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Chemical Structure| 446-08-2
Chemical Structure| 446-08-2
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Product Details of [ 446-08-2 ]

CAS No. :446-08-2 MDL No. :MFCD00055566
Formula : C7H6FNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :FPQMGQZTBWIHDN-UHFFFAOYSA-N
M.W :155.13 Pubchem ID :101412
Synonyms :

Calculated chemistry of [ 446-08-2 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 37.76
TPSA : 63.32 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) : -6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.86
Log Po/w (XLOGP3) : 1.04
Log Po/w (WLOGP) : 1.53
Log Po/w (MLOGP) : 0.32
Log Po/w (SILICOS-IT) : 0.92
Consensus Log Po/w : 0.94

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.79
Solubility : 2.49 mg/ml ; 0.016 mol/l
Class : Very soluble
Log S (Ali) : -1.96
Solubility : 1.7 mg/ml ; 0.011 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.68
Solubility : 3.27 mg/ml ; 0.0211 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.01

Safety of [ 446-08-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 446-08-2 ]

* 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 [ 446-08-2 ]
  • Downstream synthetic route of [ 446-08-2 ]

[ 446-08-2 ] Synthesis Path-Upstream   1~40

  • 1
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  • [ 446-08-2 ]
  • [ 321-69-7 ]
Reference: [1] Organic Process Research and Development, 2008, vol. 12, # 5, p. 877 - 883
[2] Synthetic Communications, 2012, vol. 42, # 1, p. 8 - 24
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 971 - 983
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 2075 - 2088
[5] Patent: US2006/116376, 2006, A1, . Location in patent: Page/Page column 15
[6] Patent: US6884801, 2005, B1, . Location in patent: Page/Page column 20
  • 2
  • [ 32315-10-9 ]
  • [ 446-08-2 ]
  • [ 321-69-7 ]
YieldReaction ConditionsOperation in experiment
91% With pyridine In dichloromethane; acetonitrile at 55℃; Example 9. Preparation of 3-(4-sec-butylphenyl)-6-fluoro-2-(4-(2-hydroxyethoxy)- 3,5-dimethylphenyl)quinazolin-4(3H)-one; [0166] To a solution of 2-amino-5-fluorobenzoic acid (1.00 g, 6.40 mmol) in acetonitrile (8 mL) was added a solution of triphosgene (0.64 g, 2.1 mmol) in dichloromethane (5 mL) and pyridine (1.1 mL, 13.0 mmol) simultaneously within 5 min. The resulting pale yellow suspension was heated at 55°C for 2 hours. The solvents were evaporated under vacuum, and the residue was stirred with water (5 ml_). The precipitate obtained was filtered and dried to afford δ-fluoro-IH-benzotcdti .Sloxazine^-dione. Yield: 1.06 g (91 percent).[0167] To a suspension 6-fluoro-1 H-benzo[d][1 ,3]oxazine-2,4-dione (1.06 g, 5.90 mmol) in DMF (5 ml_) was added 4-sec-butylphenylamine (1.95 ml_, 11.8 mmol) at room temperature. The suspension was heated at 700C for 2 days, and cooled to room temperature. The reaction mixture was poured into crushed ice (150 ml_), and extracted with dichloromethane. The organic layer was dried over Na2SO4, and evaporated under vacuum. The residue was purified by flash column chromatography on a Biotage (40 M silica column), using a gradient of hexane:ethyl acetate (9:1 to 8:2) mixture as eluent to afford 2-amino-Λ/-(4-sec-butylphenyl)-5- fluorobenzamide. Yield: 1.16 g (69percent).[0168] Anhydrous CuCI2 (0.21 g, 1.6 mmol) was added to a solution of 2- amino-Λ/-(4-sec-butylphenyl)-5-fluorobenzamide (0.15 g, 0.52 mmol), and 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.12 g, 0.63 mmol) in ethanol (30 ml_). The resulting green solution was heated at reflux for 3 hours. After cooling to room temperature , the mixture was concentrated under vacuum. The residue was stirred with water (20 mL), and extracted with ethyl acetate (2 * 25 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography on a Biotage (25 M silica column) using a gradient of hexane:ethyl acetate (8:2 to 5:5) mixture as eluent to afford the title compound. Yield: 0.19 g (77percent). MP 70-720C. 1H-NMR (400 MHz, CDCI3): δ 7.99 (m, 1H), 7.82 (m, 1 H), 7.53 (m, 1H), 7.15 (m, 2H), 7.09 (d, 2H)1 6.97 (s, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 2.59 (m, 1 H), 2.15 (s, 6H), 2.02 (t, 1 H), 1.54 (m, 2H), 1.21 (d, 2H), 0.73 (t, 3H).
90%
Stage #1: at 50℃;
Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water at 0℃;
A solution of 5-fluoroanthranilic acid (10 g, 64.46 mmol; Aesar, Fluorochem, ABCR Product List, Eur. Pat. Appl. No. EP 647 614, Apr. 12, 1995, the contents of which are hereby incorporated by reference in their entirety) in anhydrous tetrahydrofuran (200 ml) was treated with triphosgene (12.5 g, 42.158 mmol) and stirred at 50° C. overnight. The yellow solution was cooled down to 0° C., saturated sodium hydrogen carbonate solution was added to pH 7-8, and the mixture was extracted with ethyl acetate (150 ml.x.2).The combined organic layers were dried on anhydrous sodium sulfate, ethyl acetate was evaporated, and the residue was triturated with diethyl ether. The suspension was cooled down for 30 min, the precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum to give intermediate 1 (11 g, 90percent), which was a white powder. Intermediate 1 was characterized by the following spectroscopic data: 1NMR (d6-DMSO, 400 MHz) δ (ppm) 6.86 (dd, J=9.66 Hz and J=2.42 Hz, 1H), 7.09 (td, J=8.8 Hz and 2.42 Hz, 1H), 7.98 (dd, J=8.8 Hz and 6 Hz, 1H), 11.88 (brs, NH); and MS (ESI, EI+) m/z=182 (MH+).; A solution of 5-fluoroanthranilic acid (64.46 mmol) in anhydrous tetrahydrofuran (200 ml) was treated with triphosgene (42.16 mmol) and stirred at 50° C. overnight. The yellow solution was cooled down to 0° C., then a saturated sodium hydrogen carbonate solution was added to pH 7/8, and the mixture was extracted with ethyl acetate. The combined organic layers were dried on anhydrous sodium sulfate, the ethyl acetate was evaporated, and the residue was triturated with diethyl ether. The suspension was cooled down for 30 min, the precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum to give intermediate 19, which was a white powder. Intermediate 19 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 6.86 (dd, J=9.66 Hz and J=2.42 Hz, 1H), 7.09 (td, J=8.8 Hz and 2.42 Hz, 1H), 7.98 (dd, J=8.8 Hz and 6 Hz, 1H), 11.88 (brs, NH); and MS (ESI, EI+) m/z=182 (MH+).
79% at 20℃; [000209] To a solution of 5-fluoroanthranilic acid (10.0 g, 65.5 mmol) in THF ( 143 mL) was added solid triphosgene (6.70 g, 22.6 mmol, 0.35 equiv). The reaction mixture was stirred at rt overnight and the resulting suspension was filtered and dried to afford 9.23 g (79percent) of 5- fluoroisatoic anhydride: 1H NMR (400 MHz, DMSO-d6) δ 7.14 (M, 1 H), 7.60 (M, 2 H), 11.72 (s, 1 H).
61% at 20℃; After dissolving 5-fluoroanthranilic acid (2.03 g, 13.09 mmol) in THF (40 mL), triphosgene (4.08 g) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed and the residue was dried over under reduced pressure. The residue obtained after drying under reduced pressure was washed with acetone and then with hexane, and subsequently dried under reduced pressure in a desiccator to obtain 6-fluoroisatoic anhydride. The compound was identified by LC-MS. Yield: 1.516 g (61percent), M+1 = 181.9

Reference: [1] Patent: WO2010/79431, 2010, A2, . Location in patent: Page/Page column 56-58
[2] Patent: US2009/60866, 2009, A1, . Location in patent: Page/Page column 51-52; 56
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 16, p. 6434 - 6456
[4] Patent: WO2011/35124, 2011, A1, . Location in patent: Page/Page column 78-79
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1994 - 2005
[6] Patent: EP1505067, 2005, A1, . Location in patent: Page/Page column 372
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 821 - 826
[8] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 94 - 97
  • 3
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Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 4196 - 4200
  • 4
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  • [ 503-38-8 ]
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YieldReaction ConditionsOperation in experiment
96% at 20℃; for 4 h; Heating / reflux Trichloromethyl CHLOROFORMATE (7.01 ML, 58.13 mmol) was added to a stirred solution of Compound 34 (8.2 g, 52.85 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in an ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 9.1 g (96percent) of white solids. M. P. 240 C. LH NMR (DMSO-d6): d 7.19 (dd, J= 4.2, 8.9 Hz, 1H), 7.63-7. 71 (m, 1H), 11.77 (s, 1H). EIMS (NEG. MODE) M/Z 180 (M-1). Anal. (C8H4FN03) C, H, N.
96% at 20℃; for 4 h; Heating / reflux Trichloromethyl chloroformate (7.01 mL, 58.13 mmol) was added to a stirred solution of 2-amino-5-fluoro benzoic acid (8.2 g, 52.85 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h.
The solution was cooled in an ice bath and the solids formed were filtered.
The solids were washed by ether and dried under vacuum at room temperature to yield 9.1 g (96percent) of white solids. M.P. 240° C. 1H NMR (DMSO-d6): δ 7.19 (dd, J=4.2, 8.9 Hz, 1H), 7.63-7.71 (m, 1H), 11.77 (s, 1H). EIMS (neg. mode) m/z 180 (M-1). Anal. (C8H4FNO3) C, H, N.
96% at 20℃; for 4 h; Heating / reflux Trichloromethyl chloroformate (7.01 mL, 58.13 mmol) was added to a stirred solution of Compound 34 (8.2 g, 52.85 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h.
The solution was cooled in an ice bath and the solids formed were filtered.
The solids were washed by ether and dried under vacuum at room temperature to yield 9.1 g (96percent) of white solids. M.P. 240° C. 1H NMR (DMSO-d6): δ 7.19 (dd, J=4.2, 8.9 Hz, 1H), 7.63-7.71 (m, 1H), 11.77 (s, 1H). EIMS (neg. mode) m/z 180 (M-1). Anal. (C8 FNO3) C, H, N.
Reference: [1] Patent: WO2004/74218, 2004, A2, . Location in patent: Page 107
[2] Patent: US2008/139551, 2008, A1, . Location in patent: Page/Page column 43
[3] Patent: US2008/139551, 2008, A1, . Location in patent: Page/Page column 44
  • 5
  • [ 446-08-2 ]
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  • [ 321-69-7 ]
Reference: [1] Organic Process Research and Development, 2008, vol. 12, # 5, p. 877 - 883
  • 6
  • [ 446-08-2 ]
  • [ 77287-34-4 ]
  • [ 16499-56-2 ]
YieldReaction ConditionsOperation in experiment
85% at 150℃; for 2 h; Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
79% at 140℃; General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
Reference: [1] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 8
[2] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[3] Molecules, 2006, vol. 11, # 6, p. 383 - 392
[4] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 11, p. 3768 - 3774
[5] Chemistry and Biodiversity, 2018, vol. 15, # 6,
  • 7
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YieldReaction ConditionsOperation in experiment
78% With formamide In water A mixture of 2-amino-5-fluorobenzoic acid (2.07 g) and formamide (4 ml) was heated at 160° C. for 2 hours, and for a further 2 hours at 180° C.
The reaction mixture was allowed to cool and water was added.
The reaction product was filtered off and washed with water and with diethyl ether to give 6-fluoro-3,4-dihydroquinazolin-4-one in 78percent yield: m.p. 269-271° C.;
Elemental Analysis: Found C, 58.2; H, 3.0; N, 16.9; C8 H4 N2 OF requires C, 58.9; H, 2.5; N, 17.2percent.
Reference: [1] Patent: US5955464, 1999, A,
[2] Molecules, 2017, vol. 22, # 2,
  • 8
  • [ 446-08-2 ]
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  • [ 16499-56-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3860 - 3873
  • 9
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  • [ 16499-61-9 ]
Reference: [1] Patent: WO2011/11522, 2011, A2,
[2] Patent: WO2012/79079, 2012, A1,
[3] Patent: WO2014/145512, 2014, A2,
[4] Molecules, 2017, vol. 22, # 2,
  • 10
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Reference: [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
  • 11
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  • [ 394-28-5 ]
YieldReaction ConditionsOperation in experiment
73% With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0 - 100℃; for 1 h; Preparation 22; Preparation of 2-bromo-5-fluorobenzoic acid; A suspension of 2-amino-5-fluorobenzoic acid (0.465 g, 3.0 mmol) in 48percent aq. HBr (2.25 mL) was added to NaN02 (0.21 g, 3.15 mmol) dissolved in 0.65 mL of water at 0°C. The resulting solution was treated with CuBr (0.28 g, 1.98 mmol) dissolved in 0.5 mL of 48percent aq. HBr, and the mixture was heated at 100°C for 1 h. After cooling to room temperature, the mixture was extracted with ether three times. The combined organic extracts were washed with brine, dried over MgS04, and concentrated in vacuo to give the crude material as white solid. Recrystalization from cyclo- hexane/EtOAc 15: 1 gave the desired product as white crystals in 73percent yield (0.483 g). LC-MS, Method 4: M+HF = 219. 0, retention time = 1.59 min.
Reference: [1] Patent: WO2005/56544, 2005, A1, . Location in patent: Page/Page column 46
  • 12
  • [ 446-08-2 ]
  • [ 52548-63-7 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃;
Stage #2: With copper(l) iodide; potassium iodide In water at 5 - 20℃;
Step 1 : To a solution of compound 8 (25 g, 0.162 mol) in 2 N HCI solution (350 mL) was added a solution of sodium nitrite (1 1.2 g, 0.16 mol) in H20 (150 mL) drop-wise while maintaining the temperature between 0 - 5 °C. After the addition was completed, the mixture was stirred at 0-5 °C for 90 minutes. Then, the mixture was added to a solution of potassium iodide (53 g, 0.32 mol) and copper (I) iodide (15.2 g, 0.081 mol) in H20 (150 mL) drop-wise with the temperature maintained at ~5 °C. After addition was completed, the mixture was stirred at room temperature for 18 hours after which TLC (EtOAc) indicated that the reaction was complete. The mixture was filtered and the cake dried. The residue was diluted with MTBE (500 mL), refluxed for 20 minutes, and filtered. The filtrate was concentrated to afford compound 9 as a yellow solid (30 g, 75percent yield). 1 H NMR (400 MHz, Methanol-d4) δ 8.04 - 8.00 (m, 1 H), 7.59 - 7.56 (m, 1 H), 7.08 - 7.03 (m, 1 H).
52%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5℃; for 0.5 h;
Stage #2: With copper(l) iodide; potassium iodide In water at -5 - 20℃; for 4 h;
Step A: A solution of sodium nitrite (4.5 g, 65 mmol) in water (75 mL) was cooled, and added to 2-amino-5-fluorobenzoic acid (10.0 g, 65 mmol) in 2 N hydrochloric acid (150 mL) at -5° C. and the mixture was stirred for 30 minutes. In a separate vessel potassium iodide (21.5 g, 130 mmol) and copper (I) iodide (6.2 g, 32.5 mmol) was dissolved in water (75 mL) and cooled to -5° C. To this solution was added the above diazonium solution dropwise. The resulting red-brown precipitate which formed was allowed to warm to room temperature over a period of 4 hours. The precipitate was isolated by filtration and the solid was rinsed with water and dried under vacuum for over 24 hours. The brown solid was suspended in tert-butyl methyl ether and heated to 56° C.; the inorganic salt was filtered off. The filtrate was concentrated to a slurry and hexanes was added, causing more precipitate to form. The mixture was allowed to stir for over 1 hour, then filtered and rinsed with hexanes and dried further in a vacuum oven to provide 5-fluoro-2-iodo-benozic acid (9.0 g, 52percent): 1H NMR (500 MHz, CD3OD) δ 8.01 (dd, J=8.7, 5.4 Hz, 1H), 7.55 (dd, J=9.2, 3.0 Hz, 1H), 7.05-7.01 (m, 1H).
41%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5℃;
Stage #2: With potassium iodide In water at 5℃; for 1 h;
To a solution of 2-Amino-5-fluoro-benzoic acid (15.5g, 99.94mmol) in 6N HCl (300 ml) was added dropwise a solution OfNaNO2 (8.28 g, 119.93 mmol) in H2O (50 mL) at -50C. The mixture was stirred for 40 minutes, and then added to the mixture of KI (24.88 g, 149.91 mmol) and ice (200 g). After stirring for 1 hour at 50C, the mixture was extracted with H2O and dichloromethane, dried and concentrated to give the titled compound as a pale yellow solid (H g, yield 41percent).1H NMR (300 MHz, CDCl3) δ 7.17 (dt, J= 3.3, 8.7 Hz, IH), 7.54 (dd, J= 3.0, 9.3Hz, IH), 7.99 (dd, J= 5.4, 8.7 Hz, IH), 13.56 (s, IH).MS (ESF) m/z 265 (M-I)
8.9 kg
Stage #1: With sulfuric acid; sodium nitrite In water at 5℃; Large scale
Stage #2: With potassium iodide In water at 20℃; Large scale
The 6.0 kg of 2-amino-5-fluoro-benzoic acid added to the already prepared 40L A in the mixed solution (concentrated sulfuric acid/water as 4L/36L), keeping the temperature at 5 °C lower stirring, dropping 7L the 5.64mol/L sodium nitrite aqueous solution, in the solid-free stirring Go, TLC (PE/EA:1/1) monitoring after the reaction, by adding 232g urea, stirring 15 minutes, cooling to 0 °C, fast join 20L of the 0 °C solvent is concentrated sulfuric acid and water volume ratio of 1 : 9.3 containing 9 kg potassium iodide solution, slowly warming to room temperature, stirring overnight, filtering, washing the brown solid. The solid used 60L ethyl acetate solution to dissolve, for sequentially 6N hydrochloric acid (10L × 3) washing, 10percent sodium bisulfate (10L × 2) washing, saturated salt water (10L × 3) washing, drying, boil off about 50L solvent, adding 40L toluene, then residual acetic acid ethyl ester is distilled, cooled to obtain a 8.9 kg of 5-fluoro-2-iodo-benzoic acid.
14.2 g
Stage #1: With hydrogenchloride; acetic acid; sodium nitrite In water at 0℃; for 0.5 h;
Stage #2: With potassium iodide In water at 0 - 35℃; for 5 h;
To a mixture of 2-amino-5-fluorobenzoic acid (10 g) in a mixed solvent of acetic acid (150 mL), water (50 mL) and conc. hydrochloric acid (5.0 mL) was added dropwise a solution of sodium nitrite (6.67 g) in water (50 mL) in a water bath, and the mixture was stirred at 0° C. for 0.5 hr. To the reaction mixture was added potassium iodide (32.1 g) at 0° C., and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added 1N aqueous hydrochloric acid solution at 0° C., and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (14.2 g). 1H NMR (300 MHz, DMSO-d6) δ 7.17 (1H, td, J=8.5, 3.0 Hz), 7.55 (1H, dd, J=9.5, 3.0 Hz), 7.99 (1H, dd, J=8.7, 5.7 Hz), 13.59 (1H, brs).

Reference: [1] Patent: WO2013/132376, 2013, A1, . Location in patent: Page/Page column 151
[2] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
[3] Patent: US2006/52378, 2006, A1, . Location in patent: Page/Page column 146
[4] Patent: US2003/187014, 2003, A1,
[5] Patent: WO2010/31, 2010, A1, . Location in patent: Page/Page column 70
[6] Collection of Czechoslovak Chemical Communications, 1975, vol. 40, # 3, p. 719 - 737
[7] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[8] Organic Letters, 2015, vol. 17, # 17, p. 4180 - 4183
[9] Journal of Organic Chemistry, 2017, vol. 82, # 4, p. 2263 - 2268
[10] Patent: CN105732355, 2016, A, . Location in patent: Paragraph 0024; 0040; 0041
[11] Patent: US2018/155333, 2018, A1, . Location in patent: Paragraph 1738; 1739
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  • [ 446-08-2 ]
  • [ 63069-49-8 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With phosgene In tetrahydrofuran; toluene at 20℃; for 18 h;
Stage #2: With ammonia In tetrahydrofuran; water; toluene at 0 - 20℃; for 1 h;
Intermediate 32; 2-Amino-5-fluorobenzamide A round-bottomed flask was charged with 5-fluororanthranilic acid (3 g, 19.34 mmol) in tetrahydrofuran (64.5 mL) and a 20percent solution of phosgene (11.2 mL, 21.3 mmol) in toluene was added dropwise at room temperature. The mixture was stirred for 18 hr at room temperature, then cooled to 0° C., at which time concentrated ammonium hydroxide (27.9 mL, 193 mmol) was added cautiously. The mixture was then allowed to warm to room temperature and then stirred for 1 hr. The organic phase was diluted with EtOAc, washed with aqueous dipotassium hydrogen phosphate and brine, then dried over sodium sulfate and concentrated to give a white solid (2.46 g, 82percent yield). MS: M(C7H7FN2O)=154.14, (M+H-NH3)-=138.
75%
Stage #1: With thionyl chloride In benzene for 4 h; Reflux
Stage #2: With ammonia In benzene at 20℃;
A suspension of 2-amino-5-fluorobenzoic acid (1) (1.0 g, 6.3 mmol) in benzene (30 mL) underreflux was mixed with thionyl chloride (1.5 g, 12.6 mmol). The resulting mixture was stirred underreflux for 4 h, and then evaporated. The residue was dissolved in 200 mL of benzene and treated with anhydrous ammonia gas at room temperature. After removing the solvent, compound 2 wascrystalized from ethanol and obtained as brown powder [25]. Yield 75percent; m.p.: 144–146°C; 1H-NMR(DMSO-d6, 300 MHz) δ: 5.72(s, 2H, NH2,), 6.54(s, CONH2, 2H) 7.63 (d, 1H, J = 8.6 Hz, Ar-H),7.92 (d, 1H, J = 7.4 Hz, Ar-H), 8.14 (s, 1H, Ar-H). C7H7FN2O (154.05): MS (ESI) m/z 155.05 [M + 1].
67% With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6 h; To a stirred solution of 2-amino-5-fluoro-benzoic acid (15 g, 96.69 mmol) in THF (300 mL),EDC.HCl (27.70 g, 145.03 mmol), HOBt·NH3 (21.75 g, 145.03 mmol) and DIPEA (51.0 mL,290.07 mmol) were added at RT and stirred for 6 h (TLC indicated complete consumption ofstarting material). The reaction mixture was concentrated under reduced pressure to give thecrude residue which was diluted with water (150 mL) and extracted with EtOAc (3 x 150mL). The combined organic extracts were washed with water (2 x 100 mL), brine (1 x 100mL), dried over Na2S04, and concentrated under reduced pressure to give the crude residue.The crude material was purified by column chromatography (100-200 silica gel, 300 g, 40percentEtOAc-Hexane) to provide 2-amino-5-fluoro-benzamide (10.0 g, 67percent) as a pale yellow solid.LCMS: mlz: 155.38 [M+Ht.
Reference: [1] Patent: US2008/182852, 2008, A1, . Location in patent: Page/Page column 28
[2] Molecules, 2017, vol. 22, # 2,
[3] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 77
[4] Journal of Medicinal Chemistry, 2000, vol. 43, # 23, p. 4479 - 4487
[5] Patent: US6479499, 2002, B1,
  • 14
  • [ 446-08-2 ]
  • [ 917-54-4 ]
  • [ 2343-25-1 ]
Reference: [1] Chemistry - A European Journal, 2013, vol. 19, # 10, p. 3315 - 3318
[2] Chemical Communications, 2018, vol. 54, # 74, p. 10503 - 10506
  • 15
  • [ 67-56-1 ]
  • [ 446-08-2 ]
  • [ 319-24-4 ]
YieldReaction ConditionsOperation in experiment
42%
Stage #1: at 100℃;
Stage #2: With water; potassium carbonate In dichloromethane
Intermediate 53; Methyl 2-amino-5-fluorobenzoateA solution of 2-amino-5-fluorobenzoic acid (9.29 mmol, 1.440 g) in a mixture of HCI/MeOH (3N, 30 ml) was heated at 1000C overnight. The solvent was evaporated and the crude mixture was extracted between DCM and K2CO3 saturated aqueous solution. The organic phase was evaporated and the crude mixture was purified by chromatography over SiO2 with hexane/ethyl acetate mixtures affording 0.650 g (yield 42percent) of the expected product. <n="67"/>δ 1H NMR (200 MHz, CDCI3): 3.9 (s, 3H), 5.6 (s, 2H), 6.6 (dd, J=9.0, 4.7 Hz1 1 H), 7.0 (m, 1 H), 7.5 (dd, J=9.8, 3.1 Hz, 1 H). ESI/MS (m/e, percent): 170 [(M+1)\\ 100].
Reference: [1] Patent: WO2009/21696, 2009, A1, . Location in patent: Page/Page column 65-66
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 24, p. 5923 - 5936
[3] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 1, p. 64 - 69
[4] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[6] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 11175 - 11183
[7] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1919 - 1925
  • 16
  • [ 446-08-2 ]
  • [ 18107-18-1 ]
  • [ 319-24-4 ]
Reference: [1] Patent: WO2007/9774, 2007, A1, . Location in patent: Page/Page column 22
  • 17
  • [ 80-11-5 ]
  • [ 446-08-2 ]
  • [ 319-24-4 ]
Reference: [1] Heterocycles, 2006, vol. 67, # 1, p. 161 - 173
  • 18
  • [ 320-98-9 ]
  • [ 446-08-2 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogen In ethanol at 20℃; for 4 h; A solution of Compound 33 (10 g, 54 mmol) in ethanol (100 mL) was stirred under hydrogen in the presence of 10percent PD/C (0.5 g) at room temperature for 4 h. The solution was filtered through celite. The solvent was evaporated under reduced pressure to yield 8.2 g (98percent) of white solids. M. P. 142°C, 1H NMR (DMSO-d6): 6.71 (dd, J= 4.9, 8.9 Hz, 1H), 7.15 (dt, J = 2.9, 8.4 Hz, 1H), 7.37 (dd, J= 2.9, 9.8 Hz, 1H), 8.60 (s, 1H). EIMS m/z 156 (M+1).
98% With hydrogen In ethanol at 20℃; for 4 h; A solution of 5-fluoro-2-nitrobenzoic acid (10 g, 54 mmol) in ethanol (100 mL) was stirred under hydrogen in the presence of 10percent Pd/C (0.5 g) at room temperature for 4 h.
The solution was filtered through celite.
The solvent was evaporated under reduced pressure to yield 8.2 g (98percent) of white solids. M.P. 142° C. 1H NMR (DMSO-d6): 6.71 (dd, J=4.9, 8.9 Hz, 1H), 7.15 (dt, J=2.9, 8.4 Hz, 1H), 7.37 (dd, J=2.9, 9.8 Hz, 1H), 8.60 (s, 1H). EIMS m/z 156 (M+1).
98% With hydrogen In ethanol at 20℃; for 4 h; A solution of Compound 33 (10 g, 54 mmol) in ethanol (100 mL) was stirred under hydrogen in the presence of 10percent Pd/C (0.5 g) at room temperature for 4 h.
The solution was filtered through celite.
The solvent was evaporated under reduced pressure to yield 8.2 g (98percent) of white solids. M.P. 142° C. 1H NMR (DMSO-d6): 6.71 (dd, J=4.9, 8.9 Hz, 1H), 7.15 (dt, J=2.9, 8.4 Hz, 1H), 7.37 (dd, J=2.9, 9.8 Hz, 1H), 8.60 (s, 1H). EIMS m/z 156 (M+1).
Reference: [1] Patent: WO2004/74218, 2004, A2, . Location in patent: Page 106
[2] Patent: US2008/139551, 2008, A1, . Location in patent: Page/Page column 43
[3] Patent: US2008/139551, 2008, A1, . Location in patent: Page/Page column 44
[4] Patent: US5514676, 1996, A,
[5] Journal of Biological Chemistry, 1954, vol. 207, p. 411,412
[6] Asian Journal of Chemistry, 2013, vol. 25, # 2, p. 1039 - 1042
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  • [ 399-52-0 ]
  • [ 446-08-2 ]
Reference: [1] Synthetic Communications, 2010, vol. 40, # 23, p. 3480 - 3487
[2] Applied Organometallic Chemistry, 2011, vol. 25, # 1, p. 34 - 46
  • 20
  • [ 394-28-5 ]
  • [ 446-08-2 ]
Reference: [1] Patent: US5523472, 1996, A,
  • 21
  • [ 446-33-3 ]
  • [ 446-08-2 ]
Reference: [1] Patent: US2003/187014, 2003, A1,
[2] Asian Journal of Chemistry, 2013, vol. 25, # 2, p. 1039 - 1042
  • 22
  • [ 443-69-6 ]
  • [ 446-08-2 ]
Reference: [1] Chemical Communications, 2014, vol. 50, # 82, p. 12311 - 12314
[2] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1958, vol. 148, p. 481,488
[3] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
  • 23
  • [ 455-38-9 ]
  • [ 446-08-2 ]
Reference: [1] Patent: US2008/139551, 2008, A1,
  • 24
  • [ 351-09-7 ]
  • [ 446-08-2 ]
Reference: [1] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1958, vol. 148, p. 481,488
  • 25
  • [ 49579-56-8 ]
  • [ 446-08-2 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1975, vol. 40, # 3, p. 719 - 737
  • 26
  • [ 326-65-8 ]
  • [ 446-08-2 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1975, vol. 40, # 3, p. 719 - 737
  • 27
  • [ 446-08-2 ]
  • [ 391-93-5 ]
YieldReaction ConditionsOperation in experiment
50% With sulfuric acid In ethanol; toluene A.
Ethyl 2-amino-5-fluorobenzoate
2-Amino-5-fluorobenzoic acid (1.0 g, 6.4 mmol) was dissolved in ethanol (15 mL) and toluene (10 mL).
Several drops of concentrated H2SO4 were added.
The reaction was refluxed with a Dean Stark trap overnight.
The reaction was cooled to rt and the solvents removed in vacuo.
The product was isolated by chromatography on silica gel (4*15 cm column) eluted with chloroform/ methanol (98:2, v/v-500 mL followed by 95:5, 500 mL) in 50percent yield. MS (ES+): m/z 184.0 (M+1); 1H NMR (CDCl3) δ 7.55 (d, 1H, ArH), 7.03 (m, 1H, ArH), 6.61 (dd, 1H, ArH), 5.6 (bs, 2H, NH2), 4.33 (q, 2H,CH2), 1.40 (t, 3H, CH3).
Reference: [1] Patent: US2003/69271, 2003, A1,
  • 28
  • [ 64-17-5 ]
  • [ 446-08-2 ]
  • [ 391-93-5 ]
Reference: [1] Journal of Organic Chemistry, 2018, vol. 83, # 3, p. 1154 - 1159
  • 29
  • [ 446-08-2 ]
  • [ 146829-56-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
  • 30
  • [ 446-08-2 ]
  • [ 748805-85-8 ]
YieldReaction ConditionsOperation in experiment
0.83 g With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 13 h; Lithium aluminium hydride (1 M solution in tetrahydrofuran; 13 ml, 13 mmol) was added to a stirred solution of 2-amino-5-fluorobenzoic acid (1 g, 6.4 mmol) in tetrahydrofuran (10 ml) at 0 °C. The reaction mixture was stirred at 0°C for 1 hour and then allowed to warm to room temperature and stirred for 12 hours. Water (5 ml) followed by 5percent aqueous sodium hydroxide (15 ml) were added and the resulting mixture filtered. The filtrate was extracted with ethyl acetate (3 x 150 ml) and the combined organic extracts washed with water, dried over sodium sulfate and concentrated under reduced pressure to provide (2-amino-5-fluoro-phenyl) methanol (0.83 g, 91 percent) which was used without further purification. H NMR (400 MHz, CDCI3) δ 6.83 (d, 2H), 6.62 (s, 1 H), 4.61 (s, 2H) ppm.
Reference: [1] ACS Catalysis, 2013, vol. 3, # 4, p. 622 - 624
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 2080 - 2092
[3] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4252 - 4255
[4] Patent: US2010/331306, 2010, A1, . Location in patent: Page/Page column 34
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[6] Angewandte Chemie, International Edition, 2014, vol. 53, # 36, p. 9603 - 9607,5[7] Angewandte Chemie, 2014, vol. 126, # 36, p. 9757 - 9761,5
[8] Organic and Biomolecular Chemistry, 2016, vol. 14, # 38, p. 8966 - 8970
[9] Patent: WO2016/207081, 2016, A1, . Location in patent: Page/Page column 95
[10] Organic Letters, 2017, vol. 19, # 19, p. 5236 - 5239
[11] Organic Letters, 2018, vol. 20, # 10, p. 2880 - 2883
[12] Organic Letters, 2018, vol. 20, # 15, p. 4584 - 4588
[13] Organic Letters, 2018,
  • 31
  • [ 446-08-2 ]
  • [ 877264-43-2 ]
Reference: [1] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[2] Patent: WO2013/132376, 2013, A1,
[3] Organic Letters, 2015, vol. 17, # 17, p. 4180 - 4183
  • 32
  • [ 446-08-2 ]
  • [ 57-13-6 ]
  • [ 88145-90-8 ]
YieldReaction ConditionsOperation in experiment
87% at 160 - 180℃; for 8 h; Sealed tube Urea (29.0 g, 482.9 mmol) and 2-amino-5-fluorobenzoic acid (5.00 g, 32.20 mmol) were added sequentially to a 200 mL of sealed tube. The mixture was gradually warmed to 160 under vigorous stirring. After stirring for 4 h, the mixture was heated to 180 , and continued to react for 4 h. Then the mixture was cooled gradually to rt, and water (150 mL) was added. The resulting mixture was stirred for 1 h at rt, and filtered. The residue was washed with water until the filtrate was colorless, and then washed with acetone (20 mL) and methanol (70 mL) sequentially. The resulting residue was dried to give the title compound (as a brick red solid, 5.04 g, 87) .MS (ESI, neg. ion) m/z: 179.1 [M-H]- and[0294]1H NMR (DMSO-d6, 600 MHz) δ (ppm) : 11.29 (s, 2H) , 7.57 (dd, J 8.4 Hz, 2.7 Hz, 1H) , 7.53 (td, J 8.7 Hz, 2.8 Hz, 1H) , 7.19 (dd, J 8.8 Hz, 4.3 Hz, 1H)
86.8% at 160 - 180℃; for 8 h; Sealed tube Step 1) Synthesis of 6-fluoroquinazoline-2, 4 (1H, 3H) -dione To a 200 mL of sealing tube were added sequentially urea (29.0 g, 482.9 mmol) and 2-amino-5-fluoro benzoic acid (5.0 g, 32.2 mmol) , the mixture was heated gradually to 160 ? under vigorous stirring, after reaction for 4 hours, and then the mixture was heated to 180 ? for 4 hours, then cooled to rt gradually. To the resulting mixture was added water (150 mL) , the mixture was stirred at rt for 1 hour and filtered under vacuum. The residue was washed with a large amount of water until the filtrate become colorless, then washed with acetone (20 mL) and methanol (70 mL) successively, and then dried to give the title compound as a brick red solid (5.041 g, 86.8 percent) .MS (ESI, neg. ion) m/z: 179.1 [M-H] -; and1H NMR (DMSO-d6, 600 MHz) ? (ppm) : 11.29 (s, 2H) , 7.57 (dd, J = 8.4 Hz, 2.7 Hz, 1H) , 7.53 (td, J = 8.7 Hz, 2.8 Hz, 1H) , 7.19 (dd, J = 8.8 Hz, 4.3 Hz, 1H) .
86.6% at 160 - 180℃; for 8 h; Sealed tube Urea (29.0g, 482.9mmol) and 2-amino-5-fluorobenzoic acid (5.0g, 32.2mmol) were added to a sealed 200mL sealed tube, under vigorous stirring gradually warmed to 160 , 4 hours before warming to 180 , after 4 hours, gradually cooled to room temperature, water (150 mL) added to the reaction solution, followed by stirring at room temperature for 1 hour, filtered off with suction, the filter residue washed with a lot of water to the filtrate was colorless, then the filter residue washed with acetone (150 mL) , washed with methanol (70 mL), and dried to give the title compound residue (brick red solid, 5.041g, 86.8percent).
80% at 150℃; for 10 h; General procedure: A mixture of 2-aminobenzoic acid 3a (2.00 g, 14.91 mmol), urea (4.40 g,73.26 mmol) in phenol (6.00 g, 63.76 mmol) was heated at 150 Cunder the reflux for 10 h. The reaction mixture was cooled downto 100 C and ethanol/water (1:1) 10 mL was added drop-wise.The reaction mixture was cooled to rt, filtered, washed with ethanol(5 mL), and dried to afford 4a in 53percent yield (1.26 g).
71.8% at 180℃; for 1.5 h; Sealed tube Adding urea (10.45g, 174.05mmol) and 2-amino-5-fluorobenzoic acid (1.80g, 11.60mmol), The reaction temperature was raised to 180 1.5 hours in a stainless steel sealed tube. The reaction was stopped, cooled to room temperature, methanol (25mL), filtered, and dried in vacuo to give the title compound as a pale yellow solid (1.50g, 71.8percent).

Reference: [1] Patent: WO2017/12502, 2017, A1, . Location in patent: Page/Page column 52
[2] Patent: WO2017/88759, 2017, A1, . Location in patent: Paragraph 00213
[3] Patent: CN105949203, 2016, A, . Location in patent: Paragraph 0179; 0181; 0182
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7717 - 7727
[5] Patent: CN105732591, 2016, A, . Location in patent: Paragraph 0198; 0199; 0200; 0201
[6] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[7] Tetrahedron, 2012, vol. 68, # 43, p. 8908 - 8915
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 681 - 693
  • 33
  • [ 446-08-2 ]
  • [ 88145-90-8 ]
  • [ 174564-91-1 ]
Reference: [1] Patent: US5688803, 1997, A,
  • 34
  • [ 446-08-2 ]
  • [ 134517-57-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7717 - 7727
[3] Patent: CN105732591, 2016, A,
[4] Patent: WO2017/12502, 2017, A1,
[5] Patent: WO2017/88759, 2017, A1,
[6] Patent: CN105949203, 2016, A,
  • 35
  • [ 446-08-2 ]
  • [ 769158-12-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[2] Patent: WO2017/12502, 2017, A1,
[3] Patent: CN105949203, 2016, A,
  • 36
  • [ 446-08-2 ]
  • [ 953039-63-9 ]
Reference: [1] Patent: EP3287463, 2018, A1,
[2] Patent: US2018/208604, 2018, A1,
  • 37
  • [ 446-08-2 ]
  • [ 259269-84-6 ]
YieldReaction ConditionsOperation in experiment
66.4% at 20℃; N-Bromosuccinimide (631 mg, 3.55 mmol) was added portionwise to a stirred solution of 2-amino-5-fluorobenzoic acid (7, 500 mg, 3.22 mmol) dissolved in acetic acid (5 ml) and the reaction mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration, washed with petroleum ether (20 ml) and dried to a constant weight to afford 2-amino-3-bromo-5-fluorobenzoic acid (11, 501 mg, 66.4percent) as a clear beige solid, which was used without further purification: LCMS (tR=1.35 min, purity=100percent), ESI m/z, no ion detected; 1H NMR (DMSO-d6) δ (ppm) 6.76 (br s, 2H), 7.55 (dd, J=3.0 Hz, JH-F=9.4 Hz, 1H), 7.71 (dd, J=3.0 Hz, JH-F=7.8 Hz, 1H), 12.72 (br s, 1H); 13C NMR (DMSO-d6) δ (ppm) 109.4 (d, JC-F=7.1 Hz); 111.1 (d, JC-F=7.1 Hz), 116.2 (d, JC-F=22.1 Hz), 124.9 (d, JC-F=24.8 Hz), 145.1, 151.4 (d, JC-F=235.3 Hz), 168.1 (d, JC-F=2.7 Hz).
62% at 0 - 20℃; for 16 h; 2-Amino-5-fluorobenzoic acid (20 g, 129 mmol) was dissolved in acetic acid (250 mL) at 0°C, and then N-bromosuccinimide(25 g, 140 mmol) was added in batchesto the above solution. The mixture was stirred at room temperaturefor 16 hours and then filtered. The filter cake was washed with petroleum ether (100 mL 3 3). The filter cake was driedin vacuo to deliver a white solid 21-g (18.8 g, yield: 62percent), this product was used without further purification. LC-MS(ESI): m/z = 234 [M+H]+.
62% at 0 - 20℃; for 16 h; At 0° C., 2-amino-5-fluorobenzoic acid (20 g, 129 mmol) was dissolved in glacial acetic acid (250 mL), and N-bromosuccinimide (25 g, 140 mmol) was added thereto in portions.
The mixture was filtered after stirring at room temperature for 16 hours and the filter cake was washed with petroleum ether (100 mL*3).
The filter cake was dried in vacuo to give 46-g as a white solid (18.8 g, yield 62percent) which was used without further purification. LC-MS (ESI): m/z=234[M+H]+.
Reference: [1] Tetrahedron, 2012, vol. 68, # 2, p. 534 - 543
[2] Patent: EP3287463, 2018, A1, . Location in patent: Paragraph 0203; 0208
[3] Patent: US2018/208604, 2018, A1, . Location in patent: Paragraph 0502-0503
[4] Patent: WO2016/105564, 2016, A1, . Location in patent: Paragraph 0288
  • 38
  • [ 446-08-2 ]
  • [ 1022961-12-1 ]
YieldReaction ConditionsOperation in experiment
56% With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 16 h; A mixture of 2-amino-5-fluorobenzoic acid (5.0 g,32.26 mmol), NCS (4.39 g, 32.9 mmol) and DMF (30 mE) was stirred at room temperature for 16 hours. The reaction solution was diluted with water (100 mE) and extracted with ethyl acetate (3x100 mE). The organic layer was combined, washed with saturated saline, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was stirred with dichioromethane (100 mE) for 10 mm-utes, and filtrated to give compound 7-f (3.4 g, yield 56percent), which was grey solid. LC-MS (ESI): mlz=190.0 (M+H).
Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 3163 - 3170
[2] Patent: US2016/244432, 2016, A1, . Location in patent: Paragraph 0232; 0233
  • 39
  • [ 446-08-2 ]
  • [ 1262888-28-7 ]
Reference: [1] Molecules, 2017, vol. 22, # 2,
  • 40
  • [ 446-08-2 ]
  • [ 1352717-91-9 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 2, p. 534 - 543
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