113512-71-3|5-Amino-2,4-difluorophenol| Ambeed

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Quality Control of [ 113512-71-3 ] Purity: 95% SDS Specification

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Product Details of [ 113512-71-3 ]

CAS No. :	113512-71-3
Formula :	C₆H₅F₂NO
M.W :	145.11
SMILES Code :	OC1=CC(N)=C(F)C=C1F
MDL No. :	MFCD04973718
InChI Key :	CXADAFQCFSVRGN-UHFFFAOYSA-N
Pubchem ID :	2782999

Safety of [ 113512-71-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 113512-71-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	32.79
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.22
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	1.09
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.1
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.	1.68
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	1.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.52

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.87
Solubility	1.96 mg/ml ; 0.0135 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.65
Solubility	3.22 mg/ml ; 0.0222 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.0
Solubility	1.45 mg/ml ; 0.01 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	Yes
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.	-6.41 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

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	1.0 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)	1.26

Application In Synthesis of [ 113512-71-3 ]

* 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 [ 113512-71-3 ]

[ 113512-71-3 ] Synthesis Path-Downstream 1~35

1
[ 3282-30-2 ]
[ 113512-71-3 ]
[ 152169-44-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogenchloride; sodium chloride; In pyridine;	(4) 18.9 g (130 mmol) of the above <strong>[113512-71-3]5-amino-2,4-difluorophenol</strong> was dissolved in 45 mL of pyridine, 16.0 mL of pivaloyl chloride was added dropwise under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed once with 1N hydrochloric acid, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 27.0 g of 2,4-difluoro-5-pivaloylaminophenol (yield: 91%). NMR (90MHz, CDCl3) delta (ppm) 1.35 (s, 9H), 6.90 (t, 1H, J=10.4Hz), 7.65 (brs, 1H), 7.94 (brs, 1H), 8.24 (dd, 1H, J=9.1, 8.0Hz) MS (M/Z) 229 (M+) Molecular formula C11H13F2NO2=229
	With hydrogenchloride; In pyridine;	5-Amino-2,4-difluorophenol (18.9 g, 130 mmol) obtained above was dissolved in pyridine (45mL) and pivaloyl chloride (16.0 mL) was added dropwise to the mixture for 8 minutes under ice-cooling. The reaction mixture was stirred for additional 30 minutes at the same temperature. Hydrochloric acid (1 N) was added to the reaction mixture and the mixture was extracted with ether. The organic layer was washed with 1 N hydrochloric acid, water, and brine once respectively, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated to give 2,4-difluoro-5-pivaloylaminophenol (27.0 g, yield: 91%). 1H NMR (90 MHz, CDCl3) delta (ppm) 1.35 (s, 9H), 6.90 (t, J = 10.4Hz, 1H), 7.65 (brs, 1H), 7.94 (brs, 1H), 8.24 (dd, J = 9.1, 8.0Hz, 1H) EI-MS (m/e) 229 M+molecular formula C11H13F2NO2= 229

References: [1]Synthesis,1997,p. 1446 - 1450.
[2]Patent: EP638566,1995,A1 .
[3]Patent: EP755928,1997,A1 .

2
[ 113512-57-5 ]
[ 113512-71-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	carbon palladium; In nitrogen; ethyl acetate;	(3) 24.9 g (142 mmol) of the above 2,4-difluoro-5-nitrophenol was dissolved in 150 mL of ethyl acetate, 5.0 g of 10% palladium/carbon was added and the mixture was stirred at 50 to 60 C for 27 hours under a stream of hydrogen. The gaseous phase in the reaction vessel was substituted with nitrogen, the reaction solution was filtered by suction and the solvent was distilled off under reduced pressure. The residue was triturated with n-hexane to give 19.8 g of 5-amino-2,4-difluorophenol (yield: 96%). NMR (90MHz, CDCl3) delta (ppm) 4.75 (brs, 2H), 6.37 (t, 1H, J=9.1Hz), 6.87 (t, 1H, J=11.1Hz), 9.21 (s, 1H) MS (M/Z) 145 (M+) Molecular formula C6H5F2NO=145
96%	With hydrogen;palladium dihydroxide; In ethyl acetate; for 6h;	To a suspension of 2,4-difluoro-5-nitrophenol (1.01 g, 5.77 mmol) in EtOAc was added palladium hydroxide (0.08 g, 0.57 mmol) and the resulting slurry was stirred under a hydrogen atmosphere for 6 h. The mixture was filtered through a Celite pad, washing with EtOAc (2*10 mL) and the filtrate was concentrated to afford 5-amino-2,4-difluorophenol (0.8 g, 96% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) delta 9.28 (s, 1H), 6.91 (t, J=7.2 Hz, 1H), 6.35 (t, J=8.8 Hz, 1H), 4.84 (brs, 2H); MS (ESI) m/z: 146.0 (M+H+).
96%	With hydrogen; palladium(II) hydroxide; In ethyl acetate; for 6h;	To a suspension of 2,4-difluoro-5-nitrophenol (1.01 g, 5.77 mmol) in EtOAc was added palladium hydroxide (0.08 g, 0.57 mmol) and the resulting slurry was stirred under a hydrogen atmosphere for 6h. The mixture was filtered through a Celite pad, washing with EtOAc (2x10 mL) and the filtrate was concentrated to afford 5-amino-2,4- difluorophenol (0.8 g, 96% yield) as a solid. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6) delta 9.28 (s, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.35 (t, J = 8.8 Hz, 1H), 4.84 (brs, 2H); MS (ESI) m/z: 146.0 (M+H+).

94.6%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 16h;	To a stirred solution of 2,4- difluoro-5-nitrophenol (1, 25 g, 0.143 mol) in EtOAc (200 mL), 10% Pd/C (4.55 g, 0.043 mol) was added. The reaction mixture was stirred at RT under H2 for 16 h. After the reaction completion (TLC), the reaction mixture was filtered by using celite bed, washed with EtOAc (1000 mL) and concentrated under reduced pressure to afford 5-amino-2,4- difluorophenol (2) as off brown solid (20.10 g, 94.6%); LCMS (ESI positive ion) m/z: calculated: 145.03; observed: 146.2 (M+l).
	palladium on activated carbon; In nitrogen; ethyl acetate;	2,4-Difluoro-5-nitrophenol (24.9 g, 142 mmol) obtained above was dissolved in ethyl acetate (150 mL) and 10% palladium on activated carbon (5.0 g) was added to the mixture. The reaction mixture was stirred under hydrogen stream at 50 to 60 C for 27 hours. After the atmosphere in reactor was replaced with nitrogen, the reaction mixture was filtrated with suction. The solvent in filtrate was distilled off under reduced pressure, the residue was triturated with hexane to give 5-amino-2,4-difluorophenol (19.8 g, yield: 96%). 1H NMR (90 MHz, CDCl3) delta (ppm) 4.75 (brs, 2H), 6.37 (t, J = 9.1 Hz, 1H), 6.87 (t, J = 11.1 Hz, 1H), 9.21 (s, 1H) EI-MS (m/e) 145 M+molecular formula C6H5F2NO = 145

References: [1]Synthesis,1997,p. 1446 - 1450.
[2]Patent: EP638566,1995,A1 .
[3]Patent: US2008/90856,2008,A1 .Location in patent: Page/Page column 35.
[4]Patent: WO2013/36232,2013,A2 .Location in patent: Paragraph 00225.
[5]Patent: WO2018/178338,2018,A1 .Location in patent: Page/Page column 142.
[6]Patent: EP755928,1997,A1 .

3
[ 2457-47-8 ]
[ 113512-71-3 ]
5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		To a solution of <strong>[113512-71-3]5-amino-2,4-difluorophenol</strong> (0.3 g, 2.07 mmol) in DMSO (2 mL) was added potassium t-butoxide (0.23 g, 2.07 mmol) at RT. After stirring for 1 h, 3,5-dichloropyridine (0.37 g, 2.5 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the mixture was heated to 190 C. for 1 h in microwave reactor. Water (30 mL) was added, and the product was extracted with EtOAc (2*35 mL) and the combined organic layers were washed with brine solution, dried (Na2SO4), concentrated in vacuo and purified by chromatography (EtOAc/hexane) to afford 5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine (0.35 g, 66% yield) as a solid. 1H NMR (400 MHz, Acetone-d6) delta 8.33-8.30 (m, 2H), 7.44 (t, J=2.4 Hz, 1H), 7.13 (t, J=10.8 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.85 (brs, 2H); MS (ESI) m/z: 257.0 (M+H+).
66%		To a suspension of 2,4-difluoro-5-nitrophenol (1.01 g, 5.77 mmol) in EtOAc was added palladium hydroxide (0.08 g, 0.57 mmol) and the resulting slurry was stirred under a hydrogen atmosphere for 6h. The mixture was filtered through a Celite pad, washing with EtOAc (2x10 mL) and the filtrate was concentrated to afford 5-amino-2,4- difluorophenol (0.8 g, 96% yield) as a solid. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6) delta 9.28 (s, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.35 (t, J = 8.8 Hz, 1H), 4.84 (brs, 2H); MS (ESI) m/z: 146.0 (M+H+). [00226] To a solution of <strong>[113512-71-3]5-amino-2,4-difluorophenol</strong> (0.3 g, 2.07 mmol) in DMSO (2 mL) was added potassium t-butoxide (0.23 g, 2.07 mmol) at RT. After stirring for lh, 3,5-dichloropyridine (0.37 g, 2.5 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the mixture was heated to 190 C for lh in microwave reactor. Water (30 mL) was added, and the product was extracted with EtOAc (2x35 mL) and the combined organic layers were washed with brine solution, dried (Na2SC>4), concentrated in vacuo and purified by chromatography (EtOAc/hexane) to afford 5-(5-chloropyridin-3-yloxy)- 2,4-difluorobenzenamine (0.35 g, 66% yield) as a solid. FontWeight="Bold" FontSize="10" H NMR (400 MHz, Acetone-i 6) delta 8.33 - 8.30 (m, 2H), 7.44 (t, J = 2.4 Hz, 1H), 7.13 (t, J = 10.8 Hz, 1H), 6.78 (t, J = 8.4 Hz, 1H), 4.85 (brs, 2H); MS (ESI) m z: 257.0 (M+H+).

References: [1]Patent: US2008/90856,2008,A1 .Location in patent: Page/Page column 35.
[2]Patent: WO2013/36232,2013,A2 .Location in patent: Paragraph 00226.

4
[ 367-27-1 ]
[ 113512-71-3 ]

References: [1]Synthesis,1997,p. 1446 - 1450.
[2]Patent: WO2013/36232,2013,A2 .

5
[ 113512-71-3 ]
[ 152169-56-7 ]

References: [1]Synthesis,1997,p. 1446 - 1450.

6
[ 113512-71-3 ]
[ 152835-71-7 ]

References: [1]Synthesis,1997,p. 1446 - 1450.

7
[ 113512-71-3 ]
[ 152169-45-4 ]

References: [1]Synthesis,1997,p. 1446 - 1450.

8
[ 113512-71-3 ]
3-(2,2-Dimethyl-propionylamino)-2,6-difluoro-5-(tetrahydro-pyran-2-yloxy)-benzoic acid ethyl ester [ No CAS ]

References: [1]Synthesis,1997,p. 1446 - 1450.

9
[ 113512-71-3 ]
[ 152835-78-4 ]

References: [1]Synthesis,1997,p. 1446 - 1450.
[2]Synthesis,1997,p. 1446 - 1450.
[3]Synthesis,1997,p. 1446 - 1450.

10
[ 113512-71-3 ]
[ 152169-46-5 ]

References: [1]Synthesis,1997,p. 1446 - 1450.

11
[ 113512-71-3 ]
[ 152835-84-2 ]

References: [1]Synthesis,1997,p. 1446 - 1450.

12
[ 113512-71-3 ]
3-[(2,2-Dimethyl-propionyl)-ethoxycarbonyl-amino]-2,6-difluoro-5-(tetrahydro-pyran-2-yloxy)-benzoic acid ethyl ester [ No CAS ]

References: [1]Synthesis,1997,p. 1446 - 1450.

13
[ 113512-71-3 ]
N-[2-{3-[4-(2,2-Dimethyl-propionylamino)-3-fluoro-phenyl]-3-oxo-propionyl}-4,6-difluoro-3-(tetrahydro-pyran-2-yloxy)-phenyl]-2,2-dimethyl-propionamide [ No CAS ]

References: [1]Synthesis,1997,p. 1446 - 1450.

14
[ 113512-71-3 ]
N-[2-{3-[4-(2,2-Dimethyl-propionylamino)-3-fluoro-phenyl]-3-oxo-propionyl}-4,6-difluoro-3-(tetrahydro-pyran-2-yloxy)-5-trimethylsilanyl-phenyl]-2,2-dimethyl-propionamide [ No CAS ]

References: [1]Synthesis,1997,p. 1446 - 1450.

15
[ 152169-43-2 ]
[ 113512-71-3 ]

References: [1]Synthesis,1997,p. 1446 - 1450.
[2]Patent: WO2013/36232,2013,A2 .

16
Carbonic acid 2,4-difluoro-5-nitro-phenyl ester ethyl ester [ No CAS ]
[ 113512-71-3 ]

References: [1]Synthesis,1997,p. 1446 - 1450.

Yield	Reaction Conditions	Operation in experiment
19.8 g (96%)		The reaction vessel was filled with nitrogen, the reaction solution was filtered by means of suction, the solvent was distilled off under reduced pressure, and the residue was triturated with n-hexane to give 19.8 g (96%) of 5-amino-2,4-difluorophenol. NMR (90 MHz, CDCl3) delta (ppm) 4.75 (2H, brs), 6.37 (1H, t, J=9.1), 6.87 (1H, t, J=11.1), 9.21 (1H, s) MS (M/Z) 145 (M+)
		Molecular formula C6 H5 F2 NO=145 18.9 g (130 mmol) of the resulting 5-amino-2,4-difluorophenol was dissolved in 45 ml of pyridine, 16.0 ml of pivaloyl chloride was added dropwise over 8 minutes under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted with ether. The organic layer was washed once with a 1N aqueous solution of hydrochloric acid, water and an aqueous saturated solution of sodium chloride, respectively, and dried over magnesium sulfate.

18
4-chloro-6,7-dimethoxylquinazoline hydrochloride [ No CAS ]
[ 113512-71-3 ]
4-(2,4-difluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In isopropyl alcohol;	EXAMPLE 11 4-Chloro-6,7-dimethoxyquinazoline hydrochloride (300 mg, 1.15 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and <strong>[113512-71-3]2,4-difluoro-5-hydroxyaniline</strong> (184 mg, 0.90 mmol) in isopropanol (10 ml) were heated at reflux for 2 hours. The reaction mixture was then allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(2,4-difluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (250 mg, 65%) 1H NMR Spectrum: (DMSOd6) 3.99(s, 6H); 7.05(dd, 1H); 7.17(s, 1H); 7.40(dd, 1H); 8.10(s, 1H); 8.68(s, 1H) MS-ESI: 334 [MH]+

References: [1]Patent: US6184225,2001,B2 .

19
[ 196194-44-2 ]
[ 113512-71-3 ]
4-(2,4-difluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	In thionyl chloride; N,N-dimethyl-formamide;	EXAMPLE 12 6-Methoxy-7-(2-methoxyethoxy)-3,4-dihydroquinazolin-4-one (200 mg, 0.8 mmol), (prepared as described for the starting material in Example 9), and DMF (0.1 ml) in thionyl chloride (20 ml) were heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was dissolved in isopropranol (15 ml), <strong>[113512-71-3]2,4-difluoro-5-hydroxyaniline</strong> (128 mg, 0.88 mmol), (prepared as described for the starting material in Example 11), added, and the mixture heated at reflux for 2 hours. The reaction mixture was then allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(2,4-difluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (83 mg, 28%). 1H NMR Spectrum: (DMSOd6) 3.35(s, 3H); 3.77(t, 2H); 4.00(s, 3H); 4.30(t, 2H); 7.10)(dd, 1H); 7.36(s, 1H); 7.40(t, 2H); 8.20(s, 1H); 8.78(d, 2H) MS-ESI: 378 [MH]+

References: [1]Patent: US6184225,2001,B2 .

20
2,4-difluoro-5-methoxycarbonyloxyaniline [ No CAS ]
[ 113512-71-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia; In ethanol;	Concentrated aqueous ammonia (20 ml) was added to a solution of 2,4-difluoro-5-methoxycarbonyloxyaniline (2.0 g, 9.85 mmol) in ethanol (100 ml) and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and most of the organic volatiles were removed by evaporation. The aqueous residue was neutralised to pH7 and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation to give 2,4-difluoro-5-hydroxyaniline (1.2 g, 85%). 1H NMR Spectrum: (DMSOd6) 4.78(s, 2H); 6.34(t,1H); 6.87(t, 1H); 9.23(s, 1H) MS-ESI: 145 [MH]+

References: [1]Patent: US6184225,2001,B2 .

21
[ 6980-08-1 ]
[ 113512-71-3 ]
[ 956488-66-7 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 1964 - 1978.

22
[ 113512-71-3 ]
2,4-difluoro-5-(pyridin-3-yloxy)benzenamine [ No CAS ]

References: [1]Patent: WO2013/36232,2013,A2 .

23
[ 13790-39-1 ]
[ 113512-71-3 ]
4-(2,4-difluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Heating;	General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature.

References: [1]European Journal of Medicinal Chemistry,2016,vol. 112,p. 20 - 32.

24
4-hydroxy-5-oxo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile [ No CAS ]
[ 113512-71-3 ]
4-[(2,4-difluoro-5-hydroxyphenyl)amino]-5-oxo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.8 mg		Example 38 4-[(2,4-Difluoro-5-hydroxyphenyl)amino]-5-oxo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile A 1:1 mixture of 4-chloro-5-oxo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile and 4,5-dichloro-11H-pyrido[2,3-b][1,5]benzodiazepine-8-carbonitrile (100 mg, 0.37 mmol) from Intermediate 10A and <strong>[113512-71-3]5-amino-2,4-difluorophenol</strong> (59 mg, 0.41 mmol) was initially charged in 2.0 ml of isopropanol. 102 mul of a 4 M solution of hydrogen chloride in dioxane were added and the mixture was heated in a microwave apparatus to 160 C. for 20 min. Thereafter, the reaction mixture was diluted with 10 ml of water, and 2 drops of saturated aqueous sodium carbonate solution were added. The mixture was left to stir for 10 min, then the precipitate formed was filtered off with suction and washed with acetonitrile. The solids were stirred with acetonitrile and a few drops of methanol, filtered off with suction again and then dried under reduced pressure. 68.8 mg (44% of theory) of the title compound were obtained in 88% purity. LC/MS (Method 5, ESIpos): Rt=0.77 min, m/z=380 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=6.33 (d, 1H), 6.91 (t, 1H), 7.26 (d, 1H), 7.34-7.36 (m, 1H), 7.39 (d, 1H), 7.48-7.51 (m, 1H), 7.84 (d, 1H), 9.09 (br. s, 1H), 9.99 (br. s, 1H), 10.08 (br. s, 1H), 10.35 (br. s, 1H).

References: [1]Patent: US2017/253602,2017,A1 .Location in patent: Paragraph 0823-0826.

25
[ 821-48-7 ]
[ 113512-71-3 ]
2,4-difluoro-5-(piperazin-1-yl)phenol hydrochloride [ No CAS ]