1052114-81-4|5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid| Ambeed

Structure of 1052114-81-4

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Quality Control of [ 1052114-81-4 ] Purity: 97% SDS Specification

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Product Details of [ 1052114-81-4 ]

CAS No. :	1052114-81-4
Formula :	C₁₂H₈FNO₃
M.W :	233.20
SMILES Code :	O=C(C1=CNC=C(C2=CC=C(F)C=C2)C1=O)O
MDL No. :	MFCD28965085
InChI Key :	IZTVDTIADHKZNM-UHFFFAOYSA-N
Pubchem ID :	60204207

Safety of [ 1052114-81-4 ]

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

Computational Chemistry of [ 1052114-81-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	12
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	59.42
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	70.16 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.19
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	2.16
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.3
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.08
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	2.9
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.93

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.04
Solubility	0.214 mg/ml ; 0.000918 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.	-3.27
Solubility	0.126 mg/ml ; 0.000542 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	-4.11
Solubility	0.0181 mg/ml ; 0.0000778 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	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.19 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.	0.56

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	0.0 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)	2.12

Application In Synthesis of [ 1052114-81-4 ]

* 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 [ 1052114-81-4 ]

[ 1052114-81-4 ] Synthesis Path-Downstream 1~35

1
[ 688781-75-1 ]
[ 1052114-81-4 ]
[ 1052114-76-7 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5330 - 5341.

2
[ 1052114-80-3 ]
[ 1052114-81-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; at 100℃; for 1.5h;	Example A8: A suspension of Example A7 (0.750 g, 2.87 mmol) in 3M NaOH (7.5 mL,22.50 mmol) was heated at 100C for 1.5 h. The mixture was cooled to RT, acidified to pH 2 with 3M HC1 and the resulting solid was collected via filtration and dried to afford 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (669 mg, 100%) as a white solid. MS (ESI) mlz: 234.1 (M+Hj.
82%		To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute ethanol (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85C for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with IN HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4- fluorophenyl)-4-oxo-l,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS(ESI+) m/z 262 (M+H)+.[0094] The above ester (1.0 g, 3.8 mmol) was dissolved in 2N NaOH (20 mL) and heated to 65C for 2 h. The resulting clear mixture was cooled to ambient temperature and the solids were filtered off. The filtrate was then acidified with IN HCl to pH = 1 and the resulting yellow precipitate was collected as the desired product (0.73 g, 82%). 1H NMR (DMSO-^) delta 13.52 (br s, 1 H), 8.86 (s, 1 H), 8.51 (s, 1 H), 7.99-7.96 (m, 2 H), 7.55-7.51 (m, 2 H); MS(ESI+) m/z 234 (M+H)+.
14.13 g	With sodium hydroxide; In ethanol; at 65℃; for 2h;	2N NaOH solution (120ml) was added to A13(16.88g) in ethanol (50ml). The reaction mixture was stirred and heated to 65 DC for 2hrs, and then cooled to room temperature. Thereaction mixture was added in 1.5N HCl ( 400ml) to precipitate out solid. Filtration was to collectsolid. The solid was wash twice with water, and dried by vacuum to give Acid1(14.13g).de

References: [1]Patent: WO2014/145004,2014,A1 .Location in patent: Paragraph 0111.
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 5330 - 5341.
[3]Patent: WO2009/94417,2009,A1 .Location in patent: Page/Page column 28; 35-36.
[4]Patent: WO2014/713,2014,A1 .Location in patent: Page/Page column 38.

3
[ 1052114-81-4 ]
[ 1174046-76-4 ]
[ 1174047-03-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of 4-(4-amino-2-fluorophenoxy)-3-chloro-N- (diphenylmethylene)pyridin-2-amine (836 mg, 2.0 mmol) and 5-(4-fluorophenyl)-4- <n="39"/>oxo-l^-dihydropyridine-S-carboxylic acid (490 mg, 2.0 mmol) in DMF (10 mL) at room temperature were added HATU (913 mg, 2.4 mmol) and DIPEA (1.05 ml, 6.0 mmol). The reaction mixture was stirred at room temperature for 3 h prior to being quenched by the addition of cold water (50 mL). The solid that formed was collected by filtration, and washed with water and ether. The solid was dissolved in DCM and purified by flash column chromatography (SiC^, DCM to 10% MeOH in DCM) to give the desired product (987 mg, 78%) as a light yellow solid. MS(ESI+) m/z 633 (M + H)+.

References: [1]Patent: WO2009/94417,2009,A1 .Location in patent: Page/Page column 27; 36-37.

4
[ 1052114-81-4 ]
[ 1355620-90-4 ]
[ 1355620-37-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; Cooling with ice;	To a suspension of 5-(4-Fluorophenyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341 ) (8.0 g, 34.3 mmol) in anhydrous DMF (56mL) were added HATU (15.65g, 41.2mmol) and z-Pr2NEt (18mL, 104mmol) at ice bath temperature under nitrogen. The mixture turned into a clear solution after being stirred for 5 min. To the solution was added 4-(4-Amino-2-Fluoro-phenoxy)-7,8, 10,11,13,14-hexahydro-6,9, 12, 15-tetraoxa- 1 -aza- cyclododeca[b]naphthalene 7a (7.9g, 32.5mmol) slowly. The reaction mixture was stirred for 3h at room temperature and was poured into aqueous IN HCl solution. The solid that formed was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography, eluting with 1-5% of MeOH in CH2CI2 to obtain 9a as a light-yellow solid (5.9g, 40%), mp 188-190C . HPLC purity 97%; 1H NMR (400MHz, DMSO) delta 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 6.89 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+ 616.6, found 616.5.
40%		Step 6 5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8, 10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-yloxy)-phenyl]amide To a suspension of 5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol) in anhydrous DMF (56 mL) were added HATU (15.65 g, 41.2 mmol) and i-Pr2NEt (18 mL, 104 mmol) at ice bath temperature under nitrogen. The mixture turned into a clear solution after being stirred for 5 min. To the solution was added 4-(4-Amino-2-Fluoro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalene 7a (7.9 g, 32.5 mmol) slowly. The reaction mixture was stirred for 3 h at room temperature and was poured into aqueous 1N HCl solution. The solid that formed was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography, eluting with 1-5% of MeOH in CH2Cl2 to obtain 9a as a light-yellow solid (5.9 g, 40%), mp 188-190 C. HPLC purity 97%; 1H NMR (400 MHz, DMSO) delta 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 6.89 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+ 616.6, found 616.5.
40%		5- (4-Fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d(J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol)DMF (56 mL)And then under the protection of nitrogen,HATU (15.65 g, 41.2 mmol) and i-Pr2NEt (18 mL, 104 mmol) were added at ice-bath temperature.After stirring for 5 minutes, the mixture became clear,Slowly add4- (4-amino-2-fluoro-phenoxy) -7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1- Alkyl [b] naphthalene 7a (7.9 g, 32.5 mmol).After the reaction mixture was stirred at room temperature for 3 hours,Was poured into IN HCl. The formed solid was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography eluting with 1-5% MeOH in CH2Cl2 to give a light yellow solid 9a (5.9 g, 40%), m.p. 188-190C. The purity after HPLC purification was 97%.

References: [1]Patent: WO2012/6960,2012,A1 .Location in patent: Page/Page column 45.
[2]Patent: US2013/123286,2013,A1 .Location in patent: Paragraph 0256.
[3]Patent: TWI532743,2016,B .Location in patent: Page/Page column 42.

5
[ 1052114-81-4 ]
[ 1355620-85-7 ]
[ 1355620-21-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; Cooling with ice;	To a suspension of 5-(4-Fluorophenyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341 ) (8.0g, 34.3 mmol) in anhydrous DMF (56 mL) were added HATU (15.65 g, 41.2 mmol) and z'-Pr2NEt (18 mL, 104 mmol) at ice bath temperature under nitrogen. The mixture turned into a clear solution after being stirred for 5min. To the solution was added 4-(4-Amino-2-Methyl-phenoxy)-7,8,10,l l,13,14-hexahydro-6,9,12,15- tetraoxa-l,3-diaza-cyclododeca[b]naphthalene 7a (7.9g, 32.5mmol) slowly. The reaction mixture was stirred for 3h at room temperature and was poured into aqueous 1 N HC1 solution. The solid that formed was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography, eluting with 1-5% of MeOH in CH2C12 to obtain 9a as a light-yellow solid (5.9g, 40%), mp 188-190C . HPLC purity 97%; 1H NMR (400MHz, DMSO) delta 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, IH), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+ 617.6, found 617.5.
5.9 g		Nitrogen protection and ice bath temperature,willHATU (15.65 g, 41.2 mmol)And i-Pr2NEt (18 mL, 104 mmol) were addedTo(8.0 g, 34.3 mmol) of 5- (4-fluorophenyl) -4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341)In dry DMF (56 mL).The mixture became a clear solution and stirred for an additional 5 minutes. And then slowly added to the solution4- (4-amino-2-methyl-phenoxy) -7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxo- -cyclododecane [b] naphthalene 7a (7.9 g, 32.5 mmol).After stirring at room temperature for 3 hours,Was poured into 1N HCl in water. After forming a solid, it was filtered, washed with distilled water, and dried. The resulting crude product was chromatographed on silica gel eluting with 1-5% methanol in methylene chloride to give pale yellow solid 9a (5.9 g, 40%), m.p. 188-190 C. The product was further purified by HPLC to give a purity of 97%.

References: [1]Patent: WO2012/6960,2012,A1 .Location in patent: Page/Page column 36; 37; 38.
[2]Patent: TWI532743,2016,B .Location in patent: Page/Page column 35; 36.

6
[ 1052114-81-4 ]
[ 1265637-74-8 ]
[ 1265637-57-7 ]

Yield	Reaction Conditions	Operation in experiment
26%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 96h;	5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid {5-[3-(4-methoxy-benzyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-5-yloxy]-pyridin-2-yl}-amide (284)A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), <strong>[1052114-81-4]5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid</strong> (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (131.72 mul; 0.79 mmol; 3.00 eq.) was stirred at room temperature for 4 days. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 284 as a tan solid. LC-MS (M+H=593, obsd.=593).

References: [1]Patent: US2012/190654,2012,A1 .Location in patent: Page/Page column 66.

7
[ 1052114-81-4 ]
4-(4-amino-2-methyl-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalene [ No CAS ]
[ 1355620-21-1 ]

Yield	Reaction Conditions	Operation in experiment
40%		Step 2. 5-(4-Fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-yloxy)-phenyl]-amide To a suspension of 5-(4-Fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d (J. Med. Chem. 2008, 51, 5330-5341) (8.0 g, 34.3 mmol) in anhydrous DMF (56 mL) were added HATU (15.65 g, 41.2 mmol) and i-Pr2NEt (18 mL, 104 mmol) at ice bath temperature under nitrogen. The mixture turned into a clear solution after being stirred for 5 min. To the solution was added 4-(4-Amino-2-Methyl-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalene 7a (7.9 g, 32.5 mmol) slowly. The reaction mixture was stirred for 3 h at room temperature and was poured into aqueous 1 N HCl solution. The solid that formed was filtered, washed with distilled water, and dried. The crude product was purified by silica gel chromatography, eluting with 1-5% of MeOH in CH2Cl2 to obtain 9a as a light-yellow solid (5.9 g, 40%), mp 188-190 C. HPLC purity 97%; 1H NMR (400 MHz, DMSO) delta 13.13 (s, 1H), 12.68 (br s, 1H), 8.62 (m, 2H), 7.97-8.12 (m, 2H), 8.04-7.99 (m, 2H), 7.78 (m, 1H), 7.69 (m, 2H), 7.42 (d, 2H), 7.21 (m, 2H); 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+ 617.6, found 617.5.

References: [1]Patent: US2013/123286,2013,A1 .Location in patent: Paragraph 0233.

8
[ 1052114-81-4 ]
[ 6226-25-1 ]
[ 1449300-95-1 ]

Yield	Reaction Conditions	Operation in experiment
123 mg	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	2,2,2-Trifluoroethyl trifluoromethanesulfonate (371 mul) was added to a suspension of <strong>[1052114-81-4]5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid</strong> (100 mg) and cesium carbonate (838 mg) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature for three hours and diluted by adding ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by PLC [ethyl acetate:hexane=2:1 (v/v)] to give 123 mg of the title compound as a solid. 1H-NMR (CDCl3) delta: 4.37-4.46 (2H, m), 4.65-4.71 (2H, m), 7.05-7.12 (2H, m), 7.34-7.39 (1H, m), 7.49-7.56 (2H, m), 8.16 (1H, d, J=2.4 Hz). MS (ESI) m/z: 398 (M+H)+.

References: [1]Patent: US2013/281428,2013,A1 .Location in patent: Paragraph 0468; 0469; 0470; 0471.

9
[ 1052114-81-4 ]
[ 1449300-75-7 ]
[ 1449299-59-5 ]

Yield	Reaction Conditions	Operation in experiment
20 mg		HOAt (14 mg), HATU (57 mg), DMAP (6 mg) and DIPEA (29 mul) were added to a solution of <strong>[1052114-81-4]5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid</strong> (23 mg) in DMF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for three hours. The compound obtained in the above Step 2 (32 mg) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, purified by PLC [organic layer of chloroform:methanol:water=7:3:1 (v/v)] and lyophilized with a dioxane-water mixed solvent to give the title compound (20 mg) as a solid. 1H-NMR (CDCl3-CD3OD) delta: 3.98-3.88 (6H, m), 6.92-7.19 (5H, m), 7.44-7.70 (6H, m), 7.82-7.89 (2H, m), 8.15-8.21 (1H, m), 8.58-8.61 (1H, m). MS (ESI) m/z: 537 (M+H)+.

References: [1]Patent: US2013/281428,2013,A1 .Location in patent: Paragraph 0337; 0338; 0339; 0340.

10
[ 1052114-81-4 ]
[ 1449299-74-4 ]