77837-08-2|6-Oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid| Ambeed

Structure of 77837-08-2

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Quality Control of [ 77837-08-2 ] Purity: 98% SDS Specification

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Product Details of [ 77837-08-2 ]

CAS No. :	77837-08-2
Formula :	C₁₂H₉NO₃
M.W :	215.20
SMILES Code :	O=C(C(C=C1)=CN(C2=CC=CC=C2)C1=O)O
MDL No. :	MFCD07369218
InChI Key :	PETUTZMMIOWORO-UHFFFAOYSA-N
Pubchem ID :	11988812

Safety of [ 77837-08-2 ]

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

Computational Chemistry of [ 77837-08-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	12
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	59.0
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	59.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.66
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	1.19
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.54
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.	1.76
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	1.45
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.52

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.35
Solubility	0.968 mg/ml ; 0.0045 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.	-2.03
Solubility	2.0 mg/ml ; 0.0093 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	-3.0
Solubility	0.213 mg/ml ; 0.000989 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	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.	-6.77 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)	1.84

Application In Synthesis of [ 77837-08-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 77837-08-2 ]

[ 77837-08-2 ] Synthesis Path-Downstream 1~34

1
4-anilinomethylene-pentenedioic acid [ No CAS ]
[ 77837-08-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1893,vol. 273,p. 179.

2
α-anilino-methylene-glutaconic acid α-methyl ester [ No CAS ]
[ 77837-08-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1893,vol. 273,p. 179.

3
[ 500-05-0 ]
[ 77837-08-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1893,vol. 273,p. 179.
[2]Patent: WO2012/102580,2012,A1 .

4
[ 62-53-3 ]
[ 77837-08-2 ]

References: [1]Justus Liebigs Annalen der Chemie,1893,vol. 273,p. 179.
[2]Patent: US2013/317059,2013,A1 .
[3]Patent: WO2012/102580,2012,A1 .

Yield	Reaction Conditions	Operation in experiment
2%		EXAMPLE 27 1-Phenyl-6-keto-1,6-dihydronicotinic acid 2percent cream is prepared as follows: 1-Phenyl-6-keto-1,6-dihydronicotinic acid 2 g synthesised according to Example 26 is dissolved in 10 ml of 2-pyrrolidinone, and the solution is admixed with 88 g of hydrophilic ointment USP. The mixing is continued until a uniform consistency is obtained.

6
[ 77837-08-2 ]
[ 543-27-1 ]
C₁₇H₁₇NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In tetrahydrofuran; at -5℃; for 3h;	d2-5-(Hydroxymethyl)-1-phenylpyridine-2(1H)-one: Isobutyl chloroformate (0.45 mL, 3.49 mmol) was added to a solution of <strong>[77837-08-2]6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid</strong> (0.500 g, 2.32 mmol) and N-methylmorpholine (0.38 mL, 3.49 mmol) in tetrahydrofuran (10 mL) at -5° C. The mixture was stirred for 3 hours at the same temperature, diluted with tetrahydrofuran and filtered over a pad of Celite under argon. The filtrate containing the mixed anhydride was added dropwise to a suspension of sodium borodeuteride (0.117 g, 2.79 mmol) in tetrahydrofuran at -10° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, after which D2O (1 mL) was added. Standard extractive work up gave a crude residue which was purified by preparative HPLC to give the title compound as a white solid (0.290 g, 61percent). m.p. 115-120° C.; 1H NMR (400 MHz, CDCl3) delta 2.05 (br, 1H), 6.66 (d, J=9.1 Hz, 1H), 7.25-7.51 (m, 7H); IR (KBr) nu 3337, 1665, 1586, 1535, 1257 cm-1; MS 204 (M+1).
	With 4-methyl-morpholine; In tetrahydrofuran; at -5℃; for 3h;	Step 4; d2-5-(Hvdroxymethyl)-l-phenylpyridine-2(lH)-one:; Isobutyl chloroformate(0.45 mL, 3.49 mmol) was added to a solution of 6-oxo-l -phenyl- l ,6-dihydropyridine-3- carboxylic acid (0.500 g, 2.32 mmol) and N-methylmorpholine (0.38 mL, 3.49 mmol) in tetrahydrofuran (10 mL) at -5 °C. The mixture was stirred for 3 hours at the same temperature, diluted with tetrahydrofuran and filtered over a pad of Celite under argon. The filtrate containing the mixed anhydride was added dropwise to a suspension of sodium borodeuteride (0.117 g, 2.79 mmol) in tetrahydrofuran at -10 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, after which D20 (1 mL) was added. Standard extractive work up gave a crude residue which was purified by preparative HPLC to give the title compound as a white solid (0.290 g, 61percent). m.p. 115-120 °C; *H NMR (400 MHz, CDC13) delta 2.05 (br, 1H), 6.66 (d, J = 9.1 Hz, 1H), 7.25-7.51 (m, 7H); IR (KBr) upsilon 3337, 1665, 1586, 1535, 1257 cm"1; MS 204 (M + 1).

References: [1]Patent: US2008/319026,2008,A1 .Location in patent: Page/Page column 23.
[2]Patent: WO2012/122165,2012,A2 .Location in patent: Page/Page column 64.

7
[ 77837-09-3 ]
[ 77837-08-2 ]

Yield	Reaction Conditions	Operation in experiment
79%		6-Oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid: Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (1.0 g, 4.37 mmol), tetrahydrofuran (9 mL) and water (6 mL) at 0° C. The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipitate was filtered to give the title compound as a brown solid (0.740 g, 79percent). m.p. 256-263° C.; 1H NMR (400 MHz, DMSO-d6) delta 6.53 (d, J=9.4 Hz, 1H), 7.40-7.49 (m, 5H), 7.87 (dd, J=2.5, 9.8 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) nu 3446, 1708, 1645, 1577, 1263, 1228 cm-1; MS 214 (M-1).
79%		Step 3; 6-Oxo-l -phenyl- 1 ,6-dihydropyridine-3-carboxylic acid:; Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyl-6-oxo-l -phenyl- 1,6- dihydropyridine-3-carboxylate (1.0 g, 4.37 mmol), tetrahydrofuran (9 mL) and water (6 mL) at 0 °C. The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipitate was filtered to give the title compound as a brown solid (0.740 g, 79percent). m.p. 256-263 °C; *H NMR (400 MHz, DMSO-d6) delta 6.53 (d, / = 9.4 Hz, 1H), 7.40-7.49 (m, 5H), 7.87 (dd, / = 2.5, 9.8 Hz , 1H), 8.23 (d, / = 2.5 Hz, 1H); IR (KBr) upsilon 3446, 1708, 1645, 1577, 1263, 1228 cm"1; MS 214 (M - 1).
67%	With water; lithium hydroxide; In methanol; at 50℃; for 5h;	General procedure: Example 1-3 Synthesis of 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid [0042] After 750 mg (3.27 mmol) of methyl 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylate was dissolved in 9 mL of methanol and 3 mL of water, 235 mg (9.81 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50° C. for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by addition of aqueous HCl to titrate a pH of the reaction product to pH 2. After filtration of the resulting solid compound (Actual yield: 470 mg, Percent yield: 67percent), the resulting compound was used without purification. [0043] 1H-NMR (DMSO-d6,200 MHz) delta8.18 (s, 1H), 7.88 (d, 1H), 7.49 (m, 5H), 6.54 (d, 2H)

		A round-bottom flask was charged with methyl 6-oxo-l -phenyl- l ,6-dihydropyridine-3- carboxylate 12a (2.26 g, 9.87 mmol), THF (58.5 mL) and MeOH (14.6 mL). The resulting slurry was cooled to 0 C. A solution of LIOH (700 mg, 29.2 mmol) in water (29.2 niL) was added dropwise via cannula. After stirring for 5 minutes the ice bath was removed. The mixture was stirred at rt for 45 minutes and then at 35 C for 30 minutes. After cooling to rt, the mixture was acidified to pH 1 with 1 N HCl and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried (Na?SO4), filtered, and concentrated in vacuo to afford 1.95 g of a brown solid which was used without further purification,[128] A round-bottom flask was charged with 1.30 g of the brown solid, THF (35.8 niL) and MeOD (8.94 ml). A solution of NaOD (99,5 atom percent D, 1.86 ml, 40 wt. percent in D2O) was added. After stirring at rt for 1.5 h, the mixture was cooled to 0 C. acidified to pH 1 with DCl (35 wt. percent in D2O), and extracted with EtOAc (3times). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 1.31 g (100 percent) of the title compound 22 as a brown solid. 1H NMR (DMSOd6): delta 8.22 (d, J= 2.4, 1H), 7.91 (dd, J- 2.7, 9.1, 1H), 7.62-7,48 (m, 5H), 6.58 (d. ,/ = 9.44, 1H). MS (M+H): 216.1.
	With water; lithium hydroxide; In methanol; at 50℃; for 5h;	After 750 mg (3.27 mmol) of methyl 6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylate was dissolved in 9 mL of methanol and 3 mL of water, 235 mg (9.81 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50°C for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, followed by addition of aqueous HCl to titrate a pH of the reaction product to pH 2. After filtration of the resulting solid compound (Actual yield: 470 mg, Percent yield: 67 percent), the resulting compound was used without purification.[60] 1H-NMR(DMSO-d6,200MHz)delta8.18(s,1H),7.88(d,1H),7.49(m,5H),6.54(d,2H)

References: [1]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666.
[2]Patent: US2008/319026,2008,A1 .Location in patent: Page/Page column 22.
[3]Patent: WO2012/122165,2012,A2 .Location in patent: Page/Page column 63-64.
[4]Patent: US2013/317059,2013,A1 .Location in patent: Paragraph 0042-0043.
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 5079 - 5093.
[6]Patent: WO2010/65755,2010,A1 .Location in patent: Page/Page column 35-36.
[7]Patent: WO2012/102580,2012,A1 .Location in patent: Page/Page column 17-18.

8
[ 77837-08-2 ]
[ 1228275-03-3 ]

Yield	Reaction Conditions	Operation in experiment
		A round-bottom flask was charged with methyl 6-oxo-l -phenyl- l ,6-dihydropyridine-3- carboxylate 12a (2.26 g, 9.87 mmol), THF (58.5 mL) and MeOH (14.6 mL). The resulting slurry was cooled to 0 C. A solution of LIOH (700 mg, 29.2 mmol) in water (29.2 niL) was added dropwise via cannula. After stirring for 5 minutes the ice bath was removed. The mixture was stirred at rt for 45 minutes and then at 35 C for 30 minutes. After cooling to rt, the mixture was acidified to pH 1 with 1 N HCl and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried (Na?SO4), filtered, and concentrated in vacuo to afford 1.95 g of a brown solid which was used without further purification,[128] A round-bottom flask was charged with 1.30 g of the brown solid, THF (35.8 niL) and MeOD (8.94 ml). A solution of NaOD (99,5 atom percent D, 1.86 ml, 40 wt. percent in D2O) was added. After stirring at rt for 1.5 h, the mixture was cooled to 0 C. acidified to pH 1 with DCl (35 wt. percent in D2O), and extracted with EtOAc (3times). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 1.31 g (100 percent) of the title compound 22 as a brown solid. 1H NMR (DMSOd6): delta 8.22 (d, J= 2.4, 1H), 7.91 (dd, J- 2.7, 9.1, 1H), 7.62-7,48 (m, 5H), 6.58 (d. ,/ = 9.44, 1H). MS (M+H): 216.1.

References: [1]Patent: WO2010/65755,2010,A1 .Location in patent: Page/Page column 35-36.

9
[ 77837-08-2 ]
quinuclidine dihydrochloride [ No CAS ]
[ 1392219-90-7 ]

Yield	Reaction Conditions	Operation in experiment
		After dissolution of 300 mg (1.39 mmol) of <strong>[77837-08-2]6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid</strong> in 10 mL of dichloromethane, 530 mg (4.17 mmol) of oxalyl chloride was added to the solution, and a catalytic amount of DMF was then added thereto. After being stirred at room temperature for about 2 hours, the solvent was removed in vacuo. After addition of 415 mg (2.08 mmol) of quinuclidine dihydrochloride to 10 mL of acetonitrile, 898 mg (6.95 mmol) of diethylisopropylamide was added to the solution. This reaction solution was stirred at room temperature for about 24 hours. After addition of the reaction mixture distilled under reduced pressure to acetonitrile, the 3-aminoquinuclidine dihydrochloride reaction solution was slowly added thereto, followed by stirring at room temperature for about 15 hours and the solvent was removed in vacuo. The resulting compound was extracted three times with chloroform and an aqueous NaOH solution (pH=12), and was then purified using liquid chromatography (chloroform: methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 360 mg, Percent yield: 80 percent).

References: [1]Patent: WO2012/102580,2012,A1 .Location in patent: Page/Page column 18.

10
[ 77837-08-2 ]
[ 1392221-19-0 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In toluene; at 100℃; for 2h;	After 197 mg (0.91 mmol) of <strong>[77837-08-2]6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid</strong> obtained in Example 1-3 was dissolved in 10 mL of toluene, 217 mg (1.82 mmol) of thionyl chloridethionyl chloride was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 100°C for 2 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then used in Example 115-2 without an additional purification process
	With thionyl chloride; In toluene; at 100℃; for 2h;	Example 115-1 Synthesis of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonyl chloride [0396] After 197 mg (0.91 mmol) of <strong>[77837-08-2]6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid</strong> obtained in Example 1-3 was dissolved in 10 mL of toluene, 217 mg (1.82 mmol) of thionyl chloridethionyl chloride was added to the solution. Afterward, the resulting reaction solution was stirred under reflux at about 100° C. for 2 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and was then used in Example 115-2 without an additional purification process.

References: [1]Patent: WO2012/102580,2012,A1 .Location in patent: Page/Page column 71.
[2]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666.
[3]Patent: US2013/317059,2013,A1 .Location in patent: Paragraph 0396.

11
[ 77837-08-2 ]
[ 1392221-04-3 ]

References: [1]Patent: US2013/317059,2013,A1 .
[2]Patent: WO2012/102580,2012,A1 .

12
dimethyl 4-(methoxymethylene)-2-pentanedioate [ No CAS ]
[ 77837-08-2 ]

References: [1]Patent: WO2012/102580,2012,A1 .

13
[ 66171-50-4 ]
[ 77837-08-2 ]

References: [1]Patent: WO2012/122165,2012,A2 .

14
[ 77837-08-2 ]
[ 1093952-03-4 ]

References: [1]Patent: WO2012/122165,2012,A2 .

15
[ 77837-08-2 ]
d2-5-bromomethyl-1-phenyl-1H-pyridin-2-one [ No CAS ]

References: [1]Patent: WO2012/122165,2012,A2 .

16
[ 77837-08-2 ]
[ 1093951-85-9 ]

References: [1]Patent: WO2012/122165,2012,A2 .

17
[ 5006-66-6 ]
[ 77837-08-2 ]

References: [1]Patent: WO2012/122165,2012,A2 .

18
[ 77837-08-2 ]
[ 1416048-27-5 ]
C₉₁H₁₄₃N₁₇O₂₄ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5079 - 5093.

19
[ 6018-41-3 ]
[ 62-53-3 ]
[ 77837-08-2 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5079 - 5093.

20
[ 6018-41-3 ]
[ 77837-08-2 ]

References: [1]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666.

21
[ 77837-08-2 ]
6-oxo-N,1-diphenyl-1,6-dihydropyridine-3-carboxamide [ No CAS ]

References: [1]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666.

22
[ 77837-08-2 ]
6-oxo-1-phenyl-N-propyl-1,6-dihydropyridine-3-carboxamide [ No CAS ]

References: [1]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666.

23
[ 77837-08-2 ]
N-(2-methoxyethyl)-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxamide [ No CAS ]

References: [1]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666.

24
4-methoxymethylidene-2-pentenedioic acid dimethyl ester [ No CAS ]
[ 77837-08-2 ]

References: [1]Patent: US2013/317059,2013,A1 .

25
[ 77837-08-2 ]
[ 1392219-90-7 ]

References: [1]Patent: US2013/317059,2013,A1 .

26
[ 77837-08-2 ]
[ 6530-09-2 ]
[ 1392219-90-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 24h;	General procedure: Method 3: [0050] After 300 mg (1.39 mmol) of <strong>[77837-08-2]6-oxo-1-phenyl-1,6-dihydro-3-pyridinecarboxylic acid</strong> was dissolved in 10 mL of acetonitrile, 415 mg (2.08 mmol) of 3-aminoquinuclidine dihydrochloride and 718 mg (5.56 mmol) of diethylisopropylamide were added to the solution. Afterward, 207 mg (1.53 mmol) of 1-hydroxylbenzotriazole (HOBt) and 266 mg (1.39 mmol) of N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC) were added to the reaction solution. This reaction solution was stirred at room temperature for about 24 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo and then extracted three times with chloroform and an aqueous NaOH solution (pH=12), followed by purification using liquid chromatography (chloroform:methanol: ammonia water=10:1:0.1) to obtain a target compound (Actual yield: 317 mg, Percent yield: 70percent). [0051] 1H-NMR (CDCl3,200 MHz) delta8.11 (s, 1H), 7.75 (d, 1H), 7.40 (m, 4H), 6.65 (d, 1H), 6.26 (br, 1H), 4.15 (m, 1H), 3.39 (m, 1H), 2.89 (m, 4H), 2.53 (m, 1H), 2.06 (m, 1H), 1.53 (m, 4H)

References: [1]Patent: US2013/317059,2013,A1 .Location in patent: Paragraph 0049-0051.

27
[ 77837-08-2 ]
C₄₁H₅₄N₅O₁₀Pol [ No CAS ]
C₃₈H₅₁N₆O₁₀Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	General procedure: Tetrapeptides 3a-d were synthesized by manual solid-phase peptide synthesis (SPPS) using 2-chlorotritylchloride polymer resin (2-CTC, 1.63mmol/g) in a 10-mL disposable syringe fitted with a porous polyethylene filter and N-terminal fluorenylmethyloxycarbonyl-protected amino acids. Coupling of the first amino acid: Fmoc-propargyl-Gly-OH (0.8 eq.) to the 2-CTC resin (1.0 eq.) was performed in anhydrous DCM (7.5mL) in the presence of DIEA (3.0 eq.) with shaking at room temperature for 2h. Then, MeOH (2mL) was added to cap the unreacted resin and the mixture was shaken for 30min. The resin was filtered, washed with several portions of DCM, DMF and again DCM and dried under high vacuum, overnight. Loading of the starting material was calculated via increase in dry weight. Next, the resin swelling was performed in DMF for 20min, Fmoc protecting group was removed by treatment with 20percent piperidine in DMF (2×3mL, 5+20min) and the polymer was washed with DMF (5×3mL, 5×2min). Then, coupling of the appropriate amino acid: Fmoc-AA-OH (4.0 eq.) was performed in DMF (3mL) using HBTU (4.0 eq.), in the presence of DIEA (8.0 eq.) with shaking at room temperature. In the case of Fmoc-Ala-OH for 4h, with Fmoc-Orn(Boc)-OH, Fmoc-Thr (tBu)-OH and Fmoc-N-Me-Thr (tBu)-OH overnight and with Fmoc-Arg (Pbf)-OH and Fmoc-His (Trt)-OH the double coupling was performed (after 2h the resin was washed with DMF and treated with a freshly made solution of Fmoc-AA-OH, HBTU and DIEA in DMF and shaken for 2h). After each coupling, the resin was washed with DMF (4×4mL) and subsequently de-protected and washed as described above. At the end of the coupling cycle the resin was washed with several portions of DMF, MeOH and DCM and dried under high vacuum, overnight. Method (A) for coupling of the tail via HBTU activation: The coupling of the tails at the N-terminus of the synthesized tetrapeptides was performed using the acid (4 eq.) in DMF (2mL), in the presence of DIEA (8 eq.) and HBTU (4 eq.) at room temperature, shaking overnight. The resin was then washed extensively with several portions of DMF, MeOH and DCM and dried under high vacuum. Method (B) for coupling of the tail via mixed anhydride: Step 1. Heterocyclic acid derivative (0.52mmol, 1 eq.) was reacted with Boc anhydride (2.11mmol, 4 eq.) in dry tetrahydrofuran in presence of pyridine (2.64mmol, 5 eq.) at r. t. overnight. After full consumption of starting material volatiles were removed in vacuo. Aqueous 0.5M hydrochloric acid solution was added and the product was extracted with ethyl acetate. The organic layer was washed with water, separated and dried over sodium sulfate. Volatiles were removed in vacuo yielding a crude product as yellowish oil, which was used in the next step without further purification. Step 2. The 2-CTC resin containing 3a (0.13mmol, 1 eq.) was suspended in DMF (3mL) containing mixed anhydride prepared in Step 1 (presumed 0.52mmol, 4 eq.) and DIPEA (1.82mmol, 14 eq.). The reaction mixture was shaken at r. t. overnight. The resin was filtered, washed with DMF (5×2mL), DCM (5×2mL) and THF (5×4mL). General method for cleavage from the solid support. 2-CTC resin containing oligopeptides was added into a mixture of HFIP/DCM 1:4 (4mL) and the reaction mixture was shaken at room temperature for 1.5h. The resin was filtered off and washed with DCM and THF. The volatiles were evaporated in vacuo. Purification: The crude peptides were dissolved in THF (2.5mL) and H2O/MeCN (1:1, 2.5mL), filtered through a 0.45mum nylon membrane filter and purified in 1?3 runs by preparative RP-HPLC. The reported yields are based on calculated loading of the oligopeptide on 2-CTC resin.

References: [1]European Journal of Medicinal Chemistry,2018,vol. 157,p. 1346 - 1360.

28
[ 77837-08-2 ]
[ 76918-64-4 ]
C₂₀H₁₅N₃O₆ [ No CAS ]