[ CAS No. 131885-34-2 ]

Name: 131885-34-2|N-Benzyl-5-fluoro-2-nitroaniline|95%
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Quality Control of [ 131885-34-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 131885-34-2 ]

SDS Specification

Alternatived Products of [ 131885-34-2 ]

Product Details of [ 131885-34-2 ]

CAS No. :	131885-34-2	MDL No. :	MFCD17336280
Formula :	C₁₃H₁₁FN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AEFSTURDBIFIBJ-UHFFFAOYSA-N
M.W :	246.24 g/mol	Pubchem ID :	14751679
Synonyms :

Calculated chemistry of [ 131885-34-2 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.08
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	69.01
TPSA :	57.85 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	3.88
Log Po/w (WLOGP) :	3.42
Log Po/w (MLOGP) :	3.37
Log Po/w (SILICOS-IT) :	1.28
Consensus Log Po/w :	2.86

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.04
Solubility :	0.0224 mg/ml ; 0.0000911 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.79
Solubility :	0.00397 mg/ml ; 0.0000161 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.04
Solubility :	0.00227 mg/ml ; 0.0000092 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.18

Safety of [ 131885-34-2 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P330-P363-P501	UN#:
Hazard Statements:	H302-H312-H332	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 131885-34-2 ]

* 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.

Downstream synthetic route of [ 131885-34-2 ]

[ 131885-34-2 ] Synthesis Path-Downstream 1~25

1
[ 700-36-7 ]
[ 100-46-9 ]
[ 131885-34-2 ]

Yield	Reaction Conditions	Operation in experiment
86%		Under Argon and at RT, Pd(OAc)2 (32 mg, 0.14 mmol) and BINAP (90 mg, 0.14 mmol) were added to a solution of benzylamine (225 mg, 2.10 mmol) and 4-fluoro-2-bromonitrobenzene (463 mg, 2.10 mmol) in toluene (degassed by purging, 5 mL). The reaction mixture was heated at 100 C. for 3 minutes and then cooled to 0 C. Upon addition of sodium tert-butoxide (253 mg, 2.63 mmol) the reaction mixture turned red. The reaction was stirred at 70 C. for 24 hours and then at RT for 48 hours. The reaction was filtered over Kiezelguhr. Residue was rinsed with EtOAc. The filtrate was evaporated to dryness in vacuo. The crude product was purified by flash column chromatography to afford N1-benzyl-5-fluoro-2-nitroaniline as a yellow crystalline compound (440 mg, 86%, purity (LC) n.d.).NMR: 1H (CDCl3): delta 8.55 (bs, 1H), 8.24 (dd, J=6.04 Hz and J=9.32 Hz, 1H), 7.42-7.30 (m, 5H), 6.46 (dd, J=2.52 Hz and J=11.4 Hz, 1H), 6.39 (ddd, J=2.52 Hz and J=7.32 Hz and J=9.60 Hz, 1H), 2.12 (s, 2H).

Reference： [1]Patent: US2010/280268,2010,A1 .Location in patent: Page/Page column 17

2
[ 131885-34-2 ]
[ 760968-77-2 ]
[ 951666-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: benzyl-(5-fluoro-2-nitro-phenyl)-amine; methyl 5-hydroxy-2-(4-methylbenzenesulfonylamino)benzoate With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 18h; Stage #2: With potassium hydrogensulfate In water; ethyl acetate; N,N-dimethyl-formamide	A mixture of methyl 5-hydroxy-2-[(4-methylphenyl)sulfonyl]aminobenzoate (431 mg, 1.34 mmol), N1-benzyl-5-fluoro-2-nitroaniline (324 mg, 1.32 mmol), and potassium carbonate (365 mg, 2.64 mmol) in DMF (10 mL) was stirred at 80° C. for 6 hours and then at RT for 12 hours. The reaction was diluted with brine (150 mL) and was extracted with EtOAc (75 mL). The EtOAc-extract was washed with aq. 0.5 M KHSO4 (75 mL), aq. sat. NaHCO3 (75 mL), and brine (75 mL). The aqueous-layers were extracted with EtOAc (75 mL). The combined EtOAc-extracts were dried (Na2SO4), filtered, and evaporated to dryness in vacuo. The crude product was purified by column chromatography (EtOAc/heptane: 1/6 to 1/4) to obtain the desired product as a yellow solid (611 mg, 83%, purity (LC)=85%).MS: [M-H]-=546.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2010/280268, 2010, A1 Location in patent: Page/Page column 17

3
[ 446-35-5 ]
[ 100-46-9 ]
[ 131885-34-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 50℃;	Benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1" Benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1" 2,4-Difluoronitrobenzene E-1.1'" (3.448 ml; 31.429 mmol) is dissolved in dioxane (35.000 ml). DIPEA (6.601 ml; 40.857 mmol) and benzylamine (3.429 ml; 31.429 mmol) are added. The reaction mixture is stirred at 50° C. overnight. The reaction mixture is concentrated under reduced pressure. The residue crystallises after some minutes. It is triturated with diethyl ether to give the pure crystalline compound. Yield: 95% (7.36 g; 28.890 mmol) HPLC-MS: (M+H)+=247; tRet=1.37 min; method LCMS BAS1
95%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 50℃;	1 Benzyl-(5-fluoro-2-nitro-phenyl)-amine E- 1.1” Benzyl-(5-fluoro-2-nitro-phenyl)-amine E- 1.1” 2,4-Difluoronitrobenzene E-1.1” (3.448 ml; 3 1.429 mmol) is dissolved in dioxane (35.000 ml). DIPEA (6.601 ml; 40.857 mmol) and benzylamine (3.429 ml; 31.429mmol) are added. The reaction mixture is stirred at 50°C overnight. The reaction mixture is concentrated under reduced pressure. The residue crystallises after some minutes. It is triturated with diethyl ether to give the pure crystalline compound. Yield: 95% (7.36 g; 28.890 mmol)HPLC-MS: (M+H)+ = 247; tRet = 1.37 mm; method LCMS BAS1
85%	Stage #1: benzylamine With potassium carbonate at 50℃; for 0.25h; Inert atmosphere; Stage #2: 2,4-Difluoronitrobenzene at 50℃; for 3h;	98 N-benzyl-5-fluoro-2-nitroaniline (LW) To a stiiied solution of benzyl amine (1,38 mL, 12.87 mmol) in Toluene (20 mL) under argon atmosphere was added potassium carbonate (868 nig,. 6.28 mmol) at RT. The reaction mixture was stirred at 50 V'C for 15 rain. Then 2, 4-difhioro- i -nitrobenzene (LV; 2 g, 12.57 mmol) was added to the reaction mixture at 50 °C stirred for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice cold water (100 mL) to obtain the solid. The solid was filtered, dissolved in CC (50 mL), dried over anhydrous MaiSC^ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluen 2% EtOAc/Hexane) to afford compound L W (2.6 g. 10.56 mmol, 85%) as a brown solid. 1HNMR (400 MHz. CDC13): 5 8.57 (brs, IH), 8.27 (dd, J= 9.5. 6. Hz, iH), 7.49-7.31 (m, 5H), 6.49 (dd, J = 11.4, 2.6 Hz, IH), 6.51-6.4] (m, IH). 4.53 (d, J= 5.6 Hz, 2H).

99.2 %Chromat.	With potassium carbonate In toluene at 45 - 50℃; regioselective reaction;
	With triethylamine In dimethyl sulfoxide at 20℃; for 16h;
	With potassium carbonate In N,N-dimethyl-formamide at 50℃;	Example: 5-fluoro-N-(3-morpholinopropyl)-2-nitroaniline (5a) General procedure: The synthetic pathways for the preparation of compounds 6e-g are depicted in Scheme S2. In a 25 mL round bottom flask, compound 3 (159 mg, 1 mmol) and 3-morpholinopropan-1-amine (4a, 144mg, 1mmol) were dissolved in DMF (10 mL) and heated to 50 °C for overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed three times with saturated aqueous NaCl, and dried over anhydrous Na2SO4. And then, product by column chromatography purification. 5-fluoro-N-(3-morpholinopropyl)-2-nitroaniline (5a), yield 56%.
1.5 g	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide Cooling with ice; Inert atmosphere;	In a 150 mL flask with a magnetic stirring bar, 2,4-difluoronitrobenzene (1.0 g, 6.29 mmol) and DIPEA (1.6 g,12.58 mmol) were suspended in 10 mL DMSO and cooled in icewaterbath, then benzyl amine (0.67 g, 6.29 mmol) was added tothe reaction mixture. After stirring overnight, the reaction mixturewas quenched by 100 mL NaHCO3 saturated solution. The yellowprecipitate was collected by filtration and washed by 50 mL waterthree times and 50 mL hexane twice. After drying by high vacuum,1.5 g of yellow solid was generated.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2015/51208, 2015, A1 Location in patent: Paragraph 0278; 0279; 0280; 0281; 0282
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2015/22332, 2015, A1 Location in patent: Page/Page column 91; 92
[3]Current Patent Assignee: NQP 1598 LTD - WO2017/117393, 2017, A1 Location in patent: Page/Page column 333
[4]Sythana, Suresh Kumar; Naramreddy, Surendra R.; Kavitake, Santosh; Kumar; Bhagat, Pundlik R. [Organic Process Research and Development, 2014, vol. 18, # 7, p. 912 - 918]
[5]Aretz, Christopher D.; Morwitzer, M. Jane; Sanford, Austin G.; Hogan, Alicia M.; Portillo, Madelene V.; Kharade, Sujay V.; Kramer, Meghan; McCarthey, James B.; Trigueros, Renata Rusconi; Piermarini, Peter M.; Denton, Jerod S.; Hopkins, Corey R. [ACS Infectious Diseases, 2019, vol. 5, # 6, p. 917 - 931]
[6]Chen, Xiuli; Huang, Shenzhen; Li, Linli; Li, Wenpei; Sun, Weining; Tian, Chenyu; Yang, Shengyong [Bioorganic and medicinal chemistry letters, 2020, vol. 30, # 16]
[7]Xie, Haibo; Yang, Ka; Winston-McPherson, Gabrielle N.; Stapleton, Donnie S.; Keller, Mark P.; Attie, Alan D.; Smith, Kerry A.; Tang, Weiping [European Journal of Medicinal Chemistry, 2020, vol. 206]

4
[ 131885-34-2 ]
N₃-benzyl-4-nitro-benzene-1,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With ammonia In tetrahydrofuran at -70 - 90℃; for 17h;	N3-benzyl-4-nitro-benzene-1,3-diamine E-1.5" N3-benzyl-4-nitro-benzene-1,3-diamine E-1.5" Ammonia (49 mmol) is purged in THF for 1 h at -70° C., benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1" (6.000 g; 24 mmol) is added to the reaction mixture. The reaction mixture is stirred in a steel bomb vessel at 90° C. for 16 h. The reaction is then cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification (yield: 84%; 5.000 g; 20.554 mmol).
84%	With ammonia In tetrahydrofuran at 90℃; for 16h;	2 N3-benzyl-4-nitro-benzene- 1 ,3-diamine E- 1.5” N3-benzyl-4-nitro-benzene- 1 ,3-diamine E- 1.5” Ammonia (49 mmol) is purged in THF for 1 h at -70°C, benzyl-(5-fluoro-2-nitro-phenyl)-amine E-1.1” (6.000 g; 24 mmol) is added to the reaction mixture. Thereaction mixture is stirred in a steel bomb vessel at 90°C for 16 h. The reaction is then cooled to 0°C, diluted with water and extracted with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is used in the next step without further purification(yield: 84%; 5.000 g; 20.554 mmol).

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2015/51208, 2015, A1 Location in patent: Paragraph 0291; 0292; 0293
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2015/22332, 2015, A1 Location in patent: Page/Page column 94

5
[ 131885-34-2 ]
(3-benzylamino-4-nitro-phenyl)-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: ammonia / tetrahydrofuran / 17 h / -70 - 90 °C 2.1: triethylamine / dichloromethane / 0.17 h / 0 °C 2.2: 20 °C
	Multi-step reaction with 2 steps 1.1: ammonia / tetrahydrofuran / 16 h / 90 °C 2.1: triethylamine / dichloromethane / 0.17 h / 0 °C 2.2: 20 °C