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

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 1~37

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 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

26
[ 3424-43-9 ]
[ 1359669-60-5 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

27
[ 3424-43-9 ]
C₂₃H₂₂ClNO₄S [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

28
[ 3424-43-9 ]
[ 1359669-62-7 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

29
[ 3424-43-9 ]
[ 1359668-78-2 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

30
[ 3424-43-9 ]
[ 1359668-80-6 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

31
[ 3424-43-9 ]
[ 41598-57-6 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

32
[ 3424-43-9 ]
[ 31163-14-1 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.

33
[ 3424-43-9 ]
[ 31163-13-0 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.
[2]Patent: WO2018/140809,2018,A1 .

34
[ 626-34-6 ]
[ 3424-43-9 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1538 - 1552.
[2]Patent: US2013/96144,2013,A1 .

35
[ 3424-43-9 ]
[ 1196145-86-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With phosphorus(V) oxybromide; at 130℃; for 4.0h;	Step C ethyl 6-bromo-2-methylnicotinate Ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.0 g, 11 mmol) and POBr3 (8.9 g, 31 mmol) were mixed in one 100 mL flask, and the mixture was stirred at 130 C. for 4 hrs. The reaction mixture was cooled to room temperature and 50 g of ice water was added. The mixture was neutralized to pH=9 with aqueous NaHCO3 solution, extracted twice with EtOAc, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.5 g (93% yield) of the desired product. LC-MS found: 244.1 (M+H)+.

References: [1]Patent: US2013/96144,2013,A1 .Location in patent: Paragraph 0436; 0437.

36
[ 3424-43-9 ]
[ 1430058-73-3 ]

References: [1]Patent: US2013/96144,2013,A1 .

37
[ 3424-43-9 ]
[ 1430058-75-5 ]

References: [1]Patent: US2013/96144,2013,A1 .

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P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
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.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
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
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
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

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

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