4-phenylbutylamine at 60 C for 14 hours. The resin was separated and washed with dimethylformamide, methanol and dichloromethane. The resin was shaken in dimethylformamide with 3 equivalents of Fmoc-L-valine, 3 equivalents of tetramethylfluoroformamidium hexafluorophosphate (TFFH) and 6 equivalents of ethyldiisopropylamine at room temperature for two days. The resin was separated, washed with dichloromethane and dimethylformamide, and the Fmoc protecting group was cleaved off by treatment with an excess of a 20% solution of piperidine in dimethylformamide. The resin was separated, washed, and shaken in dimethylformamide with 3 equivalents of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong>, 3 equivalents of diisopropylcarbodiimide (DIC) and 3 equivalents of N-hydroxybenzotriazole (HOBT) for 16 hours at room temperature. The resin was separated, washed with dimethylformamide, dichloromethane and methanol, and shaken in dimethylsulfoxide with 15 equivalents of 3-(imidazol-1-yl)propylamine at room temperature for 16 hours. The resin was separated and washed with dimethylformamide and dichloromethane. Finally, cleavage of the prepared compound from the resin and N-acyliminium ion cyclization were effected by treatment with formic acid at room temperature for 3 to 4 hours. The crude product was purified by preparative HPLC (acetonitrile/water/trifluoroacetic acid). MS: m/e = 545 (M+H)+. Retention time (HPLC A): 4.29 min.
Example 261 Synthesis of 2-fluoro-5-nitrobenzyl alcohol Using 2-fluoro-5-nitrobenzoic acid as a starting material, the same procedure of Example 132 gave the titled compound (yield, 95%). 1H-NMR(CDCl3) delta: 2.10(1H, t, J=5.9 Hz), 4.86(2H, d, J=5.9 Hz), 7.16-7.24(1H,m), 8.15-8.25(1H,m), 8.40-8.47(1H,m)
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 1.0h;
To a stirred suspension of sodium borohydride (44.5 mmol) in dry THF (80 ml) at [0XB0;C] was added 2-fluoro-5-nitrobenzoic acid (2.43 mmol) dissolved in dry THF (50 ml). Boron trifluoride etherate (66.6 mmol) was added dropwise and the reaction mixture allowed to warm to room temperature over 1 hour. The reaction mixture was quenched with 1N HC1 and then partitioned between DCM and water. The organic layer was separated, washed with brine solution, dried [(MGSO),] filtered, evaporated and the residue purified by column chromatography on silica. Elution with mixtures of petroleum ether and ethyl acetate afforded the desired product. MS (ES): m/e 172 (M+H).
A35-b intermediate 37:Methyl 2-fluoro-5-nitrobenzoateIntermediate 36 ( 3.7 g, 20.0 mmol) was dissolved at 0 C in MeOH (100 mL) and thionyl chloride (5.3 mL, 60.0 mmol) was added dropwise. The solution was heated under reflux for 24 h and concentrated in vacuo. The residue was dissolved in EtOAc and washed several times with 1.0 M NaOH. After drying over Na2S04, the solvent was evaporated in vacuo to yield intermediate 37 as a yellow oil, which crystallized upon standing as light yellow needles. Yield: 90%; mp 47-49 C; 1H NMR (300 MHz, CDC13) δ = 4.01 (s, 3 H, OCH3), 7.35 (t, 1H, H3, 3JH3.H4 = 3JH3.F= 9.2 Hz), 8.44 (dt, 1H, U4 3 JH4-H3 = 9.2 Hz, 4JH4.F = 4JH4-H6 = 3.5 Hz), 8.87 (dd, 1H, ¾, 4JH6-F = 5.9 Hz, 4JH6-H4 = 2.7 Hz); 13C NMR (75 MHz, CDC13): 6 = 47.7 (OCH3), 113.2 (d, C3, 2JC-F = 25.1 Hz), 114.5 (d, Ci, 2JC-F = 12.0 Hz), 122.9 (d, C6> 3JC-F = 3.3 Hz), 124.3 (d, C4> 3JC-F = 10.9 Hz), 138.6 (C5), 157.4 (d, COOCH3, 3JC-F = 3.8 Hz), 159.8 (d, C2, 1JC-F = 269.0 Hz).
88%
With sulfuric acid; for 16h;Reflux;
Sulfuric acid (5 mL, 93.80 mmol) was added to a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (25.55 g, 138.03 mmol) in MeOH (250 mL) with stirring. The mixture was heated under reflux for 16 hr, concentrated under reduced pressure to a half volume, and ethyl acetate (about 300 mL) was added. The mixture was washed with water, aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate to give methyl 2-fluoro-5-nitrobenzoate (24.32 g, 122 mmol, 88%) as a grayish white solid. 1H NMR (300 MHz, CDCl3): δ 4.00(3H,s), 7.33(1H,t,J=9.3 Hz), 8.38-8.45(1H,m), 8.86(1H,dd,J=6.2,2.8 Hz).
78%
With chloro-trimethyl-silane; for 16h;Heating / reflux;
Example 10: 17-Cyclohexyl- 18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin- 1 -yl)- benzyloxyl-phenyll-1.4J l-triaza-tricvclori l.5.2.016'19licosa-7J3(20).14J6(19)J7- pentaene-3,12-dione (11)Step A.To a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> 10-1 (5.22 g, 28.2 mmol) in methanol (30 mL) was added chlorotrimethylsilane 10-2 (6.00 g, 1.96 eq.). The reaction mixture was stirred under reflux during 16h, then cooled down to room temperature, concentrated and the resulting precipitate was filtered off, washed with a small quantity of methanol, then heptane, to provide 4.36 g (78% yield) of 2-fluoro-5-nitro-benzoic acid methyl ester 10-3 as a white powder; m/z = 200 (M+H)+.
With hydrogenchloride; thionyl chloride; at 0 - 20℃;
INTERMEDIATE 10 Step A: Thionyl chloride (16ML, 0. 22MOL) was added dropwise to cooled (0C) methanol (250ML). After the addition the resulting anhydrous methanolic HC1 solution was poured into a flask containing <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (13.77g, 74. 39MMOL). THE mixture so obtained was stirred overnight at rt. The reaction mixture was concentrated and the residue collected was purified by flash chromatography using a gradient [silica, 5-30% (700mL), then 30-50% (1 L) ], giving methyl 2-fluoro-5- nitrobenzoate.
A solution containing 12.0 g of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong>, 60 ml of anhydrous tetrahydrofuran and 60 μl of dimethylformamide was cooled with ice, and 9.05 g of oxalyl chloride was added dropwise thereto. After completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours. To the reaction solution, 30 ml of anhydrous tetrahydrofuran and 30 ml of a methanol solution were added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and diluted with 240 ml of ethyl acetate. Then, the diluted solution was washed with 5% aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate and then filtered. Then, the solvent was concentrated, and to the concentrated residue, 24 ml of isopropyl ether was added to dissolve the residue. Then, the solution was cooled to 5C to deposit a crystal. The deposited crystal was filtered under reduced pressure and dried at room temperature under reduced pressure, whereby 10.5 g of methyl 2-fluoro-5-nitrobenzoate was obtained.
With hydrogenchloride; In water; at 70℃; for 24h;
To a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (5 g, 27.0 mmol) in methanol (135 mL) was added HCl (2.66 mL, 32.4 mmol, 12.2 M), and the mixture was heated with an oil bath at 70 0C for 24 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-J6) δ ppm 8.63 (dd, J= 3.0, 6.2, IH), 8.58 - 8.50 (m, IH), 7.74 - 7.61 (m, IH), 3.92 (s, 3H).
With sulfuric acid; In water; for 4h;Heating / reflux;
A solution of 2-fluoro-5-nitro-benzoic acid (3.702 g, 20 mmol) in anhydrous methanol (10.00 mL) was treated with 98% sulphuric acid and the solution was heated to reflux for 4 hours. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated aqueous sodium bicarbonate (3 X 10 mL), brine until neutrality ant then water, and dried over anhydrous sodium sulphate. The solvent was removed under vacuum to afford a thick oil that started to crystallize. After adding n-hexane (3 mL) the crude was stored for 2 days in the fridge. The crystalline compound was filtered and washed with n-hexane to yield 3.147 g of the pure compound. By concentrating the mother liquors a second crop was obtained (390 mg) (y = 89%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 3.94 (s, 3 H) 7.69 (m, 1 H) 8.55 (m, 1 H) 8.65 (m, 1 H).
With thionyl chloride; at 0 - 20℃;
Step A: Thionyl chloride (16 mL, 0.22 mol) was added dropwise to cooled (0 C.) methanol (250 mL). After the addition the resulting anhydrous methanolic HCl solution was poured into a flask containing <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (13.77 g, 74.39 mmol). The mixture so obtained was stirred overnight at rt. The reaction mixture was concentrated and the residue collected was purified by flash chromatography using a gradient [silica, 5-30% (700 mL), then 30-50% (1 L)], giving methyl 2-fluoro-5-nitrobenzoate.
With thionyl chloride; at 60℃;
To a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (37 g, 200 mmol) in methanol (500 mL) was dripped sulfoxide dichloride (36 mL, 500 mmol) at room temperature and stirred at 60C overnight. The mixture was concentrated to give the desired product methyl 2-fluoro-5- nitrobenzoate (40.0 g, crude) as a white solid. 'H NMR (400 MHz, CDCI3) δ 8.91-8.81 (m, 1H), 8.46-8.37 (m, 1H), 7.39-7.28 (m, 1H), 3.99 (s, 3H).
To a solution of 2-Fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 rnl) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and the mixture was acidified with HCL 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (M-H, 100%).
93%
EXAMPLE 2.1; Preparation of 2-Morpholin-4-yl-5-nitro-benzoic acid; To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water, and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid
93%
To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (M-H, 100%).
93%
EXAMPLE 2.8 Preparation of 2Morpholin-4-yl-5-nitro-benzoic acid To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (M-H, 100%).
93%
In 1,4-dioxane; at 20℃; for 2h;
EXAMPLE A Preparation of 2-Morpholin-4-yl-5-nitro-benzoic acid To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water, and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (MH-, 100%).
93.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: To the solution of F (20.0 g, 0.11 mol) in DMF (100 mL) was addedK2CO3 (29.8 g, 0.22 mol) and N-aliphatic amines (0.11 mol). Theresulting solution was stirred at room temperature for 2 h. When thecompletion of the reaction, the reaction mixture was poured into waterand the pH was adjusted to around 2 by 1.2 mol/L HCl. The precipitatewas collected by filtration and air-dried to give G-1 ~ G-4.
92%
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 2h;
800 mg of 5-nitrobenzoic acid (1.0 eq),376 mg of morpholine (1.0 eq) and 1.2 g of potassium carbonate (2.0 eq) were dissolved in 15 ml of DMSO and heated at reflux at 80 C for 2 h.The reaction was completed by TCL.The reaction solution was poured into 300 ml of ice water, extracted with EA three times, spun dry and mixed, and separated by column.1 g of a pale yellow solid was obtained in a yield of 92%.
76.4%
In 1,4-dioxane; at 20℃; for 2h;
2-fluorobenzoic acid (5 g, 35.7 mmol) was dissolved in 11 mL of concentrated sulfuric acid.Slowly drip 11 mL of concentrated nitric acid in an ice bath and gradually increase to room temperature for 2 h.After the reaction was completed, the reaction solution was slowly dropped into ice water, and a large amount of white solid precipitated.Filtering and drying to obtain 4.7 g of 2-fluoro-5-nitrobenzoic acid, the yield is 71.2%;2-Fluoro-5-nitrobenzoic acid (500 mg, 2.7 mmol) was dissolved in 15 mL of dioxane.Add morpholine (1.2mL, 13.5mmol), react at room temperature for 2h, spin dry solvent and excess morpholine, dissolve in water, acidify with 10% dilute hydrochloric acid, and filter to give 2-morpholinyl-5-nitrobenzoic acid yellow 520 mg solid, 76.4% yield;2-morpholinyl-5-nitrobenzoic acid (80 mg, 0.32 mmol) was dissolved in 10 mL of DCM, and p-methoxybenzylamine (48 mg, 0.35 mmol), hydroxybenzotriazole (51 mg, 0.38 mmol) , EDCI (122 mg, 0.64 mmol), stirred at room temperature for 2 h, diluted with water, ethyl acetate (25 mL×3). : 1) A yellow solid 103 mg, a yield of 88.0%
76.4%
In 1,4-dioxane; at 20℃; for 2h;
To a solution of 2-fluorobenzoic acid (10) (5.0 g, 35.7 mmol) in10 mL concentrated H2SO4, 10 mL concentrated HNO3 was addeddropwise at 0 C. After stirring for 2 h at room temperature, themixture was slowly poured into ice water. The resulting precipitatewere collected by filtration, which werewashed bywater, and driedto give 4.7 g 2-fluoro-5-nitrobenzoic acid (11) as yellow solid, yield 71.2%; To the solution of 11 (500 mg, 2.7 mmol) in 10 mL dioxane,morpholine (1.2 mL, 13.5 mmol) was added in one potion. Afterstirring for 2 h at room temperature, the solvent and remainingmorpholine were removed in vacuo. Then, the residues were dissolvedinto water and neutralized by 10% HCl aqueous. Theresulting precipitate were collected, washed by water, and dried togive 520 mg 2- morpholine-5-nitrobenzoic acid (12) as yellowsolid, yield 76.4%. 1H NMR (300 MHz, DMSO-d6) d 8.40 (d, J 2.9 Hz,1H), 8.20 (dd, J 9.2, 2.9 Hz, 1H), 7.19 (d, J 9.2 Hz, 1H), 3.72 (d,J 4.8 Hz, 4H), 3.28 (d, J 4.7 Hz, 4H); 13C NMR (75 MHz, DMSO-d6)d 167.39, 155.09, 138.17, 127.42, 127.28, 120.86, 117.75, 65.70, 50.95;ESI-MS m/z 252.1 [M H]- 251.1.
32%
In tetrahydrofuran; at 20℃; for 16h;
Example A27; 5 2-Morpholin-4-yl-5-nitro-benzoic acid; To a solution of 12.2 mmol 2-fluoro-5-nitrobenzoic acid (CAS 7304-32-7; commercially available, e.g. from Fluorochem) in 40 ml THF was added 18.2 mmol morpholine and the mixture was stirred at room temperature for 16 h. The volatiles were removed in vacuo and the residue was resuspended in 25 ml water and acidified to pH 4 by dropwise addition of aqueous HCl. The resulting mixture was stirred at room temperature for 30 min, and the resulting crystals were then collected by filtration and dried in vacuo at 50 0C to afford the title compound as a yellow solid (yield 32%). MS (m/e): 251.0 ( [M-H] 100%)
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 2h;
General procedure: Compound 2a (2 g, 9.4 mmol), appropriate amines (9.4 mmol, 1eq.) and potassium carbonate (2.6 g, 18.8 mmol) were dissolved in15 ml of DMSO and heated under reflux at 80 C for 2 h. The reactionwas monitored with TLC until it completed. The reactionsolution was poured into ice water (300 ml), extracted with EA intriplicate, concentrated by rotary evaporation and separated bysilica gel column (PE/EA system) to get compound I with 95% yield.
EXAMPLES; Example 1. Preparation of 5'-aryl ether derivatives:; 5-Amino-2- {2-benzyl-6- [6- (3-phenyl-ureido)-purin-9-yl]-tetrahydro-furo [3,4- d] [1, 3] dioxol-4-ylmethoxy}-benzoic acid:; Adenosine (10 g, 37 mmol was dissolved in N, N-dimethyl formamide (100 mL) and dimethoxypropane (25 mL) followed by addition of Amberlyst 1 SH+ resin. The mixture was stirred 3h at 55C. The resin was removed by filtration and the solvents removed in vacuo, affording 2', 3'-di-O-isopropylidene adenosine (11 g, 95%). This product (6 g, 20 mmol) was dissolved in N, N-dimethyl formamide (22 mL) and stirred with triisopropylsilyl chloride and imidazole 16 h at 23C. The solution was partitioned between ether (200 mL) and brine (100 mL) and the ether phase washed with additional brine (2 x 50 mL). The ether was dried over magnesium sulfate and evaporated, affording 5'-O-triisopropylsilyl-2', 3'-di-O-isopropylidene adenosine. This residue was dissolved in toluene (20 mL) and treated with phenylisocyanate (3.6 g, 30 mmol) for 16 h at 25C. A solution of sodium bicarbonate (1 mL of 10 M) was added and the mixture evaporated to dryness. The residue was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness. The solid was dissolved in tetrahydrofuran (20 mL) and stirred with tetrabutyl ammonium fluoride in tetrahydrofuran (20 mL of a 1 M solution) for 1 h in a dry ice/acetone bath. Removal of the solvent in vacuo followed by washing with hexane afforded the 5'-alcohol (5.3 g). A portion of the above phenylurea product (0.41 g, 0.96 mmol) was suspended in 25 mL of 20% aqueous acetic acid and 5 mL of tetrahydrofuran/dioxane (1 : 1) and was stirred at 50C for 24 h. The white suspension became a clear yellow solution. The mixture was concentrated and then lyophilized, to give 0.360 g (97% yield) of 1- [9- (3, 4- dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-9H-purin-6-yl]-3-phenyl-urea as a yellow solid. MW calculated for C17Hl8N605 (MH 387, found 387 by LCMS. A small amount of 4A flame dried molecular sieves (cooled down by a flow of argon) wasadded to a vial containing a portion of the product immediately above (0. 131 g, 0.34 mmol). The mixture was capped with a rubber septum and cooled down to 0 C. To this mixture trifluoroacetic acid (2. 5mL) was added via syringe and the mixture stirred at this temperature for 15 min. Phenyl acetaldehyde dimethylacetal (0.230 ml, 4 eq. ) was added dropwise and the mixture stirred at 0 C for 2 h. One more equivalent of phenyl acetaldehyde dimethyl acetal was added and stirred an additional five hours. The volatiles were evaporated off and the residue was purified by flash chromatography (hexane: ethyl acetate, 8 : 2, 1% triethylamine) to give 0.095 g of product (60% yield) as a yellow solid. MW calculated for C2sH24N6Os (MH+) 489, found 489 by LCMS.. A portion of this acetal product (0.068 g, 0.14 mmol) was dissolved in dry N, N- dimethyl formamide (2.5 mL) and potassium tert-butoxide (0.084 g, 5 eq) was added to give a yellow solution. To this mixture was added <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (0.046 g, 1.8 eq). After 2.5 h of stirring at room temperature the mixture was concentrated and purified by preparative HPLC to give the nucleoside analog as a white powder. MW calculated for C32H27N709 (MH+) 654, found 654 by LCMS.. The nitro group of the product immediately above was reduced under a hydrogen atmosphere with a catalytic amount of 10% Pd/C in methanol during 6 h. Filtration through Celite followed by HPLC purification yielded 52 mg (62% yield) of the title compound as clear semisolid.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 22h;
Step A] 1-Benzyl-5-nitro-1,2-dihydro-indazol-3-one To a solution of 2-fluoro-5-nitrobenzoic acid (0.5 g) in DMF (9 mL) was added TBTU (1.04 g) followed by N-ethyldiisopropylamine (2.3 mL). After 10 minutes benzylhydrazine.2HCl (0.63 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-benzyl-5-nitro-1,2-dihydro-indazol-3-one (0.26 g) as a yellow solid. MS (ESI-):268.3 ([M-H]-).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 22h;
Step A] 1-Isobutyl-5-nitro-1,2-dihydro-indazol-3-one To a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.5 g) in DMF (50 mL) was added EDCI.HCl (1.71 g) followed by N-ethyldiisopropylamine (5.51 mL). After 10 minutes isobutylhydrazine.p-toluenesulfonicacid salt (2.32 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-isobutyl-5-nitro-1,2-dihydro-indazol-3-one (0.9 g) as a yellow solid. MS (ESI-):234.1 ([M-H]-).
With triethylamine; In N,N-dimethyl-formamide; at 20℃;
16A: 2-(Isopropylthio)-5-nitrobenzoic acid; [00266] Isopropylthiol (3.06 niL, 32.8 mmol) was added to a solution of 2- fluoro-5-nitrobenzoic acid (5.06 g, 27.3 mmol) and triethylamine (8.4 mL, 60.3 mmol) in DMF (86 mL). The reaction mixture was stirred overnight at rt and then most of the DMF was removed in vacuo. The residual solution was poured into ice water (500 mL) and the resulting yellow solid was isolated by filtration to give 16A (6.5 g, 100%).
74%
With caesium carbonate; In N,N-dimethyl acetamide; at 35℃; for 4h;
To a solution of 2.67 mmol 5-fluoro-2-nitro-benzoic acid (commercially available, e.g. from Aldrich) in 3 ml N,N-dimethylacetamide were added 8.58 mmol cesium carbonate and 5.83 mmol 2-propanethiol and the mixture was stirred at 35 C. for 4 h. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as an off-white solid which was used in the next step without further purification (yield 74%). MS (m/e): 240.3 ([M-H]-, 100%).
PREPARATION 13 2-Methylthio-5-(1H-tetrazol-1-yl)benzoic Acid Combine <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (prepared by the method of Tetrahedron, 23, 4041-4045 (1967)) (37 g, 20 mmol) and sodium thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux. After 24 hours, cool the reaction mixture, adjust the pH to about 2 using aqueous 1 M hydrochloric acid solution. Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid: Rf=0.5 (silica gel, 10% methanol/dichloromethane).
With hydrogenchloride; In methanol;
PREPARATION 13 2-Methylthio-5-(1H-tetrazol-1-yl)benzoic acid Combine <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (prepared by the method of Tetrahedron, 23, 4041-4045 (1967)) (3.7 g, 20 mmol) and sodium thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux. After 24 hours, cool the reaction mixture, adjust the pH to about 2 using aqueous 1 M hydrochloric acid solution. Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid: Rf=0.5 (silica gel, 10% methanol/dichloromethane).
With hydrogenchloride; In methanol;
Preparation 13 2-Methylthio-5-(1H-tetrazol-1-yl)benzoic Acid Combine <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (prepared by the method of Tetrahedron, 23, 4041-4045 (1967)) (3.7 g, 20 mmol) and sodium thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux. After 24 hours, cool the reaction mixture, adjust the pH to about 2 using aqueous 1 M hydrochloric acid solution. Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid: Rf=0.5 (silica gel, 10% methanol/dichloromethane).
With hydrogenchloride; In methanol;
PREPARATION 13 2-Methylthio-5-(1H-tetrazol-1-yl)benzoic Acid Combine <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (prepared by the method of Tetrahedron, 23, 4041-4045 (1967)) (3.7 g, 20 mmol) and sodium thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux. After 24 hours, cool the reaction mixture, adjust the pH to about 2 using aqueous 1 M hydrochloric acid solution. Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid: Rf=0.5 (silica gel, 10% methanol/dichloromethane).
With thionyl chloride; triethylamine; In N-methyl-acetamide; dichloromethane; ethyl acetate;
PREPARATION 55 To a suspension of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (313 mg) in dichloromethane (4 mL) were added thionyl chloride (0.17 mL) and dimethylformamide (0.05 mL), and the mixture was heated for 36 hours under reflux. After evaporation of the solvent, the residue was dissolved in dichloromethane (4 mL). To this solution were added benzylamine (0.19 mL) and triethylamine (0.47 mL), and the mixture was stirred for 30 minutes at 0 C. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed successively with diluted hydrochloric acid, an aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with diisopropyl ether to give N-benzyl-2-fluoro-5-nitrobenzamide (436 mg) as a solid substance. NMR (DMSO-d6, δ): 4.50 (2H, d, J=6 Hz), 7.22-7.40 (5H, m), 7.64 (1H, t, J=8 Hz), 8.38-8.47 (2H, m), 9.19(1H, t, J=6 Hz).
In tetrahydrofuran; N-methyl-acetamide; dichloromethane;
EXAMPLE 10 4-Fluoro-3-(5-methyl-benzooxazol-2-yl)-phenylamine To a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.0 g, 5.4 mmol) in tetrahydrofuran (20 ml) was added 10 drops of dimethylformamide followed by a 2M solution of oxalyl chloride in dichloromethane (3.2 ml). After stirring for 30 minutes, the mixture was consentrated under vacuum to give 2-fluoro-5-nitrobenzoyl chloride (100% yield).
N-(3-Chloro-4-fluorobenzyl)-2-fluoro-5-nitrobenzainide[ No CAS ]
[ 247567-34-6 ]
Yield
Reaction Conditions
Operation in experiment
PREPARATION 104 N-(3-Chloro-4-fluorobenzyl)-2-fluoro-5-nitrobenzainide (976 mg) was obtained as pale yellow powders from 2-fluoro-5-nitrobenzoic acid (1000 mg) and <strong>[72235-56-4]3-chloro-4-fluorobenzylamine</strong> (948 mg) in a manner similar to Preparation 55. NMR (DMSO-d6, delta): 4.49 (2H, d, J=6 Hz), 7.32-7.46 (2H, m), 5.57 (1H, d, J=8 Hz), 7.64 (1H, dd, J=9, 9 Hz), 8.37-8.53 (2H, m), 9.21 (1H, t, J=6 Hz); Mass m/z: 325(M+).
dmap; In tetrahydrofuran; tert-butyl alcohol; for 25h;
Reference Example 180 tert-Butyl 2-fluoro-5-nitrobenzoate [Show Image] N,N-dimethylaminopyridine (801 mg) and di-tert-butyl dicarbonate (9.54 g) were added to a suspension of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (4.04 g) in tetrahydrofuran (60 mL) and stirred for 11 hours. Then, tert-butanol (60 mL) was added thereto and stirred for 24 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate (500 mL) and the suspension was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (developing solvent: hexane/ethyl acetate = 20/1) to obtain the title compound (4.652 g) as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.77-8.75 (m, 1H), 8.39-8.35 (m, 1H), 7.31-7.27 (m, 1H), 1.53 (s, 9H).
N-(2-furanylmethyl)-2-fluoro-5-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.4 g (100%)
With hydrogenchloride; NMM; sodium hydrogencarbonate; benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In tetrahydrofuran;
35.1 Preparation of N-(2-furanylmethyl) 2-fluoro-5-nitrobenzamide To a 0.2 M solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.0 g, 5.4 mmol, Aldrich) in anhydrous THF at ambient temperature was added furfurylamine (1.1 g, 5.9 mmol), HBTU (2.24 g g, 5.9 mmol, Chem-Impex), HOBT (0.8 g, 5.9 mmol, Novabiochem) and NMM (0.59 mL, 5.4 mmol, Aldrich). The resulting solution was stirred for 18 hr. To the reaction mixture was added a 1 M solution of aqueous hydrochloric acid (30 mL). The crude mixture was extracted 3* with EtOAc (50 mL). The organic layers were combined, washed one time with a saturated aqueous solution of NaHCO3 (100 mL), one time with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to yield 1.4 g (100%) of product as an off white solid which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ9.11 (t, J=5.6 Hz, 1H), 8.45-8.35 (m, 2H), 7.67-7.55 (m, 2H), 6.41 (dd, J=3.28, 1.76 Hz, 1H), 6.37 (d, J=2.8 Hz, 1H), 4.5 (d, J=5.8 Hz, 2H). MS (EI): m/z 264 (15, M+), 263 (100, M-H). Anal. Calcd for C12H9FN2O4: C, 54.55; H, 3.43; N, 10.6. Found: C, 54.74; H, 3.54; N, 10.47.
Step A 5-Amino-2-fluoro-N-phenyl-benzamide Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (5.00 g, 27.01 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (5.0 mL, 54.88 mmol) to afford the pure product (5.76 g); m.p. 120-122 C. Calculated for C13H11N2OF: C, 67.82; H, 4.82; N, 12.17. Found: C, 67.59; H, 4.80; N, 12.08.
EXAMPLE 11A To a solution of 2-fluoro-5-nitro-benzoic acid (0.74 g) and 5-chloro-2,4-dimethoxy-phenylamine (0.75 g) in THF (30 mL) at 0-5 C. was added 1M LiHMDS in THF (12 mL). The solution was stirred for 18 hours at ambient temperature, quenched with 2M HCl (20 mL) and extracted with diethyl ether. The extract was dried (MgSO4), filtered and concentrated. The concentrate was treated with ethanol/hexanes and filtered.
With triethylamine; In dichloromethane; acetonitrile;
Example 11 Preparation of 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoic acid A mixture of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.85 g, 0.01 mol), 4-[4-(3,4-dichlorophenyl)butyl]-phenylamine (2.94 g, 0.01 mol) and Et3N (2.80 mL) in acetonitrile (110 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and concentrated in vacuo to remove the solvent. The residue was dissolved in CH2Cl2 and washed with diluted HCl. The organic layer was dried (Na2SO4), concentrated in vacuo to give a crude solid. Purification by flash chromatography (silica gel, CH2Cl2) yielded 1.40 g (0.003 mol, 30%) of the desired product. Analysis for C23H19N2O4Cl2: Calcd: C, 60.27; H, 4.18; N, 6.11; Cl, 14.47. Found: C, 60.16; H, 4.41; N, 6.09; Cl, 15.69.
394A-Preparation of (2-fluoro-5-nitro-phenyl)-methanol To a solution of 2-fluoro-5-nitro-benzoic acid (2.9 g, 15.7 mmol) in THF (20 ml) was slowly added 1M BH3.THF (30 ml, 30 mmol) at 0 C. The reaction mixture was stirred at rt overnight, quenched carefully with MeOH until no H2 evolution, evaporated and redissolved in MeOH, evaporated again to give 394A (2.7g, 100%) as a yellow solid.
In a 250 ml round bottom flask DMF (10 eq.), tryptamine (1 eq.), 2-carboxy-4-nitrofluorobenzene (1 eq.) were added and stirred for 10 min. Then potassium carbonate (2.5 eq.) was added at room temperature. The stirring was continued for 2 hrs. TLC was monitored. The reaction mixture was poured into ice water, neutralized with acetic acid to pH=5 and stirred for 15 min. The resultant solid was filtered and washed with water. The crude material was crystallized from toluene. The yield was 50%.NMR: (CDCl3) δ 3.1 (t, 2H, CH2), 3.6 (t, 2H, CH2NH), 6.7 (d, 1H, 5'-H), 7.0 (m, 3H, 2-H, 5-H, 6-H), 7.4 (d, 1H, 7-H), 7.5 (d, 1H, 4-H), 8.1 (d, 1H, 4'-H), 8.8 (d, 1H, 3'-H), 8.9 (bs, 1H, NH), 10.4 (s, 1H, NH).
In a 250 ml round bottom flask DMF (10 eq.), 5-methoxytryptamine (1 eq.), 2-carboxy-4-nitrofluorobenzene (1 eq.) were added and stirred for 10 min. Then potassium carbonate (2.5 eq.) was added at room temperature. The stirring continued for 2 hrs. TLC was monitored. The reaction mixture was poured into ice water, neutralized with acetic acid to pH=5 and stirred for 15 min. The resultant solid was filtered and washed with water. The crude material was crystallized from toluene. The yield was 40%.NMR: (CDCl3) δ 3.1 (t, 2H, CH2), 3.6 (t, 2H, NH), 3.8 (s, 3H, OCH3), 6.6 (m, 2H, 4-H, 5'-H), 6.7 (m, 5H, Ar-H), 8.1 (d, 1H, 5-H), 8.7 (d, 1H, 3'-H), 8.9 (bs, 1H, NH), 10.5 (s, 1H, NH).
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; water; under 1551.49 Torr; for 0.5h;
A solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (5.0 g) in MeOH (100 mL) and 6 N HCl (15 mL) was shaken with 0.15 g of 10% Pd/C under 30 psi H2 for 30 min. The catalyst was removed by filtration, and the filtrate was evaporated. The residue was crystallized from 6N HCl to provide the product. 1H-NMR (D2O): δ 7.82 (1H, dd, J=2.8, 6.0 Hz), 7.55 (1H, ddd, J=2.8, 4.0, 8.9 Hz), 7.27 (1H, dd, J=8.9, 14.0 Hz). 13C-NMR (D2O): δ 166.5 (d, JCF=2 Hz), 161.3 (d, JCF=260 Hz), 129.7 (d, JCF=10 Hz), 126.6, 126.0 (d, JCF=3 Hz), 120.0 (d, JCF=11 Hz), 118.9 (d, JCF=25 Hz).
A portion of this acetal product (0.068 g, 0.14 mmol) was dissolved in dry N, N- dimethyl formamide (2.5 mL) and potassium tert-butoxide (0.084 g, 5 eq) was added to give a yellow solution. To this mixture was added <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (0.046 g, 1.8 eq). After 2.5 h of stirring at room temperature the mixture was concentrated and purified by preparative HPLC to give the nucleoside analog as a white powder. MW calculated for C32H27N709 (MH+) 654, found 654 by LCMS..
Step 1 2-Fluoro-5-iodo-3-nitro-benzoic Acid; To a room temperature solution of 12 (3.84 g, 15.1 mmol) in fuming sulfuric acid (20 mL) was added 2-fluoro-5-nitro-benzoic acid (2.0 g, 10.8 mmol). The reaction mixture was slowly heated to 85 C. and stirred for 12 hours, then cooled to room temperature and poured onto ice. The aqueous mixture was extracted with methylene chloride, and the combined organic layers were washed with saturated aqueous Na2S2O3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3.2 g (95%) of 2-fluoro-5-iodo-3-nitro-benzoic acid
Step D2: Preparation of 2-[2-(3-Chloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-nitro-benzoic acid To the 2-(3-chloro-phenyl)-2,3-dihydro-1H-isoindol-1H-ylamine from Example 7, Step C (2 g, 0.008 mol) in THF (100 ML), LHDMS (24.51 ML, 1 M in THF, 24.15 mmol) was added dropwise at -78C and was allowed to stir for 10 minutes at -78C. 2-Fluouro-5-nitro-benzoic acid (1.51 g, 0.008 mol) in THF (100 ML) was added dropwise and the solution stirred for 1 hour at -78C and gradually warmed to room temperature and stirred for 16 hours.. The reaction was concentrated and acidified with 3 M HCl (100 ML).. The resultant solid was filtered and washed with 10% HCl and then dried under vacuum to yield a brown solid.. The product was recrystallized using MeOH and water to give a brown solid, 0.250 g (0.0006 mmol, 7.5%) of the desired product mp: Color change at 130C, did not melt >260C. Analysis of C21H16N3O4C1·0.24 mol H2O: C, 60.90; H, 4.01; N, 10.15. Found: C, 60.91, H, 4.01; N, 9.75
2-Fluoro-5-nitrobenzoic acid 194.5 mg (1.05 mmol) and TFFH 264 mg (1.00 mmol) were dissolved in anhydrous acetonitrile (4 ml_) and DIEA (0.40 mL, 2.28 mmol) was then added. The mixture was stirred for 20 minutes and 4-(p-fluorophenoxy)-piperidine 137 mg (0.70 mmol) was added (as a solid). After stirring for 3 hours 15 minutes 0.5 M sodium carbonate solution (10 mL) was added and stirring continued for Vt hour. The mixture was diluted with water (50 mL) and extracted twice with ether (2 x 70 mL). The combined organic extracts were washed with saturated NaHCU3 (60 mL), combined, dried (MgSO4) and evaporated. The residue was purified on a column of silica (40 g) in hexane-ethyl acetate gradient 0-50% EtOAc. The nitro-substituted intermediate 210 mg (83%Y) was obtained as a pale yellow glassy solid. This intermediate 210 mg (0.579 mmol) was dissolved in a mixture of ethanol (99%, 15 mL) and acetic acid (1 mL), SnCI2«2H2O 0.80 g (3.5 mmol) was added and the mixture was refluxed under Ar in an oil bath (900C) for 1 hour. The mixture was cooled, 1M NaOH (150 mL) and dichloromethane (20 mL) were added and the mixture was stirred vigorously for 45 minutes. The mixture was extracted twice with dichloromethane (2 x 150 mL). The organic <n="34"/>extracts were washed with 1M NaOH (150 ml_) and saturated NaCI (150 mL). The combined organic extracts were dried (MgSO4) and evaporated. The obtained crude amino-substituted intermediate 200 mg (104%Y from the nitro- derivative) was used without purification for the next step.
(a) 2-(2,2-Difluoro-ethoxy)-5-nitro-benzoic acid2,2-Difluorethanol (0,376 ml 5,94 mmol) was dissolved in THF (15 ml_), KOtBu (0,702 g; 5,94 mmol) was added and it was stirred for 5 min. 2-Fluor-5-nitro-benzoic acid (1 .0 g; 5,4 mmol) was added and additional KOtBu (0.5 g and 0.2 g) was added after 2h and 5 h.Additional 2-fluor-5-nitro-benzoic acid (50μΙ_) was added and it was stirred over night. The solvent was removed i.vac. and the residue was diluted with water, acidified with 2M aq. HCI- solution, extracted with EtOAc, dried over Na2S04 and concentrated i. vac.Yield: 1 ,2 g (95%); MS [M-HV = 246; TLC: (silica gel; DCM/EtOH 9/1 ) Rf = 0,4 90
95%
2,2-Difluoroethanol (0.376 mL; 5.94 mmol) was dissolved in THF (15 mL), KOtBu (0.702 g; 5.94 mmol) was added and it was stirred for 5 min. 2-Fluor-5-nitro-benzoic acid (1.0 g; 5.4 mmol) was added and additional KOtBu (0.5 g and 0.2 g) was added after 2 h and 5 h. Additional 2-fluor-5-nitro-benzoic acid (50 μL) was added and it was stirred over night. The solvent was removed i.vac. and the residue was diluted with water, acidified with 2M aq. HCl-solution, extracted with EtOAc, dried over Na2SO4 and concentrated i. vac.Yield: 1.2 g (95%); MS [M-H]-=246; TLC: (silica gel; DCM/EtOH 9/1) Rf=0.4
In N,N-dimethyl-formamide; at 100℃; for 0.5h;Microwave irradiation;
Step 6.1 5-nitro-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid A mixture of 5.1 g of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> and 6.21 g of tetrahydro-2H-pyran-4-amine in 5 ml of DMF is irradiated in a microwave field for 15 minutes at 100 C. The mixture is irradiated a second time for 15 minutes at 100 C. The same reaction is repeated on identical amounts of reagents. All the reaction mixtures are pooled and the solvent is evaporated off under reduced pressure. The residue is recrystallized from EtOAc to give 6 g of expected product.
A stirred solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> 125 (15.0 g, 81.08 mmol) in SOCI2 (160 mL) and D F (3 drops) was heated under reflux for 4h. The excess SOCI2 was removed by distillation under reduced pressure and the residue was dissolved in THF (100 mL), cooled to -10 C and treated with ethanolamine (8.53 mL, 141.81 mmol) and warm to the room temperature for 30 min. The solvent was evaporated and the residue was dissolved in EtOAc, washed with water (3x) and brine, dried with Na2S04 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/Hexane (2:1) to give 2- fluoro-W-(2-hydroxyethyl)-5-nitrobenzamide 136 (17.0 g, 92%) as a colorless gum. 1HN R [(CD3)2SO] δ 8.58 (br, 1H), 8.46-8.44 (m, 1H), 8.41-8.31 (m, 1H), 7.60 (t, J = 9.3 Hz, 1H), 4.79 (t, J = 5.6 Hz, 1H), 3.55-3.50 (m, 2H), 3.35-3.32 (m, 2H).
A stirred solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> 125 (4.56 g, 24.63 mmol) in SOCI2 (50 mL) and DMF (3 drops) was heated under reflux for 4h. The excess SOCI2 was removed by distillation under reduced pressure and the residue was dissolved in THF (30 mL), cooled to -10 C and treated with 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanamine (3.93 g, 27.10 mmol) and warm to the room temperature for 30 min. The solvent was evaporated and the residue was dissolved in EtOAc, washed with water (3x) and brine, dried with Na2S04 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc/Hexane (1:1) to give 2-fluoro-5-nitro-W-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl) benzamide 126 (3.17 g, 41%) as a colorless oil. 1HNMR [(CD3)2SO] δ 8.67 (br, 1H), 8.42-8.38 (m, 2H), 7.64-7.59 (m, 1H), 4.62 (t, J = 3.5 Hz, 1H), 3.55-3.41 (m, 5H), 1.79-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.53-1.41 (m, 5H). HRMS(ESI) calcd for C14H17FN2Na05 [M+Na]+ m/z 335.1014: found 335.1014.
41%
A stirred solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> 1 (Matrix Scientific, USA) (4.56 g, 24.63 mmol) in SOCl2 (Scharlau Chemicals, Spain) (50 mL) and DMF (Acros Organics, USA) (3 drops) was heated under reflux for 4 h. Excess SOCl2 was removed by distillation under reduced pressure and the residue was dissolved in THF (Acros Organics, USA) (30 mL), cooled to -10 C and treated with 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanamine (Sigma Aldrich, Germany) (3.93 g, 27.10 mmol) then warmed to room temperature for 30 min. The solvent was evaporated and the residue dissolved in EtOAc (Macron Fine Chemicals, USA), washed with water (3×) and brine, dried with Na2SO4 (Scharlau Chemicals, Spain) and concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with EtOAc/Hexane (1:1) (Macron Fine Chemicals, USA) to give the amide 2 (3.17 g, 41%) as a colorless oil. 1H NMR [(CD3)2SO] δ 8.67 (br, 1H), 8.42-8.38 (m, 2H), 7.64-7.59 (m, 1H), 4.62 (t, J = 3.5 Hz, 1H), 3.55-3.41 (m, 5H), 1.79-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.53-1.41 (m, 5H). HRMS(ESI) calcd for C14H17FN2NaO5 [M+Na]+ m/z 335.1014: found 335.1014.
1-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl)-2-fluoro-5-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
Step 1: A solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.85 g, 10 mmol, 1.33 equiv) in thionyl chloride (5 mL) was refluxed for 2 h and evaporated. The residue was redissolved in 20 mL of methylene chloride and to the solution were added 4-[(2-t-butylaminosulfonyl)phenyl]aniline (2.0 g, 1.0 equiv) and 5 mL of pyridine. After stirring at rt overnight, the volatile was evaporated. Flash chromatography on silica gel 1-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl)-2-fluoro-5-nitrobenzene (2.9 g, 99%). MS found for C23H23FN3O5S (M+H)+: 472.
5-nitro-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With caesium carbonate; In 1,4-dioxane; at 110℃; for 3.5h;Inert atmosphere;
To a solution of 2- fluoro-5-nitrobenzoic acid (1.0 g, 5.4 mmol) in dioxane (20 mL) was added 1,1,1- trifluoropropan-2-ol (1.84 g, 16.2 mmol), and cesium carbonate (4.4 g, 13.5 mmol). The mixture was heated to 110 C for 3.5 h. The crude mixture was poured into 1M HC1 (100mL) and was stirred for 20-30 mm. The mixture was filtered to afford the title compound(0.89 g, 59%): 1H NMR (400MHz, DMSO-d6) = 13.42 (s, 1H), 8.45 (d, J = 3.1 Hz, 1H),8.38 (dd, J = 2.9, 9.2 Hz, 1H), 7.56 (d, J = 9.4 Hz, 1H), 5.56 (td, J = 6.4, 12.6 Hz, 1H), 1.45(d, J = 6.3 Hz, 3H).
2-Fluoro-5-nitrobenzoic acid (200 tmol) andTI3TU (200 tmol) in NMP (1.5 mE) were treated with DIPEA (400 tmol) for 2 mm. Subsequently, the mixture was added to the NMP-swollen resin and the mixture was agitated for 25 mm prior to washing the resin as described before. Afier adding THF (2 mE), methanol (1 mE) and aqueous NaOH (2 M, 1 mE), the resin was agitated for three days, followed by thorough washing with methanol and dichloromethane.
2-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)phenol[ No CAS ]
2-(2-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)phenoxy)-5-nitrobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8.3 g
With potassium carbonate; In N,N-dimethyl acetamide; at 140 - 150℃; for 9.5h;
Potassium carbonate (4.8 g) and <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (3.1 g) were added to a solution of 2-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)phenol (5.4 g) obtained in Reference Example 9-1 (1) in N,N-dimethyl acetamide (30 mL), followed by stirring at 140 C. for 5.5 hours. 2-Fluoro-5-nitrobenzoic acid (260 mg) was further added thereto, followed by stirring at 150 C. for 4 hours. After the reaction mixture was cooled to room temperature, water was added thereto, then, the pH of the resultant product was adjusted to 3.5 with 6 mol/L hydrochloric acid, and the precipitated solid was collected by filtration, whereby 2-(2-(6-((4-methoxybenzyl)oxy)-4-morpholinopyridin-2-yl)phenoxy)-5-nitrobenzoic acid (8.3 g) was obtained as a white solid
With potassium carbonate; In N,N-dimethyl acetamide; at 90 - 100℃; for 6h;
Potassium carbonate (3.5 g) and 2-bromophenol (1.0 g) were added to a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.0 g) in N,N-dimethyl acetamide (20 mL), and the resultant product was stirred at 90 C. for 5 hours, and further stirred at 100 C. for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate was added thereto, and the resultant product was washed sequentially with 1 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residues were purified by silica gel column chromatography (methanol:ethyl acetate=0:1→1:4), whereby 2-(2-bromophenoxy)-5-nitrobenzoic acid (1.8 g) was obtained as a brown solid
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;
To a solution of <strong>[7304-32-7]2-fluoro-5-nitrobenzoic acid</strong> (1.0 g, 5.40 mmol) in dichloromethane (20 mL) were added HATU (2.05 g, 5.40 mmol), methylamine hydrochloride (400 mg, 5.94 mmol) and triethylamine (1.63 g, 16.2 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (20 mL), washed with water and brine, dried over sodium sulfate and concentrated to dryness under reduced pressure to give 2-fluoro-/V- methyl-5-nitrobenzamide (1.0 g, 93%) as a yellow solid. LCMS (method B): 2.07 min [MH]+ = 199.0.
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