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Product Details of [ 29632-74-4 ]

CAS No. :29632-74-4 MDL No. :MFCD00011738
Formula : C6H5FIN Boiling Point : -
Linear Structure Formula :- InChI Key :CUMTUBVTKOYYOU-UHFFFAOYSA-N
M.W : 237.01 Pubchem ID :185694
Synonyms :

Calculated chemistry of [ 29632-74-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.52
TPSA : 26.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : 1.99
Log Po/w (WLOGP) : 2.44
Log Po/w (MLOGP) : 2.84
Log Po/w (SILICOS-IT) : 2.53
Consensus Log Po/w : 2.3

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.06
Solubility : 0.208 mg/ml ; 0.000878 mol/l
Class : Soluble
Log S (Ali) : -2.16
Solubility : 1.63 mg/ml ; 0.00688 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.27
Solubility : 0.126 mg/ml ; 0.000532 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.98

Safety of [ 29632-74-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 29632-74-4 ]

* 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.

  • Upstream synthesis route of [ 29632-74-4 ]
  • Downstream synthetic route of [ 29632-74-4 ]

[ 29632-74-4 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 348-54-9 ]
  • [ 29632-74-4 ]
YieldReaction ConditionsOperation in experiment
56% With iodine; sodium hydrogencarbonate In water at 60℃; for 3 h; 2-Fluoroaniline (54 g, 486 MMOL) was added to a vigorously stirred solution of sodium bicarbonate (41 g, 486 MMOL) in water (250 mL). The suspension was warmed to 60 °C on an oil bath and iodine (123 g, 486 MMOL) was added portion-wise. After complete addition, the dark mixture was stirred for an additional 3 h at 60 °C. After cooling to rt, methylene chloride (300 mL) was added followed by saturated HYDROGENSULFITE solution (300 mL). The biphasic system was vigorously stirred for an additional 10 min. The mixture was poured into a 2 L separatory funnel and the organic layer was released. The aqueous was further extracted with methylene chloride (3 x 200 mL) and the combined organics were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to give a black crystalline solid. Hexane (300 mL) was added and the mixture was heated to reflux. The hexane was decanted from a black, insoluble syrup. The product crystallized from the hexane on cooling as fine yellow needles. 65 g (274 MMOL) was isolated as a fine yellow solid. Yield : 56percent; mp 53 °C ; 1H NMR (400 MHz, CDCI3) 6 8.1 (t, J = 8 Hz, 1 H), 7.4 (d, J = 6 Hz, 1 H), 7.2 (d, J = 6 HZ, 1 H).
Reference: [1] Journal of the Chemical Society. Perkin Transactions 2, 1999, # 3, p. 481 - 491
[2] Arzneimittel-Forschung/Drug Research, 1984, vol. 34, # 11 A, p. 1612 - 1624
[3] Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2870 - 2873
[4] Patent: WO2004/41793, 2004, A1, . Location in patent: Page 141
[5] Chemical Communications, 2014, vol. 50, # 17, p. 2136 - 2138
[6] Patent: WO2016/206101, 2016, A1, . Location in patent: Page/Page column 46
  • 2
  • [ 29632-74-4 ]
  • [ 544-92-3 ]
  • [ 63069-50-1 ]
YieldReaction ConditionsOperation in experiment
84% at 130℃; for 8 h; Example 20: 2-[4-(fe/t-butyl)-phenoxy]-/V-(3-cyano-5-fluoro-4- methanesulfonylamino)benzylacetamideStep 1 : 4-Amino~3-fluorobenzenecarbonitrile; 2-Fluoro-2-iodoaniiine (2.Og, 8.4mmol) and coppercyanide (982mg, 11.0mmol, 1.5eq) were added into DMF (30ml). And the reaction mixture was heated to 130°C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H2O (2 times) and brine, and then dried with MgSO4. The resulting residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84percent). <n="84"/>1H NMR (300 MHz, CDCI3): 7.21-7.26 (m, 2H), 6.74 (t, 1H, J = 8.3 Hz), 4.20 (bs, 2H); Example 43: 2-[4-(fert-butyl)phenoxy]-/V-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)-thioacetamidestep 1 : 4-amino-3-fluorobenzenecarbonitrile2-Fluoro-2-iodoaniline (2.Og, 8.4mmol) and coppercyanide(982mg, H .Ommol, 1.5eq) were added to DMF(30ml). A reaction mixture was heated to 13O0C, stirred for 8hrs. The reaction mixture was diluted with ethyl acetate. A diluted solution was washed with H2O (2 times) and brine, and then dried with MgSO4. A residue was purified with column chromatography (n-Hexane: EtOAc =3 : 1) to yield solid (914mg, 84percent). 1H NMR(300MHz, CDCI3): 7.21-7.26 (m, 2H), 6.74 (t, 1 H, J = 8.3 Hz), 4.20 (bs, 2H)
Reference: [1] Patent: WO2007/120012, 2007, A1, . Location in patent: Page/Page column 82-83; 129
[2] Patent: WO2006/63113, 2006, A2, . Location in patent: Page/Page column 68-69
  • 3
  • [ 29632-74-4 ]
  • [ 557-21-1 ]
  • [ 63069-50-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5823 - 5836
  • 4
  • [ 29632-74-4 ]
  • [ 63069-50-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 10, p. 3557 - 3567
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 24, p. 8149 - 8160
  • 5
  • [ 29632-74-4 ]
  • [ 458-52-6 ]
Reference: [1] Organic Syntheses, 2002, vol. 78, p. 63 - 63
  • 6
  • [ 29632-74-4 ]
  • [ 136434-77-0 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 2, 1999, # 3, p. 481 - 491
[2] Patent: US5437815, 1995, A,
[3] Chemical Communications, 2014, vol. 50, # 17, p. 2136 - 2138
[4] Patent: WO2016/206101, 2016, A1, . Location in patent: Page/Page column 46; 47
  • 7
  • [ 29632-74-4 ]
  • [ 136434-77-0 ]
Reference: [1] Patent: US5356558, 1994, A,
  • 8
  • [ 29632-74-4 ]
  • [ 137553-42-5 ]
Reference: [1] Patent: US5314640, 1994, A,
[2] Patent: US5314640, 1994, A,
[3] Patent: US5314640, 1994, A,
  • 9
  • [ 29632-74-4 ]
  • [ 151-50-8 ]
  • [ 137553-42-5 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364
  • 10
  • [ 111-34-2 ]
  • [ 29632-74-4 ]
  • [ 73792-22-0 ]
YieldReaction ConditionsOperation in experiment
35% for 15 h; Heating / reflux Example 7: (R)-N-(4-{1 -[3-(4-tert-Butyl-benzyl)-ureido]-ethyl}-2-fluoro-6-vinyl- phenyl)-methanesulfonamide; Step i: 1-(4-Amino-3-fluorophenyl)ethanoneA 25 ml two neck round-bottom flask was filled with Ar gas and the solution of 2-fluoro-4-iodophenylamine (1500mg, 6.33mmol) in DMF, palladium ( II ) acetate (0.19mmol, 42.62mg), 1 ,3-bisdiphenyl phosphinopropane (0.06eq, 0.38mmol, 156.65mg), Thallium( I )acetate (6.96mmol, 1834.19mg), butyl vinyl ether(2eq, 12.66mmol, 1.64ml) were put into the flask. The reaction mixture was heated and stirred for 15hr. The reaction mixture was poured into the THF soulution, and then 10percent HCI was added slowly. The reaction mixture was extracted with ethyl acetate (300*3), EPO <DP n="85"/>washed with H2O and brine. The combined organic solution was dried with Na2SO4 and then purified with column chromatography (n-Hx: EA= 3: 1) to yield a pale yellow solid (343.0mg, 35.40percent).mp: 77-790C;IR (KBr pellet, cm"1): 3373, 3326, 1663, 1296; 1H NMR(400MHz, CDCI3): δ 7.53(m, 2H), 6.69(m, 1 H), 3.41 (s, 2H), 2.43(s, 3H).
35.4% With thallium(I) acetate In N,N-dimethyl-formamide for 15 h; Heating A 25 ml of two neck round-bottom flask was filled with argon gas and the solution of 2-Fluoro-4-iodophenylamine (1500mg, 6.33mmol) in DMF, Palladium(Π) acetate (0.19mmol, 42.62mg), 1,3-bisdiphenyl phosphinopropane(0.06eq, 0.38mmol, 156.65mg), Thallium( l )acetate (6.96mmol, 1834.19mg), and Butyl vinyl ether(2eq, 12.66mmol, 1.64ml) were put into the flask. The reaction mixture was heated and stirred for 15hrs. The reaction mixture was poured into the THF solution, and then 10percent HCl was added slowly. The reaction mixture was extracted with ethyl acetate(300.x.3), washed with H2O, and brine. The combined organic solution was dried over Na2SO4 and then purified with column chromatography (n-Hx: EA= 3: 1) to yield a pale yellow solid (343.0mg, 35.40percent). Mp:77~79°C; IR(KBr pellet, cm-1): 3373, 3326, 1663, 1296; 1H NMR(400MHz, CDCl3): δ 7.53(?, 2H), 6.69(?, 1H), 3.41(s, 2H), 2.43(s, 3H).
Reference: [1] Patent: WO2006/101318, 2006, A1, . Location in patent: Page/Page column 44; 83-84
[2] Patent: EP1862454, 2007, A1, . Location in patent: Page/Page column 6; 18
  • 11
  • [ 29632-74-4 ]
  • [ 73792-22-0 ]
Reference: [1] Arzneimittel-Forschung/Drug Research, 1984, vol. 34, # 11 A, p. 1612 - 1624
  • 12
  • [ 29632-74-4 ]
  • [ 147808-02-4 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 39, p. 5497 - 5500
  • 13
  • [ 29632-74-4 ]
  • [ 73183-34-3 ]
  • [ 819058-34-9 ]
YieldReaction ConditionsOperation in experiment
75% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 85℃; for 4.5 h; Inert atmosphere 2.1: 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
5.0 g (21.1 mmol) of 2-fluoro-4-iodoaniline and 5.89 g (23.2 mmol) of bis(pinacolato)diborane are dissolved in 130 ml of DMSO. 6.21 g (63.3 mmol) of potassium actetate are added and argon is bubbled through for 10 min. 1.21 g (1.50 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane (1:1), is added and the mixture is heated at 85° C. for 4.5 hours, under argon, and then cooled and diluted with 500 ml of water.
The mixture is extracted with ethyl acetate (3*200 ml), the organic phases are washed with water, dried over Na2SO4 and then evaporated to dryness.
The crude product is purified by chromatography on silica (eluent: cyclohexane/ethyl acetate 90/10).
3.73 g of product are obtained in the form of a white powder. Yield=75percent.
Melting point: 112° C.
1H NMR (400 MHz; CDCl3): δ (ppm): 1.2 (s; 12H); 3.8 (br s; 2H); 6.55 (t; 1H; 7 Hz); 7.25-7.35 (m; 2H).
Reference: [1] Patent: US2013/178472, 2013, A1, . Location in patent: Paragraph 0239; 0240
[2] Patent: WO2008/32086, 2008, A1, . Location in patent: Page/Page column 110
[3] Patent: WO2006/113432, 2006, A2, . Location in patent: Page/Page column 66
[4] Patent: WO2008/32086, 2008, A1, . Location in patent: Page/Page column 110
  • 14
  • [ 29632-74-4 ]
  • [ 25015-63-8 ]
  • [ 819058-34-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
  • 15
  • [ 29632-74-4 ]
  • [ 61079-72-9 ]
  • [ 391211-97-5 ]
YieldReaction ConditionsOperation in experiment
99% With lithium amide In tetrahydrofuran A solution of 2,3,4-uorobenzoic acid (1.35 g, 7.68 mmol), 2-uoro-4-iodoaniline (1.91 g, 8.06 mmol), and lithium amide (0.702 g,30.6 mmol) in tetrahydrofuran (10.5 ml) was reacted using a standardmethod (Cai et al., 2008) to give 3,4-diuoro-2-((2-uoro-4-iodo-phenyl)amino)benzoic acid (A 2A R PAM-1, 2.99 g, 99percent) as a brown solid(Figure S1); IR (KBr) 3311, 1673, 1602, 1520, 1500, 1444, 1273,768 cm−1;1H NMR (400 MHz CD 3 OD) δ = 7.89 (1 H, ddd, J = 2.3, 6.0,9.2 Hz), 7.48 (1 H, dd, J = 1.8, 10.5 Hz), 7.41 (1 H, ddd, J = 1.4, 1.8,8.5 Hz), 6.91 (1 H, ddd, J = 7.3, 9.4, 9.4 Hz), 6.75 (1 H, ddd, J = 5.6,8.5, 8.5 Hz);13C NMR (100 MHz acetone-d 6 ) δ = 169.9, 155.7 (dd,J C,F = 252.1, 4.8 Hz), 155.6 (d, J C,F = 252.1 Hz), 143.6 (dd,J C,F = 247.8, 14.9 Hz), 137.4 (dd, J C,F = 7.7, 2.9 Hz), 135.0 (d,J C,F = 3.8 Hz), 131.9(d, J C,F = 11.5 Hz), 129.8 (dd, J C,F = 9.6, 3.8 Hz),125.8 (d, J C,F = 21.0 Hz), 123.8 (d, J C,F = 5.8 Hz), 116.4, 110.1 (d,J C,F = 18.2 Hz), 84.7 (d, J C,F = 6.7 Hz); HRMS-ESI: m/z [M-H]-calcdfor C13H6F3INO2, 391.9395; measured, 391.9414.
80% With lithium amide In tetrahydrofuran at 45 - 55℃; for 1.25 - 2.5 h; Example 2.
Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9)
A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog No. 30,660-6) and 2,3,4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat No. 33,382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5percent) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55°C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25°C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50percent sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50°C, stirred, and added with 25 mL warm (40-50°C) water and cooled to 25-30°C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5°C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55°C. Overall chemical yield was 21.4 g, 80percent. EPO <DP n="15"/>1H NMR (400 MHz, (CD3)2SO): δ 13.74 (bs, 1H), 9.15 (m, 1 H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 7.10 (q, 1H), 6.81 (m, 1H).
78%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78 - -67℃; for 0.5 h;
Stage #2: With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78 - 20℃;
TO a stirred suspension of 2,3, 4-trifluorobenzoic acid (78g, 0.44 moles) in dry THE (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained BELOW-67C. A dark orange solution was formed and this was stirred for another 20 minutes AT-67C. The mixture was designated as Solution A. To a stirred solution of 2-fluoro-4-iodoaniline (105g, 0.44 moles, Aldrich) in dry THF (1.25 L) under nitrogen at-78C was added LIHMDS (450 ML, 1 M solution in THF/hexanes) dropwise at such a rate that he temperature was maintained below- 67C. The dark brown suspension was stirred for an additional 30 minutes at- 67C. The mixture was designated as Solution B. Solution A was transferred to solution B via a cannula under positive nitrogen pressure at-65C at such a rate to keep the temperature BELOW-55C. Then the mixture was slowly warmed to RT and stirred overnight. The reaction mixture was quenched with dry HC1 in diethyl ether (1.5 L, freshly prepared, PH-1-2. The solution was filtered through a layer of Celite. The filtrate was washed with aq. HC1 (2M, 2XLL), brine and dried. Solvent was removed under reduced pressure to give a solid, which was suspended in hexanes-acetone (9: 1, v/v, 150 mL) and stirred for 30 minutes. 3,4- dufluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid was obtained by filtration as a white solid (135g, 78percent, mp. 195-197C).
72% With lithium amide In acetonitrile for 0.75 h; Heating / reflux Example 2B.
Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide method
To a stirring solution of 2,3,4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N2 atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH2CI2 (30 mL) for 1h, filtered and dried in a vacuum oven at 45°C for 14 hours to give 8.Og (72percent) of compound (9) as an off-white solid, mp 201.5-203 °C.
53% With lithium amide In tetrahydrofuran at 0 - 58℃; for 12 h; Cooling with liquid nitrogen 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (SC-1-148 Acid) [0020] A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (73; 2.38 g, 10.05 mmol), 2,3,4-trifluorobenzoic acid, (74; 1.8 g, 10.225 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0° C. and LiNH2 (561.2 mg, 24.45 mmol) was added in portions 3 portions over 10 min. The reaction was then warmed to 58° C. and stirred for 12 h. 1 N HCl was then added to the reaction mixture at 0° C. to obtain a final pH of 1.0 (red to pHydrion paper). The reaction mixture was extracted three times with 10 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat) and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using hexane/EA and provided 2.11 g (53percent) of a white solid. mp: 199.0-200.1° C. (lit: 200-201° C.). SiO2 TLC Rf 0.51 (2:1 hexane/EA). 1H NMR (MeOD-d4): δ 7.86 (m, 1 H), 7.46 (d, J=1.6 Hz, 1 H), 7.38 (d, J=1.6 Hz, 1 H), 7.18 (m, 1 H, OH), 6.86 (m, 1 H), 6.72 (m, 1 H), 2.31 (m, 1 H, NH). Anal Calcd for C13H7F3INO2: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.
53% With lithium amide In tetrahydrofuran at 0 - 58℃; Inert atmosphere A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (38; 2.38 g, 10.0 mmol), 2,3,4-trifluorobenzoic acid, (37; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 °C and LiNH2 (561.2 mg, 24.45 mmol) was added in 3 portions over 10 min. The reaction was then warmed to an internal temperature of 58 °C and stirred for 12 h. The mixture was cooled to 0 °C and 1 N HC1 was added maintaining the reaction mixture at 0 °C to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et20, washed three times with 5 mL portions of 1 N HC1, washed with NaCl (aq, sat), and dried over Na2S04. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on Si02 using 2: 1 hexane/EA to provide 2.11 g (53percent) of a white solid. MP = 199.0 - 200.1 °C (lit. MP = 200 - 201 °C). Si02 TLC Rf 0.51 (2: 1 hexane/EA). 1H NMR (400 MHz, MeOD-d4): δ 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, = 1.8 Hz and J2 = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for Ci3H7F3IN02: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.
53% With lithium amide In tetrahydrofuran at 0 - 58℃; for 12.5 h; A 250 mL round bottom flask was charged with 2-fluoro-4-iodoaniline, (26; 2.38 g, 10.0 mmol), 2,3,4-trifluorobenzoic acid, (25; 1.80 g, 10.2 mmol), and 30 mL of anhydrous THF. The reaction mixture was cooled with an ice-bath to 0 oC and LiNH2 (561.2 mg, 24.45 mmol) was added in 3 portions over a 10 min interaval. The reaction was then warmed to an internal temperature of 58 oC and stirred for 12 h. The mixture was cooled to 0 oC and 1 N HCl was added maintaining the reaction mixture below 5 oC to yield a final pH of 1.0 (red to pHydrion paper). The reaction mixture was then extracted three times with 10 mL portions of Et2O, washed three times with 5 mL portions of 1 N HCl, washed with NaCl (aq, sat), and dried over Na2SO4. The extract was decanted and the solvent was removed under reduced pressure. The crude product was isolated on SiO2 using 2:1 hexane/EA to provide 2.11 g (53percent) of a white solid. MP = 199.0 - 200.1 oC (lit. MP = 200 - 201 oC). ADDIN EN.CITE Davis2005453454517Davis, Edward M.Nanninga, Thomas N.Tjiong, Howie I.Winkle, Derick D.Utilization of Lithium Amide in the Synthesis of N-Arylanthranilic Acids and N-ArylanthranilamidesOrg. Process Res. Dev.Org. Process Res. Dev.843-846920051083-6160&xD;1520-586Xhttp://pubs.acs.org/doi/pdfplus/10.1021/op0501242https://pubs-acs-org.autorpa.lib.fju.edu.tw/doi/pdfplus/10.1021/op050124210.1021/op05012423 SiO2 TLC Rf 0.51 (2:1 hexane/EA). 1H NMR (400 MHz, MeOD-d4): δ 6.74 (m, 1 H, Ar), 6.91 (m, 1 H, Ar), 7.38-7.45 (d, 1 H, J = 8.5 Hz, Ar), 7.47 (dd, 1H, J1 = 1.8 Hz and J2 = 10.5 Hz, Ar), 7.89 (br, 1 H, Ar). Anal Calcd for C13H7F3INO2: C, 39.72; H, 1.79; N, 3.56. Found: C, 39.41; H, 1.91; N, 3.52.

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Reference: [1] Patent: CN106866624, 2017, B,
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  • [ 393-53-3 ]
  • [ 885588-03-4 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -55℃; Inert atmosphere
Stage #2: at 20℃; for 96 h;
Stage #3: With hydrogenchloride In water
2.6 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid; A mixture of 2-fluoro-4-iodo-phenylamine (20.0 g, 84.38 mmol) in anhydrous tetrahydrofuran (80 mL) was cooled to - 65 °C under an inert atmosphere, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) at a rate that maintained the internal temperature below - 55 °C. After final addition, the thick slurry was stirred for 30 minutes and then treated with 3-fluoro-isonicotinic acid (8.0 g, 56.69 mmol). The mixture was stirred at room temperature for 4 days and then poured into aqueous 2.0 N sodium hydroxide (1000 ml.) and ethyl acetate (250 ml_). The layers were separated and the organics were again extracted with aqueous sodium hydroxide (2 x 1000 ml_). The pH of the combined aqueous fractions was adjusted to 2 with concentrated hydrochloric acid, which effected precipitation of a solid. The material was filtered, washed with water (300 ml.) and dried under high vacuum at 40 °C for 18 h to afford the product (19.05 g, 53.19 mmol, 94percent) as a yellow solid.
33%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃;
Stage #2: With ammonium chloride In tetrahydrofuran for 1 h;
Step 1 : Synthesis of 3-[(4-iodo-2-fluoro)amino]isonicotinic acid.; 3-Fluoro-isonicotinic acid (1g, 7.09mmol) and 4-iodo-2-fluoroaniline (1.68g, 7.09mmol) was added to 10mI of dry THF and the mixture was cooled to -78°C. LiHMDS (1 M in THF, 24.8ml) was added and the mixture was al lowed to warm to room temperature over night. Solid ammonium hydrochloride (2g) was added and after 1h the mixture was filtered and the volatiles were removed in vacuo. The crude material was purified by flash-chromatography using C2-modified silica a nd a gradient of 0-12percent methanol in DCM as eluent to give 932mg (2.32mmol; 33percent yield) of pure desired carboxylic acid product.
Reference: [1] Patent: WO2010/17051, 2010, A1, . Location in patent: Page/Page column 26-27
[2] Patent: WO2006/45514, 2006, A1, . Location in patent: Page/Page column 79
[3] Patent: WO2016/14390, 2016, A1, . Location in patent: Paragraph 0041
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  • [ 832755-13-2 ]
YieldReaction ConditionsOperation in experiment
92% With N,N`-dimethylethylenediamine In dimethyl sulfoxide at 120℃; To a solution of 2-fluoro-4-iodoaniline (206.8 g, 872.3 mmol) in DMSO (1.1 L), was added by the sequential addition of copper (II) trifluoromethanesulfonate-benzene complex (30.74 g, 61.1 mmol), sodium methanesulfinate (106.9 g, 1.047 mol), and N, N'-dimethylethylenediamine (13.2 mL, 122 mmol). The reaction vessel was then placed in a preheated oil bath at 120 °C and stirred overnight. After cooling to room temperature, the reaction was diluted with water and extracted repeatedly with EtOAc. The combined organic extract was rinsed with brine (5X), dried over MgS04, and the solvent was removed. The resulting purple solid was rinsed with diisopropyl ether, then dried to constant weight in a vacuum oven at room temperature overnight to furnish a dull purple solid 151.5 g, 92percent yield: 1HNMR (DMSO-d6) No. (d, 1 H, J = 11.2 Hz), 7.41 (d, 1 H, J = 8.5 Hz), 6.87 (t, 1 H, J = 8.6 Hz), 6.19 (s, 2 H), 3.10 (s, 3 H) ; MS m/z 190.3 (No.
Reference: [1] Patent: WO2005/121121, 2005, A2, . Location in patent: Page/Page column 148-149
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