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Product Details of [ 61079-72-9 ]

CAS No. :61079-72-9 MDL No. :MFCD00061232
Formula : C7H3F3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :WEPXLRANFJEOFZ-UHFFFAOYSA-N
M.W : 176.09 Pubchem ID :302932
Synonyms :

Calculated chemistry of [ 61079-72-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 33.28
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.13 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.12
Log Po/w (XLOGP3) : 1.75
Log Po/w (WLOGP) : 3.06
Log Po/w (MLOGP) : 2.9
Log Po/w (SILICOS-IT) : 2.5
Consensus Log Po/w : 2.27

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.34
Solubility : 0.808 mg/ml ; 0.00459 mol/l
Class : Soluble
Log S (Ali) : -2.15
Solubility : 1.25 mg/ml ; 0.00707 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.61
Solubility : 0.436 mg/ml ; 0.00248 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.4

Safety of [ 61079-72-9 ]

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 [ 61079-72-9 ]

* 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 [ 61079-72-9 ]
  • Downstream synthetic route of [ 61079-72-9 ]

[ 61079-72-9 ] Synthesis Path-Upstream   1~14

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Reference: [1] Journal of Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609
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Reference: [1] Journal of Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361
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Reference: [1] European Journal of Organic Chemistry, 2003, # 3, p. 447 - 451
[2] Journal of Physical Chemistry A, 2000, vol. 104, # 2, p. 352 - 361
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609
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YieldReaction ConditionsOperation in experiment
73.4% at 120℃; for 2 h; Cooling with ice Solid sodium hydroxide (4.52 g, 113 mmol) was added in portions to an ice-cooled and stirred solution of 2,3,4-trifluorobenzoic acid (5.0 g, 28 mmol) in dimethylimidazolidinone (10 mL), and the mixture was heated to 120 °C for 2 h during which TLC analysis showed the disappearance of 2,3,4-trifluorobenzoic acid. Reaction mixture was cooled to room temperature and acidified (pH 5–6) with 2 N hydrochloric acid (7.5 mL). The white solid separated out was filtered, washed with excess of water and dried. White solid (3.6 g, 73.4 percent); mp: 174–177 °C. 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 6.94–7.01 (m, 1H, aromatic),7.64–7.68 (m, 1H,). IR (KBr, cm-1) 3208.9 (OH), 1654.1 (C=O), 1625.7 (C=C) (aromatic), 1315.2 (C–O).
Reference: [1] Journal of Fluorine Chemistry, 2003, vol. 121, # 1, p. 97 - 99
[2] Medicinal Chemistry Research, 2015, vol. 24, # 9, p. 3516 - 3528
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2455 - 2458
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Reference: [1] Patent: US6166246, 2000, A,
  • 10
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Reference: [1] Journal of Fluorine Chemistry, 2003, vol. 121, # 1, p. 97 - 99
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YieldReaction ConditionsOperation in experiment
97.1% at 90 - 95℃; for 3.5 h; A stirred solution of 2,3,4-trifluorobenzoic acid (5) (10 g, 56.8 mmol) in concentrated H2SO4 (98percent, 33.0 g) was treated dropwise with the mixture of concentrated HNO3 (65percent, 6.0g) and H2SO4 (98percent, 6.3g) for 3.5 h between 90 and 95 °C. The reaction progress was monitored by TLC (30percent ethylacetate in hexane). After completion of the reaction, the reaction mixture was cooled to room temperature and ice-water (50g) was added. The precipitation was separated by centrifugation and dried between 50 and 55 °C for 8 h. The crude product was purified by column chromatography using 20percent ethylacetate:hexane as eluent. The solvent was removed under reduced pressure to afford a white solid 6 (12.2 g) in 97.1percent yield.
92% for 2.5 h; A 3 litre three neck round bottom flask was charged with 125 ml H2SO4. Fuming nitric acid was added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) was added in 5 g portions over 90 minutes. The dark brownish yellow solution was stirred for 60 minutes at which time the reaction was complete. The reaction mixture was poured into 1 litre of an ice: water mixture and extracted with diethyl ether (3 x 600 ml). The combined extracts were dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid was suspended in hexanes and stirred for 30 min after which time it was filtered to give 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-I) detected.
92% for 2.5 h; A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3.x.600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected.
92% for 2.5 h; 2, 3,4-Trifluoro-5-nitro-benzoic acid 2A 3 liter three neck round bottom flask is charged with 125 ml H2504. Fuming nitricacid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1(25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solutionis stirred for 60 mm at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combinedorganic extracts are dried (Mg504) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 mm after which time it is filtered togive 29 g (92percent) of clean desired product as an off-yellow solid: MS APCI (-) nilz 220 (M-1) detected.
78% With sulfuric acid; nitric acid In water Step a
Preparation of 5-nitro-2,3,4-trifluorobenzoic acid
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol).
Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments.
After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml).
The resulting aqueous suspension was extracted with diethyl ether (3*200 ml).
The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid.
Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; 1H-NMR (400 MHz; DMSO)δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95,1 23.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78% With sulfuric acid; nitric acid In water Step a
Preparation of 5-Nitro-2,3,4-trifluorobenzoic Acid
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol).
Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments.
After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml).
The resulting aqueous suspension was extracted with diethyl ether (3*200 ml).
The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid.
Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; 1H-NMR (400 MHz; DMSO) δ14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78% With sulfuric acid; nitric acid In water Step a:
Preparation of 5-nitro-2,3,4-trifluorobenzoic acid
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol).
Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments.
After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml).
The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml).
The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid.
Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 percent yield; m.p.;1H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78% With sulfuric acid; nitric acid In water Step a:
Preparation of 5-nitro-2,3,4-trifluorobenzoic acid
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol).
Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments.
After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml).
The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml).
The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid.
Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 percent yield; m.p.;1H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0. 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
78% for 0.75 h; To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol).
Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments.
After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml).
The resulting aqueous suspension was extracted with diethyl ether (3*200 ml).
The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid.
Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78percent yield; m.p.; 1H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ -120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m).
75% at 0 - 20℃; for 6 h; Example 1; Preparation of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid; [00238] Step A; 2,3,4-Trifluoro-5-mtrobenzoic acid; Fuming HNO3 90percent (549.0 g,7.84 mol corrected for 90percent wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution OfHNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice- water bath cooling over an hour. When addition was complete, the reaction solution was allowed to warm to room temperature. After 5 hours, the reaction was complete as determined by HPLC and the reaction mixture (brown solution) was poured into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice over 10 minutes. The yellow slurry was cooled to 14 °C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75percent) of 2,3,4-trifluoro-5-nitrobenzoic acid as a yellowish solid. HPLC was 98 apercent (220 nm) and 100percent (254 nm). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (IH, apparent dt, J 1.9, 7, Ar-H); 19F NMR (376 EPO <DP n="51"/>MHz, DMSOd6) δ -153.9, -131.5, -120.9. 13C NMR (100 MHz, DMSO-d6) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F, dd, J 265, 13), 154 (C-F, dd, J 265, 10), 163 (COOH). IR v^/cnf1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
75% at 0 - 20℃; for 6.3 h; Fuming HNO3 90percent (549.0 g,7.84 mol corrected for 90percent wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution Of HNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14 °C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven- dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75percent) of compound 2 as a yellowish solid. HPLC was 98 apercent (220 nm) and 100percent (254 nm). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (IH, apparent dt, J 1.9, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) δ -153.9, -131.5, -120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, 7251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmJcmA 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
74.3% at 15 - 25℃; for 6.25 h; Trifluorobenzoic acid (70 Kg5 398 MoI) in sulphuric acid (96 wtpercent; 194 L) and hexamethyldisiloxane (6,5 Kg5 40 MoI)5 at 23 0C, was added a 1:1 mixture of sulphuric acid (96 wtpercent) and nitric acid (98 wtpercent) (total 70.1 Kg)5 over 75 min. The temperature of the reaction mixture was maintained between 15 and 25 0C during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg)5 keeping the temperature of the ice micture below 0 °C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0 0C5 then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L)5 and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 °C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45 0C for 2 days, to provide 2,354-Trifluoro-5-nitro benzoic acid (69.4 Kg5 74.3percent yiled). 1H NMR (400 MHz5 d6 DMSO) δ 8.44 (IH, apparent dt, J 2, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) δ -153.9, -131.5, -120.9. 13C NMR (100 MHz5 d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmjcm l 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected.
50% With sulfuric acid; nitric acid In sulfuric acid at 5 - 20℃; for 2 h; Example 1 5-FLUORO-6-(2-FLUORO-4-IODO-DHENYLAMINO)-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID (2-- OH-ETHOXY)-AMIDE Step A: Preparation of 2. 3. 4-trifluoro-5-nitrobenzoic acid Fuming HNO3 was added dropwise to the cold (5 TO-10° C) conc. H2SO4 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to- 10° C. Then was added 2, 3, E-TRIFTUOROBENZOIC acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5O C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice. The mixture was extracted with ether (3 X 4.0 L) and the organic extracts were washed with water (2 X 2L), brine (2.0 L), dried over anhydrous MGS04, filtered and evaporated under vacuum. The residue (cream colored solid) obtained is re-crystallized from hot chloroform provided the title compound as a solid (yellow). Yield : 880G (50percent), mp. 128-129 OC

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[3] Patent: US2003/232869, 2003, A1, . Location in patent: Page 9; 16
[4] Patent: WO2013/142182, 2013, A2, . Location in patent: Page/Page column 21
[5] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1905 - 1917
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[7] Patent: US6506798, 2003, B1,
[8] Patent: EP1202724, 2003, B1,
[9] Patent: EP1202724, 2003, B1,
[10] Patent: US7030119, 2006, B1, . Location in patent: Page/Page column 39
[11] Patent: WO2007/2092, 2007, A1, . Location in patent: Page/Page column 49-50
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[13] Patent: WO2007/2157, 2007, A2, . Location in patent: Page/Page column 68
[14] Patent: WO2005/9975, 2005, A2, . Location in patent: Page/Page column 51-52
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[16] Patent: US2003/216460, 2003, A1,
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Reference: [1] Patent: US6160171, 2000, A,
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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.

Reference: [1] Neuropharmacology, 2019, vol. 144, p. 122 - 132
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[3] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[4] Patent: WO2006/134469, 2006, A1, . Location in patent: Page/Page column 13-14
[5] Patent: WO2004/56789, 2004, A1, . Location in patent: Page 16; 23-24; 28; 31-32; 37-38
[6] Patent: WO2006/134469, 2006, A1, . Location in patent: Page/Page column 14
[7] Patent: US2014/135519, 2014, A1, . Location in patent: Paragraph 0020
[8] Patent: WO2015/38743, 2015, A1, . Location in patent: Paragraph 0141; 0142
[9] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 13, p. 2294 - 2301
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6501 - 6504
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Reference: [1] Patent: WO2013/142182, 2013, A2,
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