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[ CAS No. 78967-07-4 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 78967-07-4

Chemical Structure| 78967-07-4

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Quality Control of [ 78967-07-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 78967-07-4 ]

SDS Specification

Alternatived Products of [ 78967-07-4 ]

Product Details of [ 78967-07-4 ]

CAS No. :	78967-07-4	MDL No. :	MFCD00712149
Formula :	C₁₉H₁₇NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DJEIHHYCDCTAAH-UHFFFAOYSA-N
M.W :	339.34	Pubchem ID :	4237
Synonyms :	N-22	Chemical Name :	2-(3,4-Bis(4-methoxyphenyl)isoxazol-5-yl)acetic acid

Calculated chemistry of [ 78967-07-4 ]

Physicochemical Properties

Num. heavy atoms :	25
Num. arom. heavy atoms :	17
Fraction Csp3 :	0.16
Num. rotatable bonds :	6
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	91.9
TPSA :	81.79 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.64
Log Po/w (XLOGP3) :	3.1
Log Po/w (WLOGP) :	3.65
Log Po/w (MLOGP) :	1.76
Log Po/w (SILICOS-IT) :	3.79
Consensus Log Po/w :	2.99

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.0
Solubility :	0.0336 mg/ml ; 0.0000991 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.49
Solubility :	0.0111 mg/ml ; 0.0000327 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.27
Solubility :	0.000181 mg/ml ; 0.000000532 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.42

Safety of [ 78967-07-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H317-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 78967-07-4 ]

* 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 [ 78967-07-4 ]

[ 78967-07-4 ] Synthesis Path-Downstream 1~35

1
[ 78967-07-4 ]
[ 120402-04-2 ]
[ 120402-03-1 ]
[ 120402-02-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

2
[ 78967-07-4 ]
[ 112453-45-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With hydrogen bromide; In acetic acid; for 5h;Reflux;	Preparation of 2- [3,4-bis(4-hydroxyphenyl)isoxazol-5-yl] acetic acid (VIII) A mixture of <strong>[78967-07-4]mofezolac</strong> 6 (2.5 g, 7.4 mmol) and 47% HBr (10 mL) in AcOH (10 mL) was heated under reflux for 5h. Then, water was added and the product extracted with ethyl acetate. The organic layer was washed with water, dried over MgS04 and solvent removed under reduced pressure. Recrystallizion of the reaction crude gave 9 (0.8 g, 35%). Mp 183-185 C (CH3CN, dec, with foaming). IR: (KBr): 1720 (C=0) cm"1. lH NMR (DMSO-i delta: 3.75 (2H, s, CH2), 6.75 ( 2H, d, J=8.8 Hz, ArH), 6.79 (2H, d, J=8.8 Hz, ArH), 7.01 (2H, d, J=8.8 Hz, ArH), 7.21 (2H, d, J=8.8 Hz, ArH), 9.64 (IH, br s, OH: exchanges with D20), 9.79 (IH, br s, OH: exchanges with D20), 12.89 (IH, br s, COOH: exchanges with D20). 13C-NMR (75 MHz, CD3OD) delta: 31.3, 115.2, 115.5, 117.6, 119.9, 120.4, 157.6, 159.0, 161.3, 162.9, 170.4. Anal.Calcd for C17H13N05: C, 65.16; H, 4.40; N, 6.33. Found: C, 65.45; H, 4.38; N, 6.44.

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146
[2]Patent: WO2014/115020,2014,A1 .Location in patent: Page/Page column 8; 14
[3]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

3
[ 78967-07-4 ]
[ 112453-43-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

4
[ 78967-07-4 ]
[ 112453-44-8 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

5
[ 78967-07-4 ]
3-(4-Methoxy-phenyl)-5-methyl-4-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

6
[ 78967-07-4 ]
[ 120402-05-3 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

7
[ 78967-07-4 ]
{4-(4-Methoxy-phenyl)-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazol-5-yl}-acetic acid [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

8
[ 78967-07-4 ]
{3-(4-Methoxy-phenyl)-4-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazol-5-yl}-acetic acid [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

9
[ 78967-07-4 ]
5-Methyl-3,4-bis-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazole [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

10
[ 78967-07-4 ]
{3,4-Bis-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-isoxazol-5-yl}-acetic acid [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1988,vol. 36,p. 3142 - 3146

11
[ 131454-49-4 ]
[ 78967-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; sodium chloride;	A 1.77 g quantity of the 5-methoxycarbonylmethyl-3,4-bis(4-methoxyphenyl)isoxazole (II a) obtained in Example 1 was added to 15 ml of 2% aqueous solution of sodium hydroxide, followed by stirring at 40 C. overnight. After the completion of reaction, the reaction mixture was washed with ether twice. While cooling the mixture with ice, 5 ml of 10% hydrochloric acid was subsequently added thereto, followed by extraction with ethyl acetate, then washing with a saturated aqueous solution of sodium chloride and thereafter drying over anhydrous magnesium sulfate. The organic layer was concentrated at a reduced pressure, giving 3,4-bis(4-methoxyphenyl)-isoxazol-5-acetic acid as a white solid product (melting at 147~148 C.).
	With hydrogenchloride; sodium hydroxide; sodium chloride;	Reference Example 2 Preparation of [3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetic acid To 15 ml of 2% aqueous solution of sodium hydroxide was added 1.77 g of methyl [3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetate obtained in Reference Example 1 and the mixture was stirred at 40 C. over night. After completion of the reaction, the reaction mixture was washed with ether twice, and thereto was added 5 ml of 10% HCl while cooling with ice. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated at a reduced pressure, giving the above-identified compound as white solid. Melting point 147~148 C. IR absorption spectrum (KBr): numax(cm-1) 1728. NMR spectrum (CDCl3) delta(ppm): 3.79(3 H, s), 3.81(2 H, s), 3.83(2 H, s), 6.82(2 H, d), 6.92(2 H, d), 7.15(2 H, d), 7.40(2 H, d), 10.10(1 H, bs).

Reference： [1]Patent: US5310926,1994,A
[2]Patent: US5142091,1992,A

12
[ 109-72-8 ]
3,4-bis(4-methoxyphenyl)-5-methylisoxazole [ No CAS ]
[ 124-38-9 ]
[ 78967-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water;	EXAMPLE 4 3,4,-Di(p-methoxyphenyl)isoxazol-5-acetic Acid n-Butyllithium (50 ml of 1.6 molar solution, 80 mmole) is added dropwise to a stirred, cold (dry-ice-acetone bath), solution of 3,4-di(p-methoxyphenyl)-5-methylisoxazol (21.72 g., 73.6 mmole, Ex. 2) in THF (220 ml) under a nitrogen atmosphere. After stirring for 1 hour at -75 C., the red coloured mixture is poured into crushed dry-ice and stirred. The stirred mixture is allowed to warm to room temperature, concentrated, and the residue dissolved in water. The resulting solution is twice extracted with ether, layered with ethyl acetate, cooled in ice and acidified with concentrated hydrochloric acid. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers are dried (MgSO4) and concentrated to give a sticky foam residue. Recrystallization from benzene gives the title compound as a colourless solid, m.p. 142-143 C. The nmr (CDCl3) spectrum tau 6.2 (8H, s, d, CH3 O and --CH2 --), 3.28 to 2.52 (8H, m, aryl H's), 0.45 (1H, broad, COOH) agrees with the assignment.

Reference： [1]Patent: US4327222,1982,A

13
[ 78967-07-4 ]
3,4-bis(4-methoxyphenyl)-5-hydroxyethylisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With BMS; In tetrahydrofuran; at 0 - 20℃;	To a solution of <strong>[78967-07-4]mofezolac</strong> (1)(200 mg, 0.589 mmol) in anhydrous THF (2 mL) kept at 0 C by anice-bath,1M BMS in THF (1.16 mL, 1.16 mmol) was added dropwise.The reaction mixture was stirred overnight at room temperature togive a pale yellow homogeneous solution. Distilled water (1 mL),20% NaOH (1 mL) and 35% H2O2 (1 mL) were added and the obtainedreaction mixture was stirred for 1 h. Then, the solution wasextracted with ethyl acetate. The organic layer was dried overanhydrous Na2SO4 and the solvent distilled under reduced pressure.The product was isolated as a yellow oil (87% yield) by flashchromatography on silica gel (hexane/ethyl acetate 6:4) of thereaction crude. FT-IR (KBr): 3391, 1610, 1574, 1248, 1029, 835,799 cm1.1H NMR (400 MHz, CDCl3, delta): 7.39 (d, 2H, J 9.0 Hz, aromaticprotons); 7.21 (d, 2H, J 9.0 Hz, aromatic protons); 6.95 (d,2H, J 9.0 Hz, aromatic protons), 6.85 (d, 2H, J 9.0 Hz, aromaticprotons), 4.26 (t, 2H, J 6.6 Hz, CH2); 4.44 (t, 2H, J 6.6 Hz, CH2),3.85 (s, 3H, CH3); 3.81 (s, 3H, CH3). HRMS (ESI-TOF) m/z: [M Na]Calcd for C19H19NO4Na: 348.3652; Found 348.3655.
68%		Preparation of 3,4-bis(4-methoxyphenyl)-5-hydroxyethylisoxazole (X) To a solution of <strong>[78967-07-4]mofezolac</strong> (VII) (200 mg, 0.589 mmol), in anhydrous THF (2 mL) kept at 0 C by a bath of ice, 1M BMS in THF (1.16 mL, 1.16 mmol) was added dropwise, and the mixture was stirred overnight at room temperature to give a pale yellow homogeneous solution. Distilled water (1 mL), 20% NaOH (I mL) and 35% H202 (1 mL) were added and the obtained reaction mixture was stirred for 1 hour. Then, the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04 and the solvent removed under reduced pressure. The product (X) was isolated as a white solid (68% yield) by flash chromatography on silica gel (hexane/ethyl acetate 6:4) of the reaction crude, the NMR (400 MHZ, CDC13, delta): 3.81 (s, 3H, CH3), 3.85 (s, 3H, CH3); 4.44 (t, 2H, J- 6.6 Hz CH2), 4.26 (t, 2H, J= 6.6 Hz CH2 6.85 (d, 2H, J= 9.0 Hz, ArH), 6.95 (d, 2H, J= 9.0 Hz, ArH), 7.21 (d, 2H, J= 9.0 Hz, ArH); 7.39 (d, 2H, J= 9.0 Hz, ArH). ESI-MS: m/z (%): C18H20NO4 (M)+, 325.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 164,p. 59 - 76
[2]Patent: WO2014/115020,2014,A1 .Location in patent: Page/Page column 8; 14-15

14
[ 78967-07-4 ]
[ 1620743-20-5 ]

Reference： [1]Patent: WO2014/115020,2014,A1
[2]European Journal of Medicinal Chemistry,2019,vol. 164,p. 59 - 76

15
[ 78967-07-4 ]
[ 1620743-21-6 ]

Reference： [1]Patent: WO2014/115020,2014,A1
[2]European Journal of Medicinal Chemistry,2019,vol. 164,p. 59 - 76

16
[ 1745-07-9 ]
[ 78967-07-4 ]
2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]ethanone [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1172 - 1187

17
5-amino-1-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]pentan-1-one hydrochloride [ No CAS ]
[ 78967-07-4 ]
2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]-N-{5-[6,7-dimethoxy-3,4-dihydroisoquinolin-2-(1H)-yl]-5-oxopentyl}acetamide [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1172 - 1187

18
[ 68076-36-8 ]
[ 78967-07-4 ]
tert-butyl (4-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}butyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	In a three necked-flask (50 mL) equipped with a magnetic stirrer, <strong>[78967-07-4]mofezolac</strong> (500 mg, 1.47 mmol) was solubilized in dry DMF (35 mL) . Then, N-BOC-butandiamine (800 mg, 4.25 mmol), 1-hydroxybenzotriazole monohydrate (HOBt 0, 309 mg, 1.80 mmol), N,N-diisopropylethylamine (0.74 ml, 4.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC HCl, 294 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for 16 h (overnight). The reaction progress is monitored by TLC (silica gel; CHCl3/MeOH = 9:1) . The reaction was blocked by adding water (30 mL) and the aqueous phase was extracted with EtOAc (5 x 30 mL) . The combined organic extracts were treated with sat. aq. NaCl to further removal of residual DMF, and then with anhydrous Na2SO4, filtered and the solvent distilled under reduced pressure. The product was isolated by column chromatography (silica gel; EtOAc/MeOH = 95:0.5). 65 % Yield. NMR (400 MHz, CDCl3, delta) : 7.36- 7.41 (m, 2H, aromatic protons); 7.14-7.18 (m, 2H, aromatic protons); 6.89-6.93 (m, 2H, aromatic protons); 6.82-6.87 (m, 2H, aromatic protons); 6.01 (s, 1H, CONJJCH2) ; 4.56 (s, 1H, NfiBOC) ; 3.83 (s, 3H, OC) ; 3.80 (s, 3H, OCH3) ; 3.68 (s, 2H, CCO) ; 3.27-3.29 (q, 2H, CONHC) ; 3.11-3.13 (q, 2H, CNHCO) ; 1.50-1.53 (m, 4H, CH2CH2 ) ; 1.43 (s, 9H , C ( C ) 3 ) . ESI-MS: m/z (%) : C28H35 3O6 (M + Na) +: 532.4.

Reference： [1]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 48; 49; 58
[2]ChemMedChem,2016,p. 1172 - 1187
[3]ChemMedChem,2016,vol. 11,p. 1172 - 1187

19
[ 78967-07-4 ]
[ 4064-06-6 ]
1,2:3,4-di-O-isopropylidene-6-O-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetyl}-D-galactopyranose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;Inert atmosphere; Cooling with ice;	To a cold (ice-bath) solution of <strong>[78967-07-4]2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetic acid</strong> (<strong>[78967-07-4]mofezolac</strong>, 300 mg, 0.885 mmol) and 1,2:3,4-Di-O-isopropylidene-D-galactose (230 mg, 0.885 mmol) in CH2Cl2 (5 mL) , 4-(dimethylamino)pyridine (DMAP) (27 mg, 0.22 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl, 680 mg, 3.56 mmol) were added in portions under argon atmosphere. The reaction mixture was stirred at room temperature for 24h and then quenched by adding distilled water. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and the solvent removed under reduced pressure. The product (375 mg) was isolated by column chromatography (silica gel; CHCl3/MeOH 95:5) of the reaction crude. 73% Yield. NMR (300 MHz, CDCl3, delta) : 7.41-7.36 (m, 2H, aromatic protons) ; 7.19-7.14 (m, 2H, aromatic protons) ; 6.94-6.89 (m, 2H, aromatic protons) ; 6.85-6.81 (m, 2H, aromatic protons) ; 5.53 (d, 1H, J = 4.95 Hz) ; 4.61 (dd, 1H, J = 8.0 Hz, J = 2.5 Hz) ; 4.34-4.25 (m, 2H) ; 4.18 (dd, 2H, J = 8.0 Hz, J = 1.9 Hz) ; 4.05-3.99 (m, 1H) ; 3.83 (s, 3H OCH3) ; 3.80 (s, 3H, OCH3) ; 3.79 (s, 2H, CH2) ; 1.45 (s, 6H, 2CH3) ; 1.32 (s, 3H) ; 1.31 (s, 3H) . ESI-MS m/z (%) : C31H35NO10 (M + Na)+: 604.
73%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;Inert atmosphere; Cooling with ice;	General procedure: The procedure to prepare 2 is described. 12 and 13 synthesisfollowed the same procedure used to obtain 2. The exact amountsof reagents are reported in Table 5.To a cold (ice-bath) solution of <strong>[78967-07-4]2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetic acid</strong> (1, <strong>[78967-07-4]mofezolac</strong>, 300 mg, 0.885 mmol) and1,2:3,4-di-O-isopropylidene-D-galactose (230 mg, 0.885 mmol) inCH2Cl2 (5 mL), 4-(dimethylamino)pyridine (DMAP) (27 mg,0.22 mmol), and N-(3-dimethylaminopropyl)-N0-ethylcarbodiimidehydrochloride (EDC HCl, 680 mg, 3.54 mmol) wereadded in small aliquots under argon atmosphere. The reactionmixture was stirred at room temperature for 24 h and thenquenched by adding distilled water. The aqueous phase wasextracted three times with EtOAc. The combined organic phaseswere dried over anhydrous Na2SO4, filtered, and the solventremoved under reduced pressure. The product (375 mg, 73% yield)was isolated by column chromatography (silica gel; CHCl3/MeOH95:5) of the reaction crude. 4.3.1 1,2:3,4-Di-O-isopropylidene-6-O-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetyl}-d-galactopyranose (2) 1H NMR (300MHz, CDCl3, delta): 7.41-7.36 (m, 2H, aromatic protons); 7.19-7.14 (m, 2H, aromatic protons); 6.94-6.89 (m, 2H, aromatic protons); 6.85-6.81 (m, 2H, aromatic protons); 5.53 (d, 1H, J=4.9Hz); 4.61 (dd, 1H, J=8.0Hz, J=2.5Hz); 4.34-4.25 (m, 2H); 4.18 (dd, 2H, J=8.0Hz, J=1.9Hz); 4.05-3.99 (m, 1H); 3.83 (s, 3H, OCH3); 3.80 (s, 3H, OCH3); 3.79 (s, 2H, CH2); 1.45 (s, 6H, 2CH3); 1.32 (s, 3H); 1.31 (s, 3H). ESI-MS m/z (%): C31H35NO10 (M+Na)+: 604.

Reference： [1]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 20
[2]European Journal of Medicinal Chemistry,2017,vol. 141,p. 404 - 416

20
[ 78967-07-4 ]
[ 4064-06-6 ]
6-O-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetyl}-D-galactopyranose [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 404 - 416

21
[ 29840-56-0 ]
[ 78967-07-4 ]
methyl 5-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		N-Diisopropyl-N-ethylamine (DIEA, 0.215 mL, 1.237 mmol) andmethyl 5-aminopentanoate hydrochloride (6) (100 mg, 0.60 mmol)were solubilized in anhydrous CH2Cl2 (5 mL) and stirred at 0 C for1 h. Then, this solution was dropwise added to a stirred solution ofN,N'-dicyclohexylcarbodiimide (DCC, 170 mg, 0.825 mmol), 1-hydroxybenzotriazole monohydrate (HOBt H2O, 180 mg,1.05 mmol) and 2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]aceticacid (<strong>[78967-07-4]mofezolac</strong>) (200 mg, 0.59 mmol) in anhydrous CH2Cl2 (20 mL)kept at 0 C. The reaction mixture was stirred for 19h at roomtemperature. Then, H2O was added and the aqueous solutionextracted with CH2Cl2. The combined organic layers were washedwith a sat. aqueous solution of K2CO3, dried over anhydrousNa2SO4, and the solvent was removed under reduced pressure.Column chromatography of the crude residue (silica gel; EtOAc/Hexane 3:7) allowed to isolated 8 (107 mg, 40% yield). FT-IR(KBr): 3458, 3089, 2987, 2948, 2849, 1737, 1652, 1609, 1562, 1516,1455, 1441, 1426, 1253, 1233, 1175, 1108, 1029, 1019, 949, 831,729 cm1. 1H NMR (300 MHz, CDCl3, delta): 7.41e7.37 (m, 2H, aromaticprotons); 7.17e7.14 (m, 2H, aromatic protons); 6.92e6.89 (m, 4H,aromatic protons); 5.95e5.90 (bs, 1H, NH: exchanges with D2O);3.83 (s, 3H, OCH3); 3.80 (s, 3H, OCH3); 3.67 (s, 2H, CH2COONH); 3.65(s, 3H, OCH3); 3.27 (q, 2H, J 6.9 Hz, NHCH2); 2.33 (t, 2H, J 6.9 Hz,CH2COO); 1.65e1.50 (m, 4H). 13C NMR (75 MHz, CDCl3, delta): 174.1,166.8, 162.8, 161.4, 160.8, 159.7, 131.2, 130.0, 121.6, 121.2, 117.8, 114.6,114.2, 55.5, 55.4, 39.7, 34.4, 33.6, 29.0, 22.2. ESI-MS: m/z (%):C25H28N2O6 (M + Na)+: 475.
40%		Diisopropyl ethylamine (DIEA, 0.215 mL, 1.237 mmol) and methyl 5-aminopentanoate hydrochloride (100 mg, 0.60 mmol) were solubilized in dry CH2Cl2 (5 mL) and stirred at 0 C for 1h. Then, this solution was dropwise added to a stirred solution of N,N'-dicyclohexylcarbodiimide (DCC, 170 mg, 0.825 mmol), 1-hydroxybenzotriazole monohydrate (HOBt H2O, 180 mg, 1.05 mmol) and 2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetic acid (<strong>[78967-07-4]mofezolac</strong>) (200 mg, 0.59 mmol) in dry CH2Cl2 (20 mL) kept at 0 C. The reaction was stirred for 19h at room temperature. Then, H2O was added and the aqueous solution extracted with CH2Cl2. The combined organic layers were washed with a sat. solution of K2CO3, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Column chromatography of the crude residue (silica gel; EtOAc/Hexane = 3:7) afforded the product as a solid (107 mg, 40% yield). FT- IR (KBr): 3458, 3089, 2987, 2948, 1737, 1652, 1609, 1562, 1516, 1455, 1441, 1426, 1253, 1233, 1175, 1108, 1029, 1019, 949, 831, 729 cnf1. NMR (300 MHz, CDCl3, delta) : 7.41-7.37 (m, 2H, aromatic protons), 7.17-7.14 (m, 2H, aromatic protons), 6.92-6.89 (m, 4H, aromatic protons), 5.9 (bs, 1H, NJJ: exchanges with D2O) , 3.83 (s, 3H, OCH3) , 3.80 (s, 3H, OCH3) , 3.67 (s, 2H, CJJ2CONH) , 3.65 (s, 3H, OCH3) , 3.27 (q, 2H, J= 6.9 Hz, NHCJJ2), 2.33 (t, 2H, J= 6.9 Hz, CJJ2CO2), 1.65-1.50 (m, 4H, CH2CH2). 13C NMR (75 MHz, CDC13, delta) : 174.1, 166.8, 162.8, 161.4, 160.8, 159.7, 131.2, 130.0, 121.6, 121.2, 117.8, 114.6, 114.2, 55.5, 55.4, 39.7, 34.4, 33.6, 29.0, 22.2. ESI-MS: m/z (%) : C25H28 206 (M + Na) +: 475.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 404 - 416
[2]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 20; 23; 24

22
[ 29833-32-7 ]
[ 78967-07-4 ]
methyl 11-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}undecanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: N-Diisopropyl-N-ethylamine (DIEA, 0.215 mL, 1.237 mmol) andmethyl 5-aminopentanoate hydrochloride (6) (100 mg, 0.60 mmol)were solubilized in anhydrous CH2Cl2 (5 mL) and stirred at 0 C for1 h. Then, this solution was dropwise added to a stirred solution ofN,N'-dicyclohexylcarbodiimide (DCC, 170 mg, 0.825 mmol), 1-hydroxybenzotriazole monohydrate (HOBt H2O, 180 mg,1.05 mmol) and 2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]aceticacid (<strong>[78967-07-4]mofezolac</strong>) (200 mg, 0.59 mmol) in anhydrous CH2Cl2 (20 mL)kept at 0 C. The reaction mixture was stirred for 19h at roomtemperature. Then, H2O was added and the aqueous solutionextracted with CH2Cl2. The combined organic layers were washedwith a sat. aqueous solution of K2CO3, dried over anhydrousNa2SO4, and the solvent was removed under reduced pressure.Column chromatography of the crude residue (silica gel; EtOAc/Hexane 3:7) allowed to isolated 8 (107 mg, 40% yield).
72%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	To a stirred solution of <strong>[78967-07-4]mofezolac</strong> (500 mg, 1.47 mmol) in dry CH2Cl2 (25 mL) , kept at 0C by an ice-bath, HOBt monohydrate (253 mg, 1.48 mmol) and EDC hydrochloride (303 mg, 1.58 mmol) were added. Separately a stirred solution of methyl 11-aminoundecanoate hydrochloride (370 mg, 1.38 mmol) in dry CH2Cl2 (13 mL) was mixed with DIEA (0.45 mL, 2.6 mmol) at room temperature. After 2h, this solution was dropwise added to the reaction mixture and stirred overnight at room temperature. Then, sat. aq. NaHCO3 was added and the aqueous solution extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, and the solvent distilled under reduced pressure. Column chromatography (silica gel; CHCls/MeOH = 5:5) of the crude residue afforded the product as a white solid (573 mg, 72% yield). NMR (300 MHz, CDCl3, delta) : 7.41- 7.26 (m, 2H aromatic protons) ; 7.25-7.13 (m, 2H aromatic protons) ; 6.93-6.71 (m, 4H aromatic protons), 5.80 (bs, 1H, exchanges with D20) , 3.82 (s, 3H, OC) , 3.80 ( s, 3H, OCH3) , 3.67 (s, 2H, CH2) , 3.65 (s, 3H, COOC) , 3.23- 3.21 (m, 2H, NHC), 2.31-2.26 (t, 2H, CCO) , 1.62-1.57 (m, 2H, CCH2CO) , 1.49-1.45 (m, 2H, CCH2NH) ; 1.25-1.10 (m, 12H, CH2) . ESI/MS m/z: C3iH4oN206 (M + Na)+: 559.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 404 - 416
[2]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 20; 27; 28

23
[ 78967-07-4 ]
5-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}pentanoic acid [ No CAS ]

Reference： [1]Patent: WO2017/187352,2017,A1

24
[ 78967-07-4 ]
1,2:3,4-di-O-isopropylidene-6-O-(5-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}pentanoyl)-D-galactopyranose [ No CAS ]

Reference： [1]Patent: WO2017/187352,2017,A1

25
[ 78967-07-4 ]
6-O-(5-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}pentanoyl)-D-galactopyranose [ No CAS ]

Reference： [1]Patent: WO2017/187352,2017,A1

26
[ 78967-07-4 ]
(2,2,7,7-tetramethyltetrahydro-2αH-bis([1,3]dioxolo)[4,5-b:4’,5’-d]pyran-5-yl)methyl 11-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}undecanoate [ No CAS ]

Reference： [1]Patent: WO2017/187352,2017,A1

27
[ 78967-07-4 ]
[(2R,3R,4S,5R,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl]methyl 11-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}undecanoate [ No CAS ]

Reference： [1]Patent: WO2017/187352,2017,A1

28
6-[(4-nitrobenz-2-oxa-1,3-diazol-7-yl)amino]-N-[4-(4'-aminophenyl)phenyl]hexanamide [ No CAS ]
[ 78967-07-4 ]
N-{4’-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}-(1,1’-biphenyl)-4-yl}-6-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]hexanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		To a limpid orange <strong>[78967-07-4]mofezolac</strong> (69 mg, 0.20 mmol) solution in anhydrous CH2Cl2 (10 mL) , under argon atmosphere and stirred at 0C, 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC HCl) (58 mg, 0.30 mmol) was added. After 20 min, 1-hydroxybenzotriazole monohydrate (HOBt H2O) (52 mg, 0.204) was added followed by a slow addition, through a dropping funnel, of the N-[4'-amino-(1,1'-biphenyl)-4-yl]-6-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]hexanamide (94 mg, 0.20 mmol) [ or N-[4'-amino-(1,1'-biphenyl)-4-yl]-12-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]dodecanamide] previously solubilized in anhydrous CH2Cl2 (14 mL) containing N,N-diisopropylethylamine (DIEA) (0.036 mL, 0.21 mmol). The reaction mixture was stirred at room temperature for 46h. The reaction progress was monitored by TLC (silica gel; CHCls/MeOH = 9:1) and ESI-MS, verifying the product formation. The solvent was removed under reduced pressure and the product was isolated by column chromatography (silica gel; CHCl3/MeOH = 9:1) . N-{4'-{2-[3,4-bis(4-methoyphenyl)isoxazol-5-yl]acetamido}-(,'-biphenyl)-4-yl}-6-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]hexanamide (n = 5). A red solid was isolated (38 mg, 24% yield). M.p. 135-140 C. FT- IR (KBr) : 3290, 3063, 2923, 2852, 1661, 1589, 1541, 1444, 1397, 1298, 1250, 1177, 1119, 1022, 833, 738, 617, 595. NMR (500 MHz, DMSO-d6, delta) : 9.93 (bs, 1H, NH) ; 9.53 (bs, 1H, NH) ; 8.46 (d, 1H, aromatic proton) ; 7.63-7.62 (m, 8H, aromatic protons, benzidine moiety) ; 7.32-7.31 (m, 3H, aromatic protons, <strong>[78967-07-4]mofezolac</strong> part, and 1 amine proton) ; 7.20-7.19 (m, 2H, aromatic protons, <strong>[78967-07-4]mofezolac</strong> part) ; 6.98-6.94 (m, 4H, aromatic protons, <strong>[78967-07-4]mofezolac</strong> part) ; 6.40-6.39 (d, 1H, aromatic proton) ; 3.89 (m, 2H, CH2CO, <strong>[78967-07-4]mofezolac</strong> part) ; 3.75 (s, 6H, 2 OCH3) ; 2.61 (m, 2H, CH2) ; 2.38-2.31 (m, 2H, CH2); 1.73-1.64 (m, 4H, 2CH2); 1.43-1.41 (m, 2H, CH2) . 13C NMR (750 MHz DMSO-d6, delta) : 171.66, 167.05, 165.69, 164.26, 160.78, 159.48, 138.86, 138.17, 135.47, 134.66, 131.99, 129.84, 126.91, 126.83, 121.76, 121.34,120.84, 119.93, 117.25, 114.77, 114.65, 55.66, 40.82, 40.53, 40.26, 39.98, 39.71, 39.43, 39.14, 36.73, 34.29, 27.94, 26.49, 25.19. ESI-MS m/z (%) : C43H39 7O8 (M-H)+: 780; (M+Na)+: 804.
24%		General procedure: To a stirred solution of <strong>[78967-07-4]mofezolac</strong> (6, 1mmol) in anhydrous CH2Cl2 (10mL) were added EDC hydrochloride (1.5mmol), HOBt monohydrate (1mmol) under argon atmosphere at 0C. After 30min, exanamide (4) or dodecanamide (5) (1mmol) and DIEA (1mmol) in of anhydrous CH2Cl2 (14mL) were dropwise added. The reaction mixture was left to warm to room temperature, stirred for 48h (TLC analysis: silica gel, CHCl3/CH3OH=9:1 as mobile phase). After the solvent evaporation under reduced pressure, the resulting brown oil underwent to chromatography on silica gel and CHCl3/CH3OH, 9:1 as mobile phase to give the product. 4.4.1 N-{4?{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}-(1,1?biphenyl)-4-yl}-6-[(4-nitrobenz-2-oxa-1,3-diazol-7-yl)amino]exanamide (7) 24% Yield, red solid. M.p. 136-140C. FT-IR (KBr): 3290, 3063, 2923, 2852, 1661, 1589, 1541, 1444, 1397, 1298, 1250, 1177, 1119, 1022, 833, 738, 617, 595cm-1. 1H NMR (500MHz, DMSO-d6, delta): 10.35 (s, 1H, NHCO; exchanged with D2O); 9.93 (s, 1H, NHCO, exchanged with D2O); 9.73 (s, 1H, NHCH2, exchanged with D2O); 8.46 (d, 1H, J=8.79Hz, aromatic proton); 7.73-7.62 (m, 8H, aromatic protons); 7.41 (d, 2H, J=8.20Hz, aromatic protons); 7.28 (d, 2H, J=8.79Hz, aromatic protons); 6.98-6.94 (m, 4H, aromatic protons); 6.39 (d, 1H, J=8.79Hz, aromatic proton); 3.89 (s, 2H, CH2CO); 3.75 (s, 6H, two OCH3); 3.58-3.38 (m, 2H, CH2NH); 2.30 (t, 2H, J=7.03Hz, COCH2); 1.78-1.58 (m, 4H, COCH2CH2CH2CH2CH2NH); 1.55-1.35 (m, 2H, CO(CH2)2CH2(CH2)2NH). 13C NMR (125MHz, DMSO-d6, delta): 171.56, 165.70, 164.27, 160.77, 160.69, 159.46, 145.62, 144.87, 144.63, 138.87, 138.40, 138.19, 135.33, 134.52, 131.38, 129.84, 126.93, 126.85, 121.79, 121.32, 120.07, 119.81, 117.20, 114.77, 55.66, 55.57, 55.36, 43.76, 36.75, 34.29, 31.73, 29.47, 29.16, 26.51, 25.21, 22.60. ESI-MS: m/z (%): C43H39N7O8, (M - H) - 780: 707, 510, 411, 294 (100), 238, 116.

Reference： [1]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 37; 39; 40
[2]European Journal of Medicinal Chemistry,2019,vol. 179,p. 16 - 25

29
[ 78967-07-4 ]
[ 4064-06-6 ]
((2R,3R,4S,5R,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyrano-2-yl)methyl (2-(3,4-di(4-methoxyphenyl)isoxazol-5-yl)acetate) [ No CAS ]

Reference： [1]Patent: WO2017/187352,2017,A1

30
C₂₂H₂₅N₄O⁽¹⁺⁾*Cl^(1-) [ No CAS ]
[ 78967-07-4 ]
N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino)butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;	To a solution of N-(4-aminobutyl)-9-dimethylimino-9ff-benzo[a]phenoxazin-5-amonium chloride (56 mg, 0.155 mmol) in anhydrous DMF (5 mL), <strong>[78967-07-4]mofezolac</strong> (53 mg, 0.155 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (39 mg, 0.20 mg) , HOBt H2O (35 mg, 0.20 mmol) and 4-dimethylaminopyridine (DMAP) (25 mg, 0.20 mmol) were added. The mixture was stirred at room temperature, under nitrogen atmosphere, for 24 h. Then, the solvent was removed under reduced pressure and a violet solid (34 mg, 31% yield) was isolated by chromatography (silica gel; CH2Cl2/CH3OH = 9:1) . Mp 142-144 C. FT- IR (KBr) : 3427, 3235, 3063, 2921, 2851, 1641, 1588, 1328, 835, 717 cnf1. NMR (500 MHz, CDCI3, delta) : 9.00-8.85 (bs, 1H, NH: exchange with D20) ; 8.80 (d, 1H, J = 8.30 Hz, aromatic proton) ; 8.31 (d, 1H, J = 8.30 Hz, aromatic proton) ; 7.90 (t, 1H, J = 7.60 Hz, aromatic proton) ; 7.80 (t, 1H, J = 7.80 Hz, aromatic proton) ; 7.70 (d, 1H, J = 9.30 Hz, aromatic proton) ; 7.14-7.04 (m, 5H, aromatic protons) ; 6.92 (s, 1H, aromatic proton) ; 6.80 (d, 2H, J = 8.80 Hz, aromatic protons) ; 6.70 (d, 2H, J = 9.30 Hz, aromatic protons) ; 6.60 (s, 1H, aromatic proton); 3.80-3.74 (m, 6H, OCH3, and ArNfiC) ; 3.72 (s, 3H OCH3) ; 3.69 (s, 2H, CCONH) ; 3.40 (t, 2H, J = 6.40 Hz, CNHCO) ; 3.20 (s, 6H, (CH3)2N+); 1.92-1.88 (m, 2H, ArNHCH2C) ; 1.79-1.76 (m, 2H, CONHCH2C) . ESI-MS m/z (%) : C41H39CIN5O5 [M + H - Cl] + : 682.5; ESI-MS-MS: 682.5: 361 (100), 290.
11%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;	To a solution of N-(4-aminobutyl)-9-dimethylimino-9H-benzo[a]phenoxazin-5-amine (56mg, 0.174mmol) in anhydrous DMF (5mL) were added <strong>[78967-07-4]mofezolac</strong> (50mg, 0.174mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (39mg, 0.186mg), HOBt?H2O (30mg, 0.2mmol) and 4-dimethylaminopyridine (DMAP) (25mg, 0.21mmol). The reaction mixture was stirred at room temperature, under inert atmosphere, for 24h. Then, the solvent was evaporated under reduced pressure. The violet residue underwent to chromatography on silica gel and CH2Cl2/CH3OH=9:1 as mobile phase. The product was isolated as a violet solid (13mg, 11% yield). M.p. 192-194C. FT-IR (KBr): 3427, 3235, 3063, 2921, 2851, 1641, 1588, 1328, 835, 717cm-1. 1H NMR (500MHz, CD3OD, delta): 8.77 (d, 1H, J=8.31Hz, aromatic proton); 8.29 (d, 1H, J=8.31Hz, aromatic proton); 7.87 (t, 1H, J=7.60Hz, aromatic proton); 7.78 (t, 1H, J=7.80Hz, aromatic proton); 7.71 (d, 1H, J=9.30Hz, aromatic proton); 7.14-7.04 (m, 5H, aromatic protons); 6.92 (s, 1H, aromatic proton); 6.80 (d, 2H, J=8.80Hz, aromatic protons); 6.70 (d, 2H, J=9.30Hz, aromatic protons); 6.60 (s, 1H, aromatic proton); 3.78-3.75 (m, 5H, OCH3 and ArNHCH2); 372 (s, 3H, OCH3); 3.69 (s, 2H, CH2CONH); 3.40 (t, 2H, J=6.36Hz, CH2NHCO); 3.20 (s, 6H, (CH3)2N+); 1.92-1.88 (m, 2H, ArNHCH2CH2); 1.79-1.76 (m, 2H, CONHCH2CH2). 13C NMR (125MHz, CD3OD, delta): 168.93, 168.40, 163.57, 160.71, 160.59, 159.64, 157.95, 155.39, 147.55, 131.98, 131.35, 131.14, 130.88, 130.79, 129.58, 129.36, 129.05, 124.21, 122.52, 121.37, 120.65, 117.04, 113.80, 113.48, 95.82, 93.49, 54.35, 54.29, 44.41, 39.57, 38.17, 32.76, 31.65, 30.40, 29.32, 29.04, 26.61, 25.44, 22.62, 22.31, 13.01. ESI-MS: m/z [M++Na]+ 682.5; ESI-MS-MS: 682, 361 (100), 290.

Reference： [1]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 41; 43; 44
[2]European Journal of Medicinal Chemistry,2019,vol. 179,p. 16 - 25

31
[ 78967-07-4 ]
[ 107-15-3 ]
N,N’-(ethane-1,2-diyl)bis(2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		General procedure: Mofezolac (3 mmol) was solubilized in anhydrous CH2Cl2 contained in an argon-flushed three-necked round bottom flask, equipped with a magnetic stirrer and an argon inlet. The resulting mixture, kept under argon atmosphere, was cold to 0C by an ice-bath. Then, 1-hydroxybenzotriazole monohydrate (HOBt, 3 mmol) ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDC, 3 mmol) were added. The yellow and limpid reaction mixture was stirred for 2h at 0 C. Then, the proper diamine (3-9, 1 mmol) and N,N-diisopropylethylamine (DIEA, 3 mmol) were very slowly added by a syringe. Such a reaction mixture was stirred for 16h (overnight) . The reaction progress was monitored by TLC (silica gel; CHCl3/MeOH = 9:1) . The reaction was blocked by adding H20 and the formed product together with the not reacted <strong>[78967-07-4]mofezolac</strong> were extracted by EtOAc (three times) . The organic extracts were treated with NaHCO3 saturated aq. solution and extracted by EtOAc (three times) to remove the not reacted <strong>[78967-07-4]mofezolac</strong>. 3N HCl was added to the aqueous phase till pH < 6, and then extracted three times with EtOAc to recover the not reacted <strong>[78967-07-4]mofezolac</strong>. The combined organic extracts, contained the reaction product, were dried with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. A solid was obtained (10-16). N,N?-(ethane-1,2-diyl)bis(2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamide) (10) . 27% Yield. Mp 145-148C (EtOAc/Hexane, white solid) . FT- IR (KBr) : 3852, 3741, 2959, 2915, 1638, 1380, 1255, 1104, 1019, 798 cnf1. NMR (300 MHz, CDC13, delta) : 7.40-7.34 (m, 4H, aromatic protons) ; 7.18-7.14 (m, 4H, aromatic protons) ; 6.92-6.86 (m, 4H, aromatic protons) ; 6.85-6.81 (m, 4H, aromatic protons) ; 6.40 (m, 2H, NJJ) ; 3.81 (s, 6H, OC) ; 3.80 (s, 6H, OC) ; 3.68 (s, 4H, CCO) ; 3.40 (s, 4H, NHC ethylendiamine) . 13C NMR (500MHz, CDC13, delta) : 167.7, 162.2, 161.1, 160.6, 159.4, 131, 129.8, 121.3, 121, 117.6, 114.4, 114.3, 114, 113.9, 55.3, 55.2, 40.2, 33.9, 31.9, 29.6, 29.3, 22.6, 14.1. ESI-MS m/z (%) : C4oH38N4Of (M+ + Na) +: 725.

Reference： [1]Patent: WO2017/187352,2017,A1 .Location in patent: Page/Page column 51-53

32
[ 15500-73-9 ]
[ 78967-07-4 ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 164,p. 59 - 76

33
[ 122-84-9 ]
[ 78967-07-4 ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 164,p. 59 - 76

34
3,4-bis(4-methoxyphenyl)-5-methylisoxazole [ No CAS ]
[ 124-38-9 ]
[ 78967-07-4 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: 1.6 N n-BuLi (5 mL) was dropwise added to astirred solution of 3,4-diaryl-5-methylisoxazole (2.0 g, 7.0 mmol) inTHF (30 mL) kept at 78 C under an argon atmosphere. After 1h, anhydrous gaseous CO2 was bubbled into the stirred red coloredreaction mixture, till the color disappearance. Then, the yellowstirred reaction mixture was allowed to warm to room temperature,and concentrated under reduced pressure, after the additionof 3N HCl (5 mL). The aqueous solution was extracted twice withEtOAc, and the combined organic extracts were dried over anhydrousNa2SO4, filtered and the solvent distilled under reducedpressure. The obtained sticky foam residue was recrystallized frommethanol to give the 3,4-diarylisoxazol-5-acetic acids as solid substances (50-71% yields).

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 164,p. 59 - 76

35
12-[(4-nitrobenz-2-oxa-1,3-diazol-7-yl)-amino]-N-[4-(4'-aminophenyl)phenyl]dodecanamide [ No CAS ]
[ 78967-07-4 ]
N-{4’-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetamido}-(1,1‘-biphenyl)-4-yl}-12-[(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]dodecanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		To a stirred solution of <strong>[78967-07-4]mofezolac</strong> (6, 1mmol) in anhydrous CH2Cl2 (10mL) were added EDC hydrochloride (1.5mmol), HOBt monohydrate (1mmol) under argon atmosphere at 0C. After 30min, exanamide (4) or dodecanamide (5) (1mmol) and DIEA (1mmol) in of anhydrous CH2Cl2 (14mL) were dropwise added. The reaction mixture was left to warm to room temperature, stirred for 48h (TLC analysis: silica gel, CHCl3/CH3OH=9:1 as mobile phase). After the solvent evaporation under reduced pressure, the resulting brown oil underwent to chromatography on silica gel and CHCl3/CH3OH, 9:1 as mobile phase to give the product.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 179,p. 16 - 25

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
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P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
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P241	Use explosion-proof electrical/ventilating/lighting/equipment.
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P263	Avoid contact during pregnancy/while nursing.
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P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
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P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
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P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
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P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
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P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
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P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
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P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere