849217-60-3|N-(4-Fluorophenyl)-N'-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide| Ambeed

Structure of 849217-60-3

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 849217-60-3 ] Purity: 95% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 849217-60-3 ]

CAS No. :	849217-60-3
Formula :	C₁₇H₁₅FN₂O₃
M.W :	314.31
SMILES Code :	O=C(C1(C(NC2=CC=C(O)C=C2)=O)CC1)NC3=CC=C(F)C=C3
MDL No. :	MFCD22045581
InChI Key :	FSFMBVMXIPQPMJ-UHFFFAOYSA-N
Pubchem ID :	57810197

Safety of [ 849217-60-3 ]

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

Computational Chemistry of [ 849217-60-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	23
Num. arom. heavy atoms	12
Fraction Csp3	0.18
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	3.0
Molar Refractivity	83.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	78.43 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.37
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	3.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.86
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.	2.06
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	2.61
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.64

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.86
Solubility	0.0436 mg/ml ; 0.000139 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.	-4.62
Solubility	0.00749 mg/ml ; 0.0000238 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-5.42
Solubility	0.00119 mg/ml ; 0.0000038 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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	Yes
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.	-5.87 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.	0.55

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	2.0 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<0.0
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)	1.85

Application In Synthesis of [ 849217-60-3 ]

* 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 [ 849217-60-3 ]

[ 849217-60-3 ] Synthesis Path-Downstream 1~35

1
[ 849217-48-7 ]
[ 123-30-8 ]
[ 849217-60-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide;	will1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride(5.15 g, 26.9 mmol)Aminophenol (2.93 g, 26.9 mmol) and1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (5.00 g, 22.4 mmol)In N, N-dimethylacetamide (30 mL).The reaction was stirred until the reaction was complete and the mixture was poured into saturated aqueous sodium bicarbonate(200 ml) and stirred for 1 hour.The residue was filtered, washed with water (50 ml) and then with chloroform (50 ml)Drying tooN- (4-fluorophenyl) -N'-(4-hydroxyphenyl) -cyclopropane-1,1-dicarboxamide(6.22 g, yield: 88%).
88%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ISOPROPYLAMIDE; at 20℃; for 3h;	To a solution of 4-aminophenol (2.93 g, 26.9 mmol) and 1- (4-FLUORO-PHENYLCARBAMOYL)-CYCLOPROPANECARBOXYLIC acid (5.00 g, 22.4 mmol) in DMA (30 mL) was added EDCI (5.15 g, 26.9 mmol). The mixture was stirred vigorously until the reaction was complete (-3 h). With vigorous stirring, the reaction mixture was then poured into a flask containing sat. aqueous NAHCO3 solution (200 mL). The stirring was continued for 1 h. The resulting suspension was then filtered. The solid was washed with water (50 mL), chloroform (50 ML) and dried under vacuum, affording 1- (4-FLUORO- phenylcarbamoyl) -cyclopropanecarboxylic acid (6.22g, 88% yield) as a powder (>95% purity by HPLC AND 1H NMR).
87.9%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: To a solution of the intermediate 9 (1.0g, 4.48mmol) and substituted aminophenol (5.38mmol) in DMF (15mL) was added EDCI (1.03g, 5.38mmol). The solution was stirred at room temperature for 3h. Then water (50mL) was added to precipitate white solid, adjusting pH to 4.0-5.0 by 1M HCl. The white solid was filtered off, washed and dried in vacuum to afford 10a-b [45]. 5.3.1 N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (10a) Yield: 87.9%; MS (ESI) m/z: 315.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) delta: 10.17 (s, 1H, CONH), 9.73 (s, 1H, CONH), 9.23 (s, 1H, OH), 7.83-6.68 (m, 8H, Ar-H), 1.48 (s, 4H, CH2CH2).

85%

With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 20℃; for 4h;

General procedure: To a solution of 3a-k (6.40 mmol) in MeOH/H2O (30 mL,1:1=V:V), lithium hydroxide (230 mg, 9.6 mmol) was added, whichwas stirredat room temperature for 2 h. The pH value was then adjustedto 3 with dilute hydrochloric acid, and a large amount of solid wasprecipitated, which was filtered and dried to give an off-white solid (4a-k). The next step was carried out without purification of these products.A mixture of 4a-k (1 mmol), aminophenol (1 mmol), and 3-(ethyliminomethyleneamino)-N,N- dimethyl-propan-1-amine (1 mmol) in 10 mLDMA, was stirred at room temperature for 4 h. The reaction mixturewas monitored by TLC. After the starting material disappeared, thewater was added and the product was extracted with ethyl acetate andthe solvent was then evaporated. Finally, the product was separated bycolumn chromatography to give a pure product (5a-k).

References: [1]Patent: CN106632028,2017,A .Location in patent: Paragraph 0079; 0084; 0085.
[2]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 205.
[3]European Journal of Medicinal Chemistry,2017,vol. 140,p. 212 - 228.
[4]Bioorganic Chemistry,2019,vol. 88.

2
[ 849217-54-5 ]
[ 849217-60-3 ]
[ 849217-68-1 ]

Yield	Reaction Conditions	Operation in experiment
44%	With 2,6-dimethylpyridine; at 165℃; for 18h;Sealed tube;	6,7-Dimethoxyquinolin-4-yl trifluoromethanesulfonate (5 g, 14.8 mmol) was added to a solution ofN- (4-fluorophenyl) -N '- (4-hydroxyphenyl) -cyclopropane-1,1-dicarboxamide (6.98 g, 22.2 mmol)2,6-lutidine (50 ml).The reaction mixture was stirred in a borning jar at 165 C for 18 hours.The reaction mixture was evaporated to dryness under reduced pressure and the remaining solid was dissolved in dichloromethane (250 ml)Wash twice with aqueous sodium hydroxide (1 N).The crude product was passed through a column of solid N- [4 - [(6,7-dimethoxy-Quinolyl) oxy] phenyl] -N '- (4-fluorophenyl) -1,1- cyclopropane dicarboxamide (3.2 g, yield: 44%),Captopinib
44%	With 2,6-dimethylpyridine; at 165℃; for 18h;	To a solution of cyclopropane-l, L-DICARBOXYLIC acid (4- fluoro-phenyl) -amide (4-hydroxy-phenyl) -amide (6.98 g, 22.2 mmol) in anhydrous 2,6- lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165C in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc- hexanes, affording N- (4- { [6,7-bis (methyloxy) quinolin-4-yl] OXY} PHENYL)-N- (4- fluorophenyl) cyclopropane-l, L-DICARBOXAMIDE (3.2 g, 44%).

References: [1]Patent: CN106632028,2017,A .Location in patent: Paragraph 0079; 0086; 0087.
[2]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 212.

3
[ 849217-59-0 ]
[ 849217-60-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With cyclohexa-1,4-diene;palladium 10% on activated carbon; In ethanol; for 2 - 5h;Heating / reflux;	To a refluxing mixture of cyclopropane-l, L-DICARBOXYLIC acid (4-benzyloxy- phenyl) -amide (4-fluoro-phenyl) -amide (46 g, 113 mmol), 10% Pd/C (2 g) in EtOH (400 mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirring was continued for 2-5 h until the reaction was complete. The mixture was cooled to rt, filtered through celite, and washed with EtOH. The solution was then concentrated under reduced pressure. To the flask containing the crude product was added CHC13 (200 mL). The resulting suspension was stirred for 15 min at rt. The solid was filtered, and dried in the air to give cyclopropane-l, L-DICARBOXYLIC acid (4-fluoro-phenyl) -amide (4-hydroxy- phenyl) -amide (34.4 g, 95%, yield).

References: [1]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 205.

4
[ 849217-60-3 ]
C₁₃H₁₁ClN₂O₂ [ No CAS ]
N-(4-((7,8-dimethoxy-5H-pyrido[3,2-b]indol-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-diamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.3%	With copper; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.166667h;Microwave irradiation;	Intermediate M-4 (0.26g, 1mmol) and intermediate M-1' (0.47g, 1.5mmol) dissolved in DMF 3mL was added Cu powder (6.1mg, 0.1mmol) and Cs2CO3 (0.98g, 3mmol). It was placed in a microwave reactor setting power at 60W. The reaction was stirred at 100C for 10min. After completion of the reaction, it was filtered. The solvent was evaporated to dryness. Water 10mL was slowly added dropwise with stirring. Solid precipitated. Column chromatography, eluted with petroleum ether: ethyl acetate (V / V, 1: 1), to give the desired product 0.45g I-4, yield: 83.3%.

References: [1]Patent: CN104045642,2016,B .Location in patent: Paragraph 0114; 0115; 0116.

5
[ 849217-60-3 ]
[ 98792-02-0 ]
N-(4-((5H-pyrimido[5,4-b]indol-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-diamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.1%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;Inert atmosphere;	4-chloro-5H-pyrimido[5,4-b]indole (M-1) (1.22g, 6mmol) and <strong>[849217-60-3]N'-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-diamide</strong> (1.57g, 5mmol) (M-1') dissolved in DMF 35mL was added K2CO3 (2.07g, 15mmol). The reaction mixture was placed under nitrogen. The reaction was stirred at 80C for 24h. After completion of the reaction, ethyl acetate 100mL was added and diluted. It was washed successively with 100mL water and 100mL saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Concentrated under reduced pressure. The residue was treated with ethyl acetate and petroleum ether (V / V, 10: 1) and beating washed to obtain a white 2.17g desired product I-1, yield: 75.1%.

References: [1]Patent: CN104045642,2016,B .Location in patent: Paragraph 0095; 0096; 0097.

6
[ 598-10-7 ]
[ 849217-60-3 ]

References: [1]European Journal of Medicinal Chemistry,2017,vol. 140,p. 212 - 228.
[2]Patent: CN106632028,2017,A .
[3]Patent: WO2005/30140,2005,A2 .
[4]Patent: WO2005/30140,2005,A2 .

7
[ 371-40-4 ]
[ 849217-60-3 ]

References: [1]European Journal of Medicinal Chemistry,2017,vol. 140,p. 212 - 228.
[2]Patent: CN106632028,2017,A .
[3]Patent: CN107793363,2018,A .
[4]Patent: US2018/244667,2018,A1 .
[5]Patent: WO2005/30140,2005,A2 .
[6]Patent: WO2005/30140,2005,A2 .

8
[ 849217-60-3 ]
methyl 6-((6-chloro-5-nitropyrimidin-4-yl)amino)-2,3-dimethoxybenzoate [ No CAS ]
methyl 6-((6-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)-5-nitropyrimidin-4-yl)amino)-2,3-dimethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.0%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 13h;	General procedure: A mixture of 19 (2.0g, 5.43mmol), 10a-b (4.53mmol) and K2CO3 (1.88g, 13.59mmol) in DMF (15mL) was heated at 50C for 13h. Upon cooling to room temperature, the reaction mixture was added water (100mL), and extracted by EA (15mL×3). The organic phase was combined and concentrated to get the crude product, which was purified by silica gel chromatography using PE/EA (5:1) to afford the intermediates 20a-b as a pale-yellow solid. 5.14.1 Methyl6-((6-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)-5-nitropyrimidin-4-yl)amino)-2,3-dimethoxybenzoate (20a) Pale-yellow solid; Yield: 84.0%; MS (ESI) m/z: 647.11 [M+H]+, 1H NMR (400MHz, DMSO-d6) deltappm: 10.92 (s, 1H), 10.17 (t, J=8.6Hz, 2H), 8.59 (s, 1H), 7.77 (s, 1H), 7.44 (s, 1H), 7.29-7.12 (m, 4H), 7.02-6.84 (m, 4H), 3.88 (t, J=8.6Hz, 9H), 1.45 (s, 4H).