168268-00-6|4-(Benzyloxy)-3-fluoroaniline| Ambeed

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 [ 168268-00-6 ] Purity: 96% 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 [ 168268-00-6 ]

CAS No. :	168268-00-6
Formula :	C₁₃H₁₂FNO
M.W :	217.24
SMILES Code :	NC1=CC=C(OCC2=CC=CC=C2)C(F)=C1
MDL No. :	MFCD08686866
InChI Key :	XLEYXHRMSUPJST-UHFFFAOYSA-N
Pubchem ID :	21951892

Safety of [ 168268-00-6 ]

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

Computational Chemistry of [ 168268-00-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	12
Fraction Csp3	0.08
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	61.78
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.23
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	2.81
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.26
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.	3.09
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	3.07
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.89

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.31
Solubility	0.105 mg/ml ; 0.000485 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.	-3.21
Solubility	0.135 mg/ml ; 0.00062 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	-4.99
Solubility	0.00224 mg/ml ; 0.0000103 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	Yes
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.	-5.63 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	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)	1.62

Application In Synthesis of [ 168268-00-6 ]

* 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 [ 168268-00-6 ]

[ 168268-00-6 ] Synthesis Path-Downstream 1~35

1
[ 76243-24-8 ]
[ 168268-00-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonium formate; iron; In water; toluene;Heating / reflux;	A mixture of iron powder (45.2 g, 0.809 g atoms), ammonium formate (53.6 g, 0.850 mol), l-benzyloxy-2-fluoro-4-nitrobenzene (50.0 g, 0.200 mol), toluene (400 mL) and water (400 mL) was heated to reflux overnight. The mixture was filtered through Celite and washed with hot ethyl acetate. The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to afford 4-benzyloxy-3-fluoroaniline (44 g, 100 %). 1H NMR (400 MHz, J6-DMSO): delta 7.43-7.26 (m, 5H), 6.90 (dd, IH), 6.49 (dd, IH), 6.34 (m, IH), 4.99 (br s, 2H), 4.98 (s, 2H); 13C NMR (100 MHz, J6-DMSO): delta 171.1, 155.1, 152.7, 144.9, 138.0, 137.2, 129.6, 129.0, 128.5, 118.9, 110.0, 102.9, 72.5; IR (cm"1): 1510, 1454, 1277, 1215, 1126, 1007, 957, 843, 800, 789, 739, 694, 604; LC/MS (M+H = 218).
100%	With ammonium formate; iron; In water; toluene;Heating / reflux;	A mixture of iron powder (45.2 g, 0. 809 g atoms), ammonium formate (53.6 g, 0. 850 mol), 1-benzyloxy-2-fluoro-4-nitrobenzene (50.0 g, 0.200 mol), toluene (400 mL) and water (400 ML) was heated to reflux overnight. The mixture was filtered through Celite and washed with hot ethyl acetate. The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to afford 4-benzyloxy-3-fluoroaniline (44 g, 100 %).
99.9%	With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate; In ethanol; at 80℃; for 2h;	The compound of formula (2) (154 g, 0.624 mol), ferric chloride hexahydrate (3.24 g, 0.012 mol) and15.4 g of activated carbon was added to 1.23 L of ethanol, heated at 80 C., and 80% hydrazine hydrate (156 g, 3.12 mol) was added dropwise.Drops, reaction 2h. After hot filtration, the filtrate was evaporated to dryness under reduced pressure to give 135 g of a dark yellow oil.That is, the compound (4) 4-benzyloxy-3-fluoroaniline, a yield of 99.9%;

94%	With iron; ammonium chloride; In ethanol; water; at 90℃; for 2h;	compound 1 (72.80 g, 294.74 mmol, 1 eq), reduced iron powder (99.00 g,1768.42 mmol, 6 eq) and ammonium chloride (94.59 g, 1768.42 mmol, 6 eq) were mixed with EtOH:H2O(2:1), and refluxed at 90C for 2 h. After cooling to room temperature, the mixture was filtered. Thefiltered and concentrated to give the brown oily substance compound 2 (60.00 g, 94%). 1H-NMR(400 MHz, CDCl3) delta 7.42 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.0 Hz, 1H), 6.80 (t,J = 9.0 Hz, 1H), 6.46 (dd, J = 12.4, 2.8 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 5.03 (s, 2H). ESI-MS (m/z): 217.9[M + H]+
83.17%	With ammonium formate; iron; In ethanol; water;Reflux;	4-Benzyloxy-3-fluoroaniline.A mixture of iron powder (1.07g, 16.96mmol), ammonium formate (1.07g, 16.96mmol),1-benzyloxy-2-fluoro-4-nitrobenzene (1g, 4.04mmol), ethanol (400 mL) and water(100 mL) was heated to reflux overnight. The mixture was filtered throughCelite and washed with hot ethyl acetate. The combined organic layers werewashed with water and brine, then dried over sodium sulfate and concentrated toafford 4-benzyloxy-3-fluoroaniline (0.73g,83.17 %).
83.17%	With water; ammonium formate; iron; In toluene; for 8h;Reflux;	A mixture of iron powder (1.07 g, 16.96 mmol), ammonium formate (1.07 g, 16.96 mmol), 1-benzyloxy-2-fluoro-4-nitrobenzene (1 g, 4.04 mmol), methylbenzene (30 mL) and water (30 mL) was heated to reflux overnight. The mixture was filtered through celite and washed with hot ethyl acetate. The combined organic layers were washed with water and brine, then dried over anhydrous Na2SO4 and concentrated to afford 4-benzyloxy-3-fluoroaniline (0.73 g, 83.17 %). 1H-NMR (300MHz, CDCl3) delta: 7.43-7.27 (m, 5H), 6.82-6.77 (t, J = 8.82 Hz, 1H), 6.48-6.43 (dd, J = 2.61, 12.58 Hz, 1H), 6.33-6.30 (m, 1H), 5.02 (s, 2H), 3.50 (s, Ar-NH2, 2H).
	With hydrazine;Raney nickel; In methanol; at 20℃; for 2h;	2.91 ml of hydrazine monohydrate and about 1 g of developed Raney nickel catalyst were added to a methanol (60 ml) solution of 4.94 g of 4-benzyloxy-3-fluoronitrobenzene, and the reaction liquid was stirred at room temperature for 2 hours. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow oily substance.

References: [1]Patent: WO2006/108059,2006,A1 .Location in patent: Page/Page column 90-91.
[2]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 201.
[3]Patent: CN108069919,2018,A .Location in patent: Paragraph 0041; 0054; 0055; 0060; 0063; 0066; 0069; 0072.
[4]Molecules,2019,vol. 24.
[5]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 3353 - 3358.
[6]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6674 - 6679.
[7]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.
[8]Patent: WO2005/23801,2005,A1 .Location in patent: Page/Page column 19.
[9]Patent: WO2005/23801,2005,A1 .Location in patent: Page/Page column 24.
[10]Patent: EP1702919,2006,A1 .Location in patent: Page/Page column 112.
[11]Chinese Chemical Letters,2010,vol. 21,p. 1326 - 1329.
[12]European Journal of Medicinal Chemistry,2018,vol. 158,p. 814 - 831.

2
[ 168268-00-6 ]
[ 98556-31-1 ]
[ 231278-23-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.

3
[ 168268-00-6 ]
[ 231278-82-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.

4
[ 403-19-0 ]
[ 168268-00-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.
[2]Chinese Chemical Letters,2010,vol. 21,p. 1326 - 1329.
[3]Patent: WO2005/30140,2005,A2 .
[4]Molecules,2019,vol. 24.

5
[ 100-39-0 ]
ZnCr-benzoate*3H₂O [ No CAS ]
[ 168268-00-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4686 - 4691.

6
[ 168268-00-6 ]
[ 94-05-3 ]
6-benzyloxy-7-fluoro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[168268-00-6]4-benzyloxy-3-fluoroaniline</strong> (6.06 g, 27.9 mmol) (US 5,622, 967) and ethyl (ethoxymethylene) cyanoacetate (5.08 g, 30.0 mmol) was heated at 120C for 45 minutes then cooled to room temperature. This solid was added in portions to a 3: 1 mixture of diphenyl ether: biphenyl at 245 C. This mixture was heated at 245C for 3 hours then cooled and the solids were collected by filtration, washing with hexane and diethyl ether to provide 2.60 g of 6-benzyloxy-7-fluoro-4-oxo-1, 4- dihydro-3-quinolinecarbonitrile, mp >250C. MS 293.1 (M-H) -
	at 120℃; for 0.75h;	A mixture of <strong>[168268-00-6]4-benzyloxy-3-fluoroaniline</strong> (6.06 g, 27.9 mmol) (U.S. Pat. No. 5,622,967) and ethyl (ethoxymethylene)cyanoacetate (5.08 g, 30.0 mmol) is heated at 120 C. for 45 minutes then cooled to room temperature. This solid is added in portions to a 3:1 mixture of diphenyl ether:biphenyl at 245 C. This mixture is heated at 245 C. for 3 hours then cooled and the solids are collected by filtration, washing with hexane and diethyl ether to provides 2.60 g of 6-benzyloxy-7-fluoro-4-oxo-1, 4-dihydro-3-quinolinecarbonitrile, mp>250 C. [0198] MS 293.1 (M-H)-

References: [1]Patent: WO2005/47259,2005,A1 .Location in patent: Page/Page column 11; 22-23.
[2]Patent: US2003/212276,2003,A1 .Location in patent: Page/Page column 12.

7
[ 168268-00-6 ]
[ 501-53-1 ]
[ 790703-40-1 ]

Yield	Reaction Conditions	Operation in experiment
98.9%	With sodium carbonate; In water; acetone; at 0 - 5℃; for 0.25h;	A solution of 1.23 L of acetone and 600 ml of water in sodium carbonate (132 g, 1.25 mol) was added to the oil and thenCool down to 05C, add benzyl chloroformate (127.8g, 0.748mol) dropwise, continue stirring for 15min,Filtration gave 133 g of a yellow solid as a compound of formula (4) with a yield of 98.9%.
91%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0℃; for 0.5h;	a saturated sodium bicarbonate solution (0.50 L) was added to compound 2 (60.00 g,276.50 mmol, 1 eq) in anhydrous THF (0.50 L) and cooled to 0 C. The mixed solution was treateddropwise with benzyl carbonochloridate (51.88 g, 304.15 mmol, 1.1 eq) and then stirred for 30 min at0 C. The mixture was extracted with EtOAc (3.00 L*2) and brine (2.40 L). The organic layer was dried(Na2SO4), filtered, and concentrated in vacuo to give compound 3 (88.00 g, 91%) as a yellow solid,m.p., 116-118 C. 1H-NMR (400 MHz, CDCl3) delta 7.48-7.27 (m, 11H), 6.95-6.87 (m, 2H), 6.57 (s, 1H), 5.19(s, 2H), 5.10 (s, 2H). ESI-MS (m/z): 351.9 [M + H]+.

References: [1]Patent: WO2005/23801,2005,A1 .Location in patent: Page/Page column 19; 24.
[2]Patent: CN108069919,2018,A .Location in patent: Paragraph 0041; 0054; 0056; 0061; 0064; 0067; 0070; 0073.
[3]Molecules,2019,vol. 24.

8
[ 168268-00-6 ]
[ 98-97-5 ]
[ 859537-68-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;	2.59 g of pyrazine-2-carboxylic acid and 4.73 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (60 ml) solution of 4.13 g of <strong>[168268-00-6]4-benzyloxy-3-fluoroaniline</strong>, and the reaction liquid was stirred overnight at room temperature. Pyridine was evaporated away under reduced pressure, and then water was added to it. The resulting deposit was taken out through filtration to obtain the entitled compound as a brown solid.

References: [1]Patent: EP1702919,2006,A1 .Location in patent: Page/Page column 112.

9
[ 168268-00-6 ]
[ 4755-77-5 ]
[ 163485-46-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; at 20℃; for 0.25h;	Ethyl oxalyl chloride (44 mL, 390 mmol) was added to a solution of <strong>[168268-00-6]4-benzyloxy-3-fluoroaniline</strong> (44 g, 180 mmol) in diisopropylethylamine (69 mL, 400 mmol) and stirred at room temperature for 15 min. The mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to afford ethyl [(4- benzyloxy-3-fluorophenyl)amino](oxo)acetate (58.4 g, 100 %). 1H NMR (400 MHz, J6- DMSO): delta 10.87 (s, IH), 7.73 (d, IH), 7.69 (d, IH), 7.53 (d, IH), 7.46-7.40 (m, 4H), 5.17 (s, 2H), 4.31 (q, 2H), 1.31(t, 3H); IR (cm"1): 1732, 1705, 1558, 154I, 1508, 1456, 1273, 1186, 1167, HOl, 999, 858, 741, 694; LC/MS (M+H = 318).
100%	With N-ethyl-N,N-diisopropylamine; at 20℃; for 0.25h;	Ethyl oxalyl chloride (44 mL, 390 mmol) was added to a solution of <strong>[168268-00-6]4-benzyloxy-3-fluoroaniline</strong> (44 g, 180 mmol) in DIISOPROPYLETHYLAMINE (69 mL, 400 mmol) and stirred at room temperature for 15 min. The mixture was extracted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to afford ethyl [ (4- benzyloxy-3-fluorophenyl) amino] (oxo) acetate (58. 4 g, 100 %).

References: [1]Patent: WO2006/108059,2006,A1 .Location in patent: Page/Page column 90-91.
[2]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 201.

10
[ 168268-00-6 ]
[ 849217-48-7 ]
[ 849217-57-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	Toa stirred mixture of 4-benzyloxy-3-fluoro-phenylamine (33.7 g, 155.3mmol),1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (38.13 g, 170.8mmol)and anhydrous dichloromethane (600 ml) was added EDCI (44.7 g, 233.9mmol) inportions. After stirring at RT for 1 h, the reaction mixture was diluted withsaturated sodium bicarbonate (400 ml) and stirred for 30 minutes. Theprecipitate was filtered and air dried to give the 1st crop of product. Thebiphasic filtrate was separated, and the organic phase was washed with brine(300 ml), dried over sodium sulfate, and concentrated. The residue was taken upin DCM (100 ml), stirred for 15 minutes, and filtered to give a 2nd crop ofproduct. The combined yield of cyclopropane-1,1-dicarboxylicacid(4-benzyloxy-3-fluoro-phenyl)-amide(4-fluoro-phenyl)-amide was 64.5 g(98%). Cyclopropane-1,1-dicarboxylic acid(4-benzyloxy-3-fluoro-phenyl)-amide(4-fluoro-phenyl)-amide, yield 64.5 g (98%)
98%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	To a stirred mixture of 4-benzyloxy-3-fluoro-phenylamine (33.7 g, 155.3mmol), 1-(4-fluoro-phenylcarbamoyl)-cyclopropane carboxylic acid (38.13 g, 170.8mmol) and anhydrous DCM (600 ml) was added EDCI (44.7 g, 233.9mmol) in portions. After stirring at r.t. for 1 h, the reaction mixture was diluted with saturated sodium bicarbonate (400 ml) and stirred for 30 minutes. The precipitate was filtered and air dried to give the 1st crop of product. The biphasic filtrate was separated, and the organic phase was washed with brine (300 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was taken up in DCM (100 ml), stirred for 15 minutes, and filtered to give a 2nd crop of product. The combined yield of Cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-3-fluoro-phenyl)-amide(4-fluoro-phenyl)-amide 64.5 g, yield: 98%. 1H-NMR (300MHz, CDCl3) delta: 8.9 (m, 2H), 7.35-7.18 (m, 8H), 6.95-6.85 (m, 4H), 5.03 (s,2H), 1.53(s, 2H).
98%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	To a stirred mixture of 4-benzyloxy-3-fluoro-phenylamine (155.3 mmol, 33.7 g), 1- (4-FLUORO-PHENYLCARBAMOYL)-CYCLOPROPANECARBOXYLIC acid (170.8 mmol, 38.13 g) and anhydrous dichloromethane (600 ml) was added EDCI (233.9 mmol, 44.7 g) in portions. After stirring at RT for 1 hr, the reaction mixture was diluted with saturated sodium bicarbonate (400 ml) and stirred for 30 minutes. The precipitate was filtered and air dried to give the 1ST CROP of product. The biphasic filtrate was separated, and the organic phase was washed with brine (300 ml), dried over sodium sulfate, and concentrated. The residue was taken up in DCM (100 ml), stirred for 15 minutes, and filtered to give a 2ND crop of product. The combined yield of cyclopropane-1, 1- dicarboxylic acid (4-benzyloxy-3-fluoro-phenyl) -amide (4-fluoro-phenyl) -amide was 64.5 g (98%).

References: [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 3353 - 3358.
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 6674 - 6679.
[3]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 203.
[4]European Journal of Medicinal Chemistry,2018,vol. 158,p. 814 - 831.

11
[ 168268-00-6 ]
[ 122-51-0 ]
[ 1258001-16-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium azide; acetic acid; at 95℃; for 2.5h;Inert atmosphere;	Preparation 8: 1-[4-(Benzyloxy)-3-fluorophenyl1-1 H-tetrazoleTo a suspension of <strong>[168268-00-6]4-(benzyloxy)-3-fluoroaniline</strong> (1.04 g, 4.8 mmol) (WO 2005030140) under a nitrogen atmosphere was added acetic acid (2.3 ml_, 38.3 mmol), triethy lorthoformate (2.44 ml_, 14.4 mmol) and sodium azide (0.34 g, 5.3 mmol), and the reaction mixture heated at 95 0C for 2.5 hours. The solution was then allowed to cool to room temperature, and water was added followed by extraction with ethyl acetate three times. The extracts were combined and washed with brine and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure, and the crude material purified by chromatography on silicon gel (20 - 40 % ethyl acetate in heptane) to give the title compound as a white solid (1.12 g, 86 %). 1H NMR (400 MHz, deuteromethanol) delta 9.65 (s, 1 H), 7.73 - 7.68 (dd, 1 H, J=11 , 2.5 Hz), 7.60 - 7.57 (m, 1 H) 7.47 - 7.45 (m, 2H), 7.40 - 7.30 (m, 5H), 5.24 (s, 2H); LCMS (ES+): 271.1 (M+1 ).
86%	With sodium azide; acetic acid; at 95℃; for 2.5h;Inert atmosphere;	To a suspension of <strong>[168268-00-6]4-(benzyloxy)-3-fluoroaniline</strong> (1.04 g, 4.8 mmol) (WO 2005030140) under a nitrogen atmosphere was added acetic acid (2.3 ml_, 38.3 mmol), triethy lorthoformate (2.44 ml_, 14.4 mmol) and sodium azide (0.34 g, 5.3 mmol), and the reaction mixture heated at 95 C for 2.5 hours. The solution was then allowed to cool to room temperature, and water was added followed by extraction with ethyl acetate three times. The extracts were combined and washed with brine and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure, and the crude material purified by chromatography on silicon gel (20 - 40 % ethyl acetate in heptane) to give the title compound as a white solid (1.12 g, 86 %). 1H NMR (400 MHz, deuteromethanol) delta 9.65 (s, 1 H), 7.73 - 7.68 (dd, 1 H, J=1 1 , 2.5 Hz), 7.60 - 7.57 (m, 1 H) 7.47 - 7.45 (m, 2H), 7.40 - 7.30 (m, 5H), 5.24 (s, 2H); LCMS (ES+): 271 .1 (M+1 ).

References: [1]Patent: WO2010/140092,2010,A1 .Location in patent: Page/Page column 52; 53.
[2]Patent: WO2012/69948,2012,A1 .Location in patent: Page/Page column 52-53.

12
[ 168268-00-6 ]
[ 1256261-50-3 ]