284030-57-5|4-Amino-2,3-difluoro-5-nitrobenzoic acid| Ambeed

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Quality Control of [ 284030-57-5 ] Purity: 95% SDS Specification

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Product Details of [ 284030-57-5 ]

CAS No. :	284030-57-5
Formula :	C₇H₄F₂N₂O₄
M.W :	218.11
SMILES Code :	O=C(O)C1=CC([N+]([O-])=O)=C(N)C(F)=C1F
MDL No. :	MFCD08543937
InChI Key :	WXXHOWQPFHXRDY-UHFFFAOYSA-N
Pubchem ID :	16244088

Safety of [ 284030-57-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 284030-57-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	6.0
Num. H-bond donors	2.0
Molar Refractivity	46.54
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	109.14 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.48
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.35
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.0
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.28
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.69
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.57

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.21
Solubility	1.35 mg/ml ; 0.00621 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.24
Solubility	0.124 mg/ml ; 0.00057 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.36
Solubility	9.54 mg/ml ; 0.0438 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.67 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	3.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.11

Application In Synthesis of [ 284030-57-5 ]

* 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.

Downstream synthetic route of [ 284030-57-5 ]

[ 284030-57-5 ] Synthesis Path-Downstream 1~35

1
[ 284030-57-5 ]
[ 18107-18-1 ]
[ 284030-58-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With methanol; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	Step C: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4. A 2 M solution of TMS diazomethane in hexanes (6.88 mL, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> 3 (2.00 g, 9.17 mmol) in 25 mL of 4:1 THF:MeOH at 0 C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 hours, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-1) detected.
92%		A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> 3 (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-1) detected.
92%	In tetrahydrofuran; methanol; hexane; at 0 - 20℃; for 0.5h;Inert atmosphere;	4-Amino-2, 3-difluoro-5-nitro-benzoic acid methyl ester 4A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> 3 (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 C under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure anddried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-1) detected.

84%

In methanol; at 0℃; for 1h;

Trimethylsilylated diazomethane (1.26 g, 11.02 mmol) was slowly added dropwise to a solution of compound 3 (2.0 g, 9.17 mmol) in methanol at 0 C, and the reaction was continued for 1 h. The reaction was quenched by the addition of a few drops of acetic acid, and then the mixture was evaporated. EtOAc (EtOAc) Methanol (10 ml) was beaten to obtain a pure product of 1.8 g in a yield of 84%.

References: [1]Patent: US2004/116710,2004,A1 .Location in patent: Page 6; 16.
[2]Patent: US2003/232869,2003,A1 .Location in patent: Page 9; 16.
[3]Patent: WO2013/142182,2013,A2 .Location in patent: Page/Page column 22.
[4]Patent: CN109438362,2019,A .Location in patent: Paragraph 0100-0103; 0108-0109.

2
[ 197520-71-1 ]
[ 284030-57-5 ]

Yield	Reaction Conditions	Operation in experiment
95%		Step B: 4-Amino-2,3-difluoro-5-nitro-benzoic acid 3 [0122] Ammonium hydroxide solution (30% in water) (35 mL, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 mL water at 0 C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 hours, the reaction mixture is cooled to 0 C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.
95%		Ammonium hydroxide solution (-30% in water) (35 ml, 271 mmol) was added to a solution of 2,3,4-trifluoro-5- nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 0C with stirring. Upon completion of the ammonium hydroxide addition, the reaction mixture was warmed to room temperature with stirring. After 2.5 hours, the reaction mixture was cooled to 0 0C and concentrated HCl was carefully added until pH of reaction mixture was 0. The reaction mixture was diluted <n="20"/>with water (30 ml) and extracted with diethyl ether (3 x 50 ml). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-I) detected.
95%		Ammonium hydroxide solution (30% in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 ml water at 0 C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3×50 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.

95%	With ammonium hydroxide; In water; at 0 - 20℃; for 2.5h;	4-Amino-2, 3-difluoro-5-nitro-benzoic acid 3Ammonium hydroxide solution (-30% in water) (35 ml, 271 mmol) is added to asolution of 2,3,4-trifluoro-5-nitro-benzoic acid 2 (15 g, 67.8 mmol) in 30 ml water at 0 C with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 C andconcentrated HC1 is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3 x 50 ml). combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product: MS APCI (-) m/z 217 (M-1) detected.
88%		Step B; 4-Amino-2.3-difluoro-5-nitrobenzoic acid; To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (167.2 g, 0.756 mol, 1 equiv.) in 400 mL of distilled water was added concentrated ammonium hydroxide (28 % NH3 solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv), ensuring that internal temperature was below 6.0 C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90% complete as determined by HPLC, the mixture was cooled in an ice-water bath, and concentrated HCl (350 mL) was then added dropwise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and then filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 0C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 a% (220 nm) and 96.96 a% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 a% (220 nm) and 95.40 a% (254 nm). Combined yield of 4-amino-2,3-difluoro-5- nitrobenzoic acid was 144.8 g (88 %). 1H NMR (400 MHz, DMSO-d6) delta 8.0 (2H, br s, NH2) 8.42 (IH, dd, J 1.5, 7.6, Ar-H); 19F NMR (376 MHz, DMSO- d6) delta -153.9, -129.0. 13C NMR (100 MHz, DMSO-d6) delta 106 (Q d, J 10), 126 (CH), 128 (C), 140 (C-F, dd, J241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR vmjcm~l 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected. EPO <DP n="52"/>
88%		To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 mL of distilled water EPO <DP n="65"/>was added concentrated ammonium hydroxide (28% NH3 solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv.) ensuring that internal temperature was below 6.0 0C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90% complete by HPLC, the reaction mixture was cooled in an ice- water bath and concentrated HCl (350 mL) was then added dropwise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 a% (220 nm) and 96.96 a% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 a% (220 nm) and 95.40 a% (254 nm). Combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88%). 1H NMR (400 MHz, d6 DMSO) delta 8.0 (2H5 br s, NH2) 8.42 (IH, dd, J 1.5, 7.6, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -129.0. 13C NMR (100 MHz, d6 DMSO) delta 106 (C, d, J 10), 126 (CH), 128 (C), 140 (C-F, dd, J 241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v^/cm"1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected.; To a mixture of 2,3,4- trifluoro-5-nitrobenzoic acid (2) (167.2 g, 0.756 mol, 1 equiv) in 400 niL of distilled water was added concentrated ammonium hydroxide (28% NH3 solution; 340 g, 380 mL, 4.23 mol, 5.6 equiv.) ensuring that internal temperature was below 6.0 C over 2-2.5 hours. The mixture was stirred for 50 minutes and then warmed to room temperature for 3-4 hours. When the reaction was >90% complete by HPLC, the reaction mixture was cooled in an ice- water bath and concentrated HCl (350 mL) was then added drop-wise to adjust pH = 2. The slurry was stirred for 1 hour with ice bath cooling and filtered. The cake was rinsed with 1 L of distilled water and then with 350 mL of MTBE. The cake was oven-dried at 48 C overnight to give 134.9 g of a yellow solid. HPLC was 83.6 a% (220 nm) and 96.96 a% (254 nm). The MTBE filtrate was concentrated on a rotary evaporator and pumped overnight to give 9.9 g of a second crop as a yellow solid: HPLC was 81.1 a% (220 nm) and 95.40 a% (254 nm). Combined yield of 4-amino-2,3-difluoro-5-nitrobenzoic acid (3) was 144.8 g (88%). 1H NMR (400 MHz, d6 DMSO) delta 8.0 (2H, br s, NH2) 8.42 (IH, dd, J 1.5, 7.6, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -129.0. 13C NMR (100 MHz, d6 DMSO) delta 106 (C, d, J 10), 126 (CH), 128 (C), 140 (C-F5 dd, J241, 16), 140.8 (C, dd, J 12, 4), 153 (C-F, dd, J 263, 11), 164 (COOH). IR v^/cm"1 3494, 3383, 1697, 1641, 1280. MS APCI (-) m/z 217 (M-I) detected.
81%	With ammonium hydroxide; In water; at 0℃; for 6h;	At 0 C,NH3·H2O (2.38 g, 67.87 mmol) was slowly added dropwise to an aqueous solution of compound 2 (3 g, 13.57 mmol).After the addition was completed, the reaction was continued for 6 hours. The reaction was quenched by the addition of 1 M hydrochloric acid until the pH of the solution was adjusted to about 2, and extracted with dichloromethane (60 ml × 3).The solvent was removed to give a pale yellow solid product (2.4 g, yield 81%)
64%	In ammonium hydroxide;	Step b Preparation of 4-amino-2,3-difluoro-5-nitrobenzoic acid Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10% aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64% yield; 1H-NMR (400 MHz; DMSO) delta13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); 19F-NMR (376 MHz; DMSO) delta-128.69 to -128.76 (m), -153.60 (d).
64%		Solid 5-nitro-2,3,4-trifluorobenzoic acid (0.75 g, 0.00339 mol) was dissolved in concentrated ammonium hydroxide (25 ml) to give instantly a yellow solution. A precipitate began to form within five minutes, after which time the mixture was acidified to pH 0 with concentrated aqueous hydrochloric acid. A yellow precipitate rapidly formed. The mixture was heated to boiling and was filtered hot. The yellow solids were washed with 10% aqueous hydrochloric acid and were suction dried to afford 0.47 g of a yellow powder; 64% yield; 1H-NMR (400 MHz; DMSO) delta 13.32 (s, 1H), 8.36 (d, 1H, J=7.6 Hz), 7.98 (s, 2H); 19F-NMR (376 MHz; DMSO) delta -128.69 to -128.76 (m), -153.60 (d).
14 g (95%)	With hydrogenchloride; ammonium hydroxide; In water;	Step B 4-Amino-2,3-difluoro-5-nitro-benzoic acid Ammonium hydroxide solution (~30% in water) (35 ml, 271 mmol) is added to a solution of 2,3,4-trifluoro-5-nitro-benzoic acid (15 g, 67.8 mmol) in 30 ml water at 0 C. with stirring. Upon completion of ammonium hydroxide addition the reaction mixture is warmed to room temperature with stirring. After 2.5 h, the reaction mixture is cooled to 0 C. and concentrated HCl is carefully added until pH of reaction mixture is near 0. The reaction mixture is diluted with water (30 ml) and extracted with diethyl ether (3*50 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give 14 g (95%) of pure desired product.

References: [1]Patent: US2004/116710,2004,A1 .Location in patent: Page 6; 16.
[2]Patent: WO2007/76245,2007,A2 .Location in patent: Page/Page column 18-19.
[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; 22.
[5]Patent: WO2007/2092,2007,A1 .Location in patent: Page/Page column 50.
[6]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 2; 63; 64; 76.
[7]Patent: CN109438362,2019,A .Location in patent: Paragraph 0100-0103; 0106-0107.
[8]Patent: US6469004,2002,B1 .
[9]Patent: US7030119,2006,B1 .Location in patent: Page/Page column 39-40.
[10]Patent: US2003/216460,2003,A1 .

3
[ 186581-53-3 ]
[ 284030-57-5 ]
[ 284030-58-6 ]

Yield	Reaction Conditions	Operation in experiment
1.95 g (92%)	With acetic acid; In tetrahydrofuran; methanol;	Step C 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product.

References: [1]Patent: US2003/216460,2003,A1 .

4
[ 284030-57-5 ]
[ 284030-58-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With diazomethyl-trimethyl-silane; In tetrahydrofuran; methanol; hexane; at 0 - 20℃; for 0.5h;	A 2 M solution of tetramethylsilane (TMS) diazomethane in hexanes (6.88 ml, 13.75 mmol) was added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> (2.00 g, 9.17 mmol) in 25 ml of 4: 1 Tetrahydrofuran (THF):MeOH at 0 0C under nitrogen atmosphere. Upon completion of addition, reaction mixture was warmed to room temperature. After 0.5 hours, excess TMS diazomethane was destroyed by the careful addition of acetic acid. The reaction was then concentrated under reduced pressure and dried in vacuo 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-I) detected.
70%	With hydrogenchloride; In methanol;	Step c Preparation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5-184 C.; 1H-NMR (400 MHz; DMSO) delta8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) delta-128.85 to -128.92 (m), -153.29 (d); MS (APCl-) 231 (M-1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm-1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.
70%	With hydrogenchloride; In methanol; for 23h;Heating / reflux;	Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5-184 C.; 1H-NMR (400 MHz; DMSO) delta 8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) delta -128.85 to -128.92 (m), -153.29 (d); MS (APCl-) 231 (M-1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm-1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.

References: [1]Patent: WO2007/76245,2007,A2 .Location in patent: Page/Page column 19.
[2]Patent: US6469004,2002,B1 .
[3]Patent: US7030119,2006,B1 .Location in patent: Page/Page column 40.

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Yield	Reaction Conditions	Operation in experiment
92%	With chloro-trimethyl-silane; for 15.0833h;Heating / reflux;	Step C; 4-Amino-2,3-difluoro-5-nitrobenzoic acid methyl ester; TMSCl (132 g, 1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3- difluoro-5-nitrobenzoic acid (132.3 g, 0.607 mol, 1 equiv.) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. When the reaction was complete as determined by HPLC, the mixture was cooled in an ice-water bath for 45 minutes. The reaction mixture was then filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 0C under high vacuum to give 128.8 g (92%) of 4-amino-2,3-difluoro-5- nitrobenzoic acid methyl ester. HPLC was 97.9 a% (220 n?i) and 99.2 a % (254 nm). 1H NMR (400 MHz, DMSO-d6) delta 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (IH, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, D6 DMSO) delta -153.6, -129.2. 13C NMR (100 MHz, DMSO-d6) delta 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J 2.7,), 128 (CH, d, J 5), 140 (C-F, dd, J 244, 15,), 141 (C, dd, J 14, 5), 152 (C-F, dd, J263, 11), 162 (COO, t, J3). IR vmjcm l 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m/z 231 (M-I) detected.
92%	With chloro-trimethyl-silane; for 15h;Heating / reflux;	TMSCl (132 g,1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5- nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice- water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 C under high vacuum to provide 128.8 g (92%) of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> methyl ester (4). HPLC was 97.9 a% (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 3.84 (3H, s, OMe)5 8.1 (2H, br s, NH2), 8.43 (IH, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.6, -129.2. 13C NMR (100 MHz, d6 DMSO) delta 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J2.7,), 128 (CH5 d, J 5), 140 (C-F5 dd, J244, 15,), 141 EPO <DP n="66"/>(C, dd, J 14, 5), 152 (C-F, dd, J263, 11), 162 (COO, t, J 3). IR vmax/cm'' 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m/z 23.1 (M-I) detected.; TMSCl (132 g,1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5- nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was EPO <DP n="78"/>heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 C under high vacuum to provide 128.8 g (92%) of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> methyl ester (4). HPLC was 97.9 a% (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (IH, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.6, -129.2. 13C NMR (100 MHz, d6 DMSO) delta 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J2.7,), 128 (CH, d, J5), 140 (C-F, dd, J244, 15,), 141 (C, dd, J 14, 5), 152 (C-F, dd, J263, 11), 162 (COO, t, J 3). IR vmjcra l 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m/z 231 (M-I) detected.

References: [1]Patent: WO2007/2092,2007,A1 .Location in patent: Page/Page column 51.
[2]Patent: WO2007/2157,2007,A2 .Location in patent: Page/Page column 2; 64; 65; 76; 77.

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References: [1]Patent: WO2013/142182,2013,A2 .
[2]Patent: CN109438362,2019,A .

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[ 606143-94-6 ]