3424-43-9|Ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate| Ambeed

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Quality Control of [ 3424-43-9 ] Purity: 98% SDS Specification

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Product Details of [ 3424-43-9 ]

CAS No. :	3424-43-9
Formula :	C₉H₁₁NO₃
M.W :	181.19
SMILES Code :	O=C(C(C=C1)=C(C)NC1=O)OCC
MDL No. :	MFCD01871481
InChI Key :	UEZSEPUDNLUVNJ-UHFFFAOYSA-N
Pubchem ID :	3299500

Safety of [ 3424-43-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H320-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 3424-43-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	48.12
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	59.16 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.88
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	0.52
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.86
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.85
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	2.14
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.25

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.43
Solubility	6.66 mg/ml ; 0.0368 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.33
Solubility	8.41 mg/ml ; 0.0464 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.8
Solubility	0.287 mg/ml ; 0.00158 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	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.	-7.04 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	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)	1.87

Application In Synthesis of [ 3424-43-9 ]

* 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 [ 3424-43-9 ]

[ 3424-43-9 ] Synthesis Path-Downstream 1~35

1
[ 141-52-6 ]
[ 95387-37-4 ]
[ 3424-43-9 ]

References: [1]Journal of Organic Chemistry,1985,vol. 50,p. 1512 - 1516.

2
[ 141-52-6 ]
[ 95387-40-9 ]
[ 3424-43-9 ]
[ 95387-42-1 ]

References: [1]Journal of Organic Chemistry,1985,vol. 50,p. 1512 - 1516.

3
[ 67-56-1 ]
[ 50-00-0 ]
[ 3424-43-9 ]
[ 74-88-4 ]
5,6,7,8-tetrahydro-2-methoxy-6-oxo-5-quinolinecarboxylic acid methyl ester [ No CAS ]

References: [1]Tetrahedron Letters,1989,vol. 30,p. 2089 - 2090.

4
[ 4027-39-8 ]
[ 3424-43-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 1,4-dioxane; for 5.0h;Heating / reflux;	Ethyl 2-methyl-6-oxo-l,4,5,6-tetrahydropyridine-3-carboxylate (2g, 10.93mmol) and DDQ (5.21g, 22.95mmol) in 1,4-dioxaxne (110ml) were heated under reflux for 5h. The residue obtained after evaporation of solvent under reduced pressure was partitioned between DCM and water and washed with sat. sodium hydrogen carbonate solution. The aqueous layer was extracted with DCM twice. The organics were combined, washed with brine, dried and the solvent was evaporated to give a solid which was purified by chromatography eluting with MeOH:DCM (1 :99 to 4:96). Insoluble material in DCM and MeOH, prior to purification, was filtered off to give pure product. The product obtained after purification was dissolved in DCM and passed through a pre-equilibrated neutral alumina column, eluting with DCM, then 5% MeOH:DCM. Re-evaporation of solvent gave the title compound as a solid which was dried in vac oven overnight at 50C (1.23g, 62%). NMR (400MHz): 1.28 (t, 3H), 2.53 (s, 3H), 4.21 (q, 2H), 6.21 (d, IH), 7.82 (d, IH), 12.00 (s, IH); m/z 182. As an alternative to the above, the reaction mixture may be diluted with DCM and passed through a pre-equilibrated neutral alumina column, eluting with DCM, then MeOH. EPO <DP n="62"/>Chromatography on silica gel, then neutral alumina column eluting with DCM gave the product.

References: [1]Patent: WO2006/95159,2006,A1 .Location in patent: Page/Page column 60-61.
[2]Medicinal Chemistry Research,1995,vol. 5,p. 587 - 594.

5
[ 3424-43-9 ]
[ 74-88-4 ]
[ 173261-76-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With silver carbonate; at 50℃; for 16.0h;	: To a suspension of ethyl2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.2 g, 1.06 mmol) and Ag2CO3(0.44 g, 1.59 mmol) was added methyl iodide (0.3 mL, 4.24 mmol)and the reaction mixture was heated at 50 C for 16 h. The reaction mixture wascooled to room temperature, filtered and concentrated. The crude residue waspurified by Combiflash with 20% EtOAc in Hexane to afford the title compound asoff-white solid (0.25 g, 75%). 1H NMR (DMSO-d6, 400 MHz) δ1.37 (t, J = 7.2 Hz, 3H), 2.75 (s,3H), 3.96 (s, 3H), 4.33 (q, J = 7.2Hz, 2H), 6.57 (d, J = 8.4 Hz, 1H),8.11 (d, J = 8.8 Hz, 1H); MS (ESI) m/z196.1 (M+H)+.

References: [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 922 - 925.
[2]Medicinal Chemistry Research,1995,vol. 5,p. 587 - 594.

7
[ 4027-39-8 ]
[ 546-67-8 ]
2-acetoxymethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester [ No CAS ]
2-acetoxymethyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester [ No CAS ]
[ 3424-43-9 ]

References: [1]Synthetic Communications,2005,vol. 35,p. 2993 - 3001.

8
[ 6296-99-7 ]
[ 141-97-9 ]
[ 3424-43-9 ]

References: [1]Tetrahedron,2006,vol. 62,p. 6222 - 6227.
[2]Synthetic Communications,2005,vol. 35,p. 2993 - 3001.

9
[ 141-97-9 ]
[ 100643-08-1 ]
[ 3424-43-9 ]

References: [1]Synthetic Communications,2005,vol. 35,p. 2993 - 3001.

10
[ 3424-43-9 ]
1,6-dihydro-2-methyl-6-oxo-nicotinic acid [ No CAS ]

References: [1]Tetrahedron,2006,vol. 62,p. 6222 - 6227.

11
[ 3424-43-9 ]
[ 919354-84-0 ]

Yield	Reaction Conditions	Operation in experiment
14%	With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In acetonitrile;Heating / reflux;	Example 1; 25 Ethyl 6-(4-[(benzylsulfoϖyl)amino]carbonyl}piperidin-l-yl)-5-chloro-2- (difluoromethyl)nicotinate(a) Ethyl 2-(difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate30 Ethyl 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (2.0 g, 11.04 mmol) ( Sobczak, A et al, Synth. Comrnun, VoL 35, No. 23, 2005, pρ2993-3001) was added to a solution of 2- methoxy-N-(2-merhoxyethyl)-N-(trifiuoro-λ4-sulfanyl)ethanamine (7.82 g, 22.08 mmol) in <n="86"/>85CH3CN under an atmosphere of nitrogen. The reaction was refluxed over night after which further 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethanamine (2.73 g, 7.7 mmol) was added and the stirring was continued until all starting material was consumed. The reaction was diluted with diethyl ether, filtered to remove black solids, washed with5 water and NaHCO3 (aq,sat). Both phases were filtered again to remove more of black solids. The aqueous phase was extracted with diethyl ether (2 times) and the combined organic phase was dried (MgSO4), filtered and concentrated and slurried in diethyl ether to remove yellow impurities. Drying of the remaining white solid gave ethyl 2- (difluoromethyl)-6-oxo-l,6-dihydropyridine-3-carboxylate. Yield: 370 mg (14 %). io 1H NMR (400 MHz, CDCi) δ 1.38 (3H, t, J= 7.2 Hz), 4.36 (2H, q, J= 7.2 Hz), 6.69 (IH, d, J= 10 Hz), 7.56 (IH, t, J= 54 Hz), 7.99 (IH, d, J= 10 Hz).;

References: [1]Patent: WO2008/4946,2008,A1 .Location in patent: Page/Page column 84-85.

12
[ 10444-33-4 ]
[ 3424-43-9 ]

References: [1]Medicinal Chemistry Research,1995,vol. 5,p. 587 - 594.

13
[ 3424-43-9 ]
[ 32383-10-1 ]

References: [1]Medicinal Chemistry Research,1995,vol. 5,p. 587 - 594.

14
[ 3424-43-9 ]
[ 173261-78-4 ]

References: [1]Medicinal Chemistry Research,1995,vol. 5,p. 587 - 594.

15
[ 3424-43-9 ]
[ 173261-77-3 ]

References: [1]Medicinal Chemistry Research,1995,vol. 5,p. 587 - 594.

16
[ 23941-84-6 ]
[ 3424-43-9 ]

References: [1]Journal of Organic Chemistry,1985,vol. 50,p. 1512 - 1516.

17
[ 3424-43-9 ]
[ 31163-12-9 ]

Yield	Reaction Conditions	Operation in experiment
94.7%		As shown in step 8-i of Scheme 8, according to the procedure of International Patent Application Publication No. WO2006/095159, a mixture of ethyl 2-methyl-6-oxo- 1 ,6- dihydropyridine-3-carboxylate (5.92 g, 32.6 mmol) in phosphorous oxychloride (45 mL) was heated at 90C for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure and ice water was added to the residue, followed by addition 28% ammonium hydroxide to adjust the pH to 7. The resulting white solid was collected by filtration, washed with ice water, and dried under high vacuum to give ethyl 6-chloro-2- methylnicotinate (Compound 2027, 6.18 g, 94.7% yield): ESMS (M+l) 200.19; 1H NMR (CDCls) δ 8.18 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.84 (s, 3H), 1.42 (t, J = 7.4, 3H).
81%	With trichlorophosphate;Heating / reflux;	Ethyl 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (Method 2; 2.281g, 12.60mmol) and phosphorus oxychloride (50ml) were heated under reflux overnight. The oil obtained on evaporation of solvent was poured onto ice and solution neutralised with aq NH3. The resulting precipitate was filtered off, washed with water and air-dried, to give the title compound as a solid (2.32g, 81%). NMR (400MHz): 1.33 (t, 3H), 2.70 (s, 3H), 4.33 (q, 2H), 7.49 (d, IH), 8.21 (d, IH); m/z 200-202.

References: [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 5245 - 5256.
[2]Patent: WO2011/87776,2011,A1 .Location in patent: Page/Page column 62; 64.
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.
[4]Patent: WO2006/95159,2006,A1 .Location in patent: Page/Page column 3.
[5]Journal of Medicinal Chemistry,2010,vol. 53,p. 3814 - 3830.
[6]Patent: WO2018/140809,2018,A1 .Location in patent: Paragraph 00477.

18
[ 3424-43-9 ]
[ 919354-64-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-chloro-succinimide; In N,N-dimethyl-formamide; at 20 - 100℃; for 1.5h;	Ethyl 2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (2.00 g, 11.0 mmol), (Raileanu D., et. al. Tetrahedron , VoI 30 pp 623-32, 1974) was dissolved in DMF (35 mL) under a nitrogen atmosphere. NCS (1.53g, 11.5 mmol) taken upp in DMF (5.0 mL) at r.t. The reaction mixture was heated at 1000C for Ih. An additional amount of NCS (500mg, 3.8 mmol) was added and the reaction mixture was stirred for 0.5h. The reaction mixture was diluted with DCM were washed with water and brine once each. The aqueous phase was extracted with DCM twice and the combined organic phases were passed through a phase separator and the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica (Biotage horizon)frst EtO Ac/heptane 1:1 followed by EtOAc to give ethyl 5-chloro-2-methyl-6-oxo- l,6-dihydropyridine-3-carboxylate as a yellow solid Yield=1.362g( 52%). 1H NMR (400 MHz, DMSO-d6) 5 1.37 (3H, 1, J= 7.3 Hz), 2.74 (3H, s), 4.32 (2H, q, J= 7.3) Hz, 8.19 (IH, s>

References: [1]Patent: WO2007/8140,2007,A1 .Location in patent: Page/Page column 194.

19
[ 3424-43-9 ]
[ 1174665-76-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-iodo-succinimide; In acetonitrile; at 95℃; for 5.0h;	N-lodosuccinimide (4Og, 180mmol) was added to a suspension of intermediate (5b), 2-methyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid ethyl ester (18.1g, lOOmmol) in acetonitrile (40OmL), under a nitrogen atmosphere. The resulting suspension was heated at 950C for 5 hours to give an initial orange solution. An off-white precipitate slowly formed. The resulting suspension was allowed to cool and was poured into water (120OmL) to give an off-white precipitate. The separated by filtration and the <n="51"/>solids washed with water (50OmL) to give an off-white powder. The solids were dried in vacuo (6O0C) to give the product as an off-white powder, 28.3g (92%)

References: [1]Patent: WO2009/93012,2009,A1 .Location in patent: Page/Page column 23; 49-50.

20
[ 53256-26-1 ]
[ 3424-43-9 ]

Yield	Reaction Conditions	Operation in experiment
36%	In N,N-dimethyl-formamide; at 175℃; for 24.0h;	A solution of intermediate (5a), (E)-4-[1-amino-eth-(Z)-ylidene]-pent-2-enedioic acid diethyl ester (51 g, 225mmol) in N,N-dimethylformamide (25OmL) was heated at 1750C for 24 hours to give a dark brown solution. The resulting solution was allowed to cool and a pale brown precipitate slowly formed. The precipitate was removed by filtration and the solids washed with dichloromethane (75ml_) and hexane (10OmL) to give a pale yellow powder. The solids were dried in vacuo (6O0C) to give the title compound as a pale yellow powder, 14.45g (36%)

References: [1]Patent: WO2009/93012,2009,A1 .Location in patent: Page/Page column 23; 49.

21
[ 53256-25-0 ]
[ 3424-43-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	In N,N-dimethyl-formamide; at 165℃; for 14.0h;	Step B ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 5-Ethyl 1-methyl (2E,4Z)-4-(1-aminoethylidene)pent-2-enedioate (10 g, 50 mmol) and DMF (30 mL) were mixed in one 100 mL flask, and the mixture was stirred at 165 C. for 14 hrs. The reaction mixture was cooled to room temperature, then filtered to give the crude product, which was washed with DMF and small amount of methanol to give 5 g (60% yield) of the pure product. LC-MS found: 182.1 (M+H)+.

References: [1]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0434; 0435.
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 3814 - 3830.
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

22
[ 3424-43-9 ]
[ 1315544-62-7 ]

References: [1]Patent: WO2011/87776,2011,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 5245 - 5256.

23
[ 3424-43-9 ]
[ 1315544-63-8 ]

References: [1]Patent: WO2011/87776,2011,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 5245 - 5256.

24
[ 141-97-9 ]
[ 3424-43-9 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 922 - 925.

25
[ 3424-43-9 ]
2-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one [ No CAS ]