38116-61-9|2-Hydroxy-6-methylpyridine-3-carboxylic acid| Ambeed

CAS No. :	38116-61-9
Formula :	C₇H₇NO₃
M.W :	153.14
SMILES Code :	O=C(O)C1=C(O)N=C(C)C=C1
MDL No. :	MFCD00460503
InChI Key :	XRIHTJYXIHOBDQ-UHFFFAOYSA-N
Pubchem ID :	94960

Safety of [ 38116-61-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H319
Precautionary Statements:	P305+P351+P338

Computational Chemistry of [ 38116-61-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	38.19
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	70.42 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.86
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	1.31
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.79
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.	-0.96
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	0.7
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.54

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.95
Solubility	1.71 mg/ml ; 0.0112 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.	-2.39
Solubility	0.625 mg/ml ; 0.00408 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	-1.19
Solubility	9.8 mg/ml ; 0.064 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	No
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.	-6.3 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.	0.56

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)	1.49

Application In Synthesis of [ 38116-61-9 ]

* 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 [ 38116-61-9 ]

[ 38116-61-9 ] Synthesis Path-Downstream 1~54

1
[ 186581-53-3 ]
[ 38116-61-9 ]
[ 51146-06-6 ]

References: [1]Journal of the American Chemical Society,1952,vol. 74,p. 1915.

2
[ 4241-27-4 ]
[ 38116-61-9 ]

References: [1]Chemische Berichte,1940,vol. 73,p. 156.

3
[ 67-56-1 ]
[ 38116-61-9 ]
[ 51146-06-6 ]

Yield	Reaction Conditions	Operation in experiment
64.1%	With sulfuric acid; at 0℃; for 21h;Reflux;	To a solution of <strong>[38116-61-9]2-hydroxy-6-methylnicotinic acid</strong> (10.0 g, 0.0653 mole) in methanol (100 mL), sulfuric acid (3.5 mL) was added drop wise at 0 C and the mixture was stirred for 21 h under reflux. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate solution under ice-cooling, and the mixture was extracted with 5 % methanol in chloroform (200 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2S04 and the solvent was concentrated under vacuum to afford the title compound. (0233) Yield: 7.0 g, 64.1%; 1H - NMR (DMSO- 6, 400 MHz) d ppm: 2.23 (s, 3H), 3.70 (s, 3H), 6.09 - 6.11 (d, J = 7.24 Hz, 1H), 7.98 - 8.00 (d, J = 7.36 Hz, 1H), 12.10 (s, 1H); Mass (m/z): 168.1 (M+H)+.

References: [1]Patent: WO2019/102365,2019,A1 .Location in patent: Page/Page column 24.
[2]Archiv der Pharmazie,1957,vol. 290,p. 61,65.

4
[ 38116-61-9 ]
2-hydroxyl-3-hydroxymethyl-6-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38 g	With lithium aluminium tetrahydride; In tetrahydrofuran; at 70℃; for 1h;Inert atmosphere;	Reference Production Example 40 (0661) To a mixture of 50.0 g of <strong>[38116-61-9]2-hydroxy-6-methylnicotinic acid</strong> and 500 ml tetrahydrofuran, 18.6 g of lithium aluminum hydride was added in a nitrogen atmosphere at 70 C. for 1 hour. To the reaction mixture, 19 ml of water was added dropwise under ice cooling, followed by stirring at 0 C. for 1 hour. Furthermore, 16 ml of an aqueous 15% sodium oxide solution was added dropwise, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered through Cerite and the filtrate was concentrated under reduced pressure to obtain 38.0 g of 2-hydroxy-3-hydroxymethyl-6-methylpyridine (hereinafter referred to as 40A). (0662) 1H-NMR (DMSO-D6) delta:6.82 (1H, d, J=6.8 Hz), 5.83 (1H, d, J=6.8 Hz), 4.25 (2H, s), 2.06 (3H, s).
38 g	With lithium hydroxide; In tetrahydrofuran; at 70℃; for 1h;Inert atmosphere;	In the 70 C, to 50.0g of 2-hydroxy-6-methyl-nicotinic acid and 500 ml mixture of tetrahydrofuran, is added in the nitrogen atmosphere 18.6g alchlor hydrogenation of 1 hour. Frozen under the, dropping to the reaction mixture 19 ml of water, then in the 0 C stirring 1 hour. Furthermore, dropping 16 ml of a 15% sodium hydroxide aqueous solution, followed by stirring at room temperature 1 hour. The reaction mixture is filtered through a Cerite, and the filtrate concentrated under reduced pressure, to obtain 38.0g of 2-hydroxy-3-hydroxymethyl-6-methylpyridine (called below 40A).

References: [1]Journal of the American Chemical Society,1952,vol. 74,p. 1915.
[2]Patent: US2016/157489,2016,A1 .Location in patent: Paragraph 0661; 0662.
[3]Patent: CN105492432,2016,A .Location in patent: Paragraph 1055; 1056; 1057; 1058.

5
[ 38116-61-9 ]
[ 51146-06-6 ]

References: [1]Archiv der Pharmazie,1957,vol. 290,p. 61,65.

6
[ 38116-61-9 ]
[ 64-17-5 ]
[ 51146-04-4 ]

Yield	Reaction Conditions	Operation in experiment
27%	With hydrogenchloride; In 1,4-dioxane; for 16h;Reflux;	Preparation 211ethyl 2-hydroxy-6-methylpyridine-3-carboxylate To a solution of <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (2.0 g, 13.06 mmol) in ethanol (20 mL), was added HCI in dioxane (10 mL) dropwise and the reaction was refluxed for 16 hours. The reaction was concentrated in vacuo and basified with saturated aqueous sodiumbicarbonate solution. The mixture was extracted with ethyl acetate (twice), the organic layers were combined, washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (650 mg, 27%). 1H NMR (400 MHz, DMSO-d6): O ppm 1.24 (t, 3H), 2.22 (s, 3H), 4.16 (q, 2H), 6.08 (d, 1H), 7.97(d, 1H).

References: [1]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 200; 201.
[2]Heterocycles,1993,vol. 35,p. 93 - 97.

7
[ 38116-61-9 ]
[ 39853-81-1 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2993 - 3006.

8
[ 38116-61-9 ]
[ 117449-75-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1; Step A:; A solution of NaOCl (1.2 L, of 5%) was cooled to 0 0C in ice bath. 2-hydroxy-6- methylpyrridine-3-carboxylic acid 1-1 (100 g, 0.65mol) was added in small portions. The resulting homogenous mixture was stirred at 0 0C for 1 hour and then at 1O0C for 5 hours. Another portion NaOCl(300 mL, of 5%) was added at O0C and the mixture was stirred at 100C overnight. The solution was acidified to pH = 1 with 12N HCl, and the resulting solid was filtered, washed with water, and oven dried to afford white solid product 1-2 (m/z (ES) (M+H)+= 188).

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.
[2]Patent: WO2007/41052,2007,A2 .Location in patent: Page/Page column 86-88.

9
[ 38116-61-9 ]
[ 100-51-6 ]
[ 147269-61-2 ]

References: [1]Journal of Organic Chemistry,2002,vol. 67,p. 741 - 746.
[2]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

10
[ 38116-61-9 ]
[ 100-51-6 ]
[ 147269-61-2 ]

Yield	Reaction Conditions	Operation in experiment
56%		Diphenylphosphoryl azide (11.9 mL, 55 mmol) was added to a solution of <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (7.65 g, 50 mmol) and triethylamine (7.7 mL, 55 mmol) in dry dioxane (100 mL) and the resulting solution was heated to reflux. After 16 h more triethylamine (7.7 mL, 55 mmol) and benzyl alcohol (5.7 mL, 50 mmol) were added and the solution was refluxed for a further 24 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride (200 mL) and brine (100 mL), acidified to pH 1 with 10% HCl. The organic layer was washed with saturated NaHCO3 (2×100 mL), brine (100 mL), dried over Na2SO4 and filtered. After evaporating the solvent in vacuo, methanol (100 mL) and hexane (20 mL) were added to the residue, the solid was collected, washed with methanol (50 mL) and dried to give the title compound as a white solid (7.2 g, 56%). 1H-NMR (300 MHz, CDCl3) delta12.82 (s, 1H), 8.06 (d, J=7.0 Hz, 1H),7.69 (s, 1H), 7.42 (m, 5H), 6.09 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.32 (s, 3H).

References: [1]Patent: US6350764,2002,B2 .Location in patent: Page column 40.
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

12
2-amino-6-methyl-pyridine-nicotinic acid [ No CAS ]
[ 38116-61-9 ]

References: [1]Chemische Berichte,1940,vol. 73,p. 542,546.

13
[ 38116-61-9 ]
[ 75-36-5 ]
[ 51146-06-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol;	Step A Methyl-2-hydroxy-6-methylpyridine-3-carboxylate Acetyl chloride (50 ml) was added cautiously to a stirred suspension of <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (14.3 g, 93.44 mmol) in dry methanol (500 ml) and the resulting solution was heated to reflux. After 16 h the solution was evaporated in vacuo to give the title compound (15.62 g, 100%) as a solid: 1 H NMR (DMSO) shows the methyl singlet at delta 3.71.

References: [1]Patent: US5668289,1997,A .

14
[ 67-56-1 ]
[ 38116-61-9 ]
[ 885277-48-5 ]

Yield	Reaction Conditions	Operation in experiment
79%		Phosphorus oxybromide (21.53 g, 75 mmol) was added to the stirred solution of 2-hydroxy-6- methylnicotinic acid (5 g, 32.7 mmol), pyridine (0.475 mL, 5.88 mmol) in chlorobenzene (100 mL) at room temperature under nitrogen. The reaction mixture was refluxed for 1 h and concentrated under vacuum before treating with an excess of cold methanol. The solution was stirred for an additional 1 h and again concentrated under vacuum. The residue was dissolved in water and pH was adjusted to ~8.0 by adding K2CO3 before extraction of the product with CH2CI2. The organic layer was washed with water and brine solution, dried over anhydrous Na2S04. Filtrate was evaporated completely under reduced pressure to give crude residue. The resulted crude compound was purified by flash column chromatography (100-200 silica mesh, eluent was 30% EtOAc in pet ether) to obtained methyl 2-bromo-6-methylnicotinate (6.1 g, 79% yield) as colorless oil. 1H NMR (400 MHz, CDCI3): d 8.00 (d, /= 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 2.59 (s, 3H); LCMS (ES) m/z 230.0 (M+H)+

References: [1]Patent: WO2019/149959,2019,A1 .Location in patent: Page/Page column 60.
[2]Tetrahedron,2005,vol. 61,p. 4569 - 4576.

15
Fmoc-D,L-Hcy(Trt)-OH [ No CAS ]
[ 38116-61-9 ]
[ 86123-10-6 ]
2-{2-[(2-hydroxy-6-methyl-pyridine-3-carbonyl)-amino]-4-mercapto-butyrylamino}-3-phenyl-propionic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5169 - 5175.

16
[ 38116-61-9 ]
[ 853179-76-7 ]

References: [1]Tetrahedron,2005,vol. 61,p. 4569 - 4576.
[2]Patent: WO2019/149959,2019,A1 .

17
[ 38116-61-9 ]
[ 853179-88-1 ]

References: [1]Tetrahedron,2005,vol. 61,p. 4569 - 4576.
[2]Patent: WO2019/149959,2019,A1 .

18
[ 38116-61-9 ]
[ 173064-91-0 ]

References: [1]Tetrahedron,2005,vol. 61,p. 4569 - 4576.
[2]Patent: WO2019/149959,2019,A1 .

19
[ 38116-61-9 ]
(1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)carbamic acid benzyl ester [ No CAS ]

References: [1]Journal of Organic Chemistry,2002,vol. 67,p. 741 - 746.

20
[ 38116-61-9 ]
[ 147269-63-4 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

21
[ 38116-61-9 ]
[ 179524-33-5 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.
[2]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

22
[ 38116-61-9 ]
[ 179524-34-6 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.
[2]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

23
[ 38116-61-9 ]
[ 179523-60-5 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.
[2]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

24
[ 38116-61-9 ]
[ 179524-35-7 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.
[2]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

25
[ 38116-61-9 ]
3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

26
[ 38116-61-9 ]
L-374087 [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

27
[ 38116-61-9 ]
[ 187237-49-6 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

28
[ 38116-61-9 ]
3-(2-phenethylamino)-6-methyl-1-(2-tert-butylcarbonylamino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

29
[ 38116-61-9 ]
(6-methyl-5-[2-(6-methyl-2-oxo-3-phenylmethanesulfonylamino-2<i>H</i>-pyridin-1-yl)-acetylamino]-methyl}-pyridin-2-yl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

30
[ 38116-61-9 ]
[ 216979-24-7 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4466 - 4474.

31
[ 38116-61-9 ]
[ 187163-89-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

32
[ 38116-61-9 ]
L-373890 [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

33
[ 38116-61-9 ]
4-[2-(6-Methyl-2-oxo-3-phenylmethanesulfonylamino-2H-pyridin-1-yl)-acetylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1497 - 1500.

34
[ 38116-61-9 ]
[ 117449-74-8 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.

35
[ 38116-61-9 ]
[ 117450-13-2 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.

36
[ 38116-61-9 ]
[ 117450-14-3 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.

37
[ 38116-61-9 ]
Sodium; 5-chloro-6-methyl-2-(1-methyl-pyrrolidin-3-yloxy)-nicotinate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.

38
[ 38116-61-9 ]
[ 117427-85-7 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.

39
[ 38116-61-9 ]
[ 117427-87-9 ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2178 - 2199.

40
[ 38116-61-9 ]
[ 3395-05-9 ]

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.

41
[ 38116-61-9 ]
[ 54364-26-0 ]

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.

42
[ 38116-61-9 ]
[ 39073-14-8 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; n-heptane; phosphorus pentachloride; toluene; trichlorophosphate;	EXAMPLE 85A Ethyl 2-chloro-6-methyl pyridine-3-carboxylate To <strong>[38116-61-9]2-hydroxy-6-methyl pyridine-3-carboxylic acid</strong> (25 g, 0.163 mol) suspended in 50 mL of phosphorous oxychloride and cooled in an ice bath was added phosphorous pentachloride (68 g, 0.313 mol) in portions. The mixture was stirred at 115 C. for 2 hours. The phosphorous oxychloride was removed in vacuo and chased with toluene. Ethanol (80 mL) was added with cooling, and the solution was refluxed for 20 minutes. The ethanol was removed under reduced pressure and the residue obtained dissolved in toluene. The toluene solution was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue obtained was dissolved in heptane, stirred with silica gel and filtered. The filtrate was concentrated in vacuo to afford 25.10 g of the title compound.

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.
[2]Patent: US5250548,1993,A .

43
[ 38116-61-9 ]
7-Methyl-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxylic acid [ No CAS ]

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.

44
[ 38116-61-9 ]
Imidazol-1-yl-(6-methyl-2-thioxo-1,2-dihydro-pyridin-3-yl)-methanone [ No CAS ]

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.

45
[ 38116-61-9 ]
3-(6-Methyl-2-thioxo-1,2-dihydro-pyridin-3-yl)-3-oxo-propionic acid tert-butyl ester [ No CAS ]

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.

46
[ 38116-61-9 ]
7-Methyl-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Heterocycles,1993,vol. 35,p. 93 - 97.

47
[ 38116-61-9 ]
[ 39745-40-9 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2993 - 3006.

48
[ 38116-61-9 ]
[ 54957-84-5 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2993 - 3006.

49
[ 38116-61-9 ]
2-<(3-amino-6-methyl-2-pyridinyl)amino>ethanol [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2993 - 3006.

50
[ 38116-61-9 ]
2-hydroxy-6-methyl-nicotinoyl azide [ No CAS ]

References: [1]Archiv der Pharmazie,1957,vol. 290,p. 61,65.
[2]Archiv der Pharmazie,1957,vol. 290,p. 61,65.

51
[ 38116-61-9 ]
[ 85614-96-6 ]

References: [1]Archiv der Pharmazie,1957,vol. 290,p. 61,65.
[2]Archiv der Pharmazie,1957,vol. 290,p. 61,65.

52
[ 38116-61-9 ]
[ 503437-35-2 ]

Yield	Reaction Conditions	Operation in experiment
99%		5-Bromo-2-hydroxy-6-methylnicotinc acid A solution of NaOBr was prepared by adding Br2 (11.4 g, 3.66 mL, 71.3 mmol) to a cooled (0 C.) and stirred solution of NaOH (7.8 g, 196 mmol) in water (90 mL). This solution was warmed to room temperature and was then added to a solution of commercially available (Aldrich) <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (10.0 g, 65.1 mmol) and NaOH (7.8 g, 196 mmol) in water (30 mL). After stirring for 5 min, the mixture was cooled to 0 C. and carefully acidified with conc. HCl. The precipitate was filtered and dried over MgSO4 to afford 5-bromo-2-hydroxy-6-methylnicotinc acid (15.0 g, 99%): 1H NMR (DMSO-d6) 8.25 (s, 1H), 2.41 (s, 3H); MH+: 232.0. Elemental analysis calculated for C7H6BrNO3: C, 36.23; H, 2.61; N, 6.04; Br, 34.44. Found: C, 36.07; H, 2.44; N, 5.91; Br, 34.43.
		Bromine (3.59 mL, 69.7 mmol) was added dropwise to a cooled solution (0C, ice bath) containing sodium hydroxide (15.6 g, 390 mmol) and water (120 mL). The solution was allowed to proceed at 0C for 15 minutes and allowed to warm to room temperature. 2-hydroxy-6- methylnicotinic acid was added and the resulting solution was maintained for 20 minutes. The solution was again cooled (0C, ice bath) and acidified to pH 1-2 by the dropwise addition of concentrated hydrochloric acid (20 mL). 5-bromo-2- hydroxy-6-methylnicotinic acid precipitated as a white solid and was collected by filtration. It was washed with water (500 mL) and allowed to air dry. m/z 233 (MH+).

References: [1]Patent: US6677352,2004,B1 .Location in patent: Page/Page column 60.
[2]Patent: WO2011/112186,2011,A1 .Location in patent: Page/Page column 224.

53
[ 38116-61-9 ]
[ 864244-74-6 ]
N-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide, trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 72h;	To a solution of <strong>[38116-61-9]2-hydroxy-6-methylnicotinic acid</strong> (Lancaster, 72 mg, 0.47 mmol) and HOBt (50 mg) in DMF (5 mL) at rt was added EDCI.HCl (130 mg, 0.68 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 110 mg, 0.50 mmol), and the reaction mixture was stirred at rt over 72 h. Purification of the reaction mixture by preparative HPLC afforded the desired product (125 mg, 55%) as a beige-colored solid (TFA salt). 1H NMR (CD3OD) delta 8.46 (d, 1H, J=7.9 Hz), 8.03 (dd, 1H, J=12.7, 2.8 Hz), 7.83 (d, 1H, J=7.1 Hz), 7.44 (dd, 1H, J=8.8, 2.2 Hz), 7.33 (t, 1H, J=8.8 Hz), 6.67 (dd, 1H, J=7.7, 2.7 Hz), 6.45 (d, 1H, J=7.7 Hz), 6.21 (d, 1H, J=2.8 Hz), 2.40 (s, 3H); MS (ESI+) m/z 355.2 (M+H)+.

References: [1]Patent: US2005/245530,2005,A1 .Location in patent: Page/Page column 62.

54
[ 38116-61-9 ]
[ 147269-61-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	With diphenyl-phosphinic acid; triethylamine; benzyl alcohol; In 1,4-dioxane;	Step A 3-Benzyloxycarbonylamino-6-methyl-2-pyridinone DPPA (35.6 ml, 165 mmol) was added to a stirred solution of <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (22.97 g, 165 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300 ml) and the resulting solution was heated to reflux. After 16 h more triethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 150 mmol) were added and the solution was refluxed for a further 24 h. The reaction was concentrated in vacuo to remove most of the volatiles. The residue was partitioned between methylene chloride (500 ml) and brine (500 ml), acidified to pH 1 with 1M HCl (165 ml). The aqueous layer was extracted with methylene chloride (2 times) and the combined organic layers were washed with sodium hydrogen carbonate solution and brine, dried (Na2 SO4) and evaporated in vacuo to a brown solid. This was recrystallized from methanol, to give the title compound (22.70 g, 59%) as a tan solid: 1 H NMR (CDCl3) delta 2.29 (s, 3H, CH3), 5.20 (s, 2 H, PhCH2), 6.06 (d, J=7.6 Hz, pyridinone-5-H), 7.32-7.43 (m, 5 H, Ph), 7.67 (br s, 1 H, CbzNH), 8.03 (br d, pyridinone-4-H).
56%	With diphenylphosphoranyl azide; triethylamine; benzyl alcohol; In 1,4-dioxane; methanol; hexane;	1. 3-Benzyloxycarbonylamino-6-methyl-2-pyridinone Diphenylphosphoryl azide (11.9 mL, 55 mmol) was added to a solution of <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (7.65 g, 50 mmol) and triethylamine (7.7 mL, 55 mmol) in dry dioxane (100 mL) and the resulting solution was heated to reflux. After 16 h additional triethylamine (7.7 mL, 55 mmol) and benzyl alcohol (5.7 mL, 50 mmol) were added and the solution was refluxed for a further 24 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride (200 mL) and brine (100 mL), and acidified to pH 1 with 10% HCl. The organic layer was washed with saturated NaHCO3 (2*100 mL), brine (100 mL), dried over Na2SO4, and filtered. After evaporating the solvent in vacuo, methanol (100 mL) and hexane (20 mL) were added to the residue, the solid was collected, washed with methanol (50 mL) and dried to give the title compound as a white solid (7.2 g, 56%). 1H NMR (300 MHz, CDCl3) delta 12.82 (s, 1H), 8.06 (d, J=7.0 Hz, 1H), 7.69 (s, 1H), 7.42 (m, 5H), 6.09 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.32 (s, 3H).
55%	With diphenyl-phosphinic acid; triethylamine; benzyl alcohol; In 1,4-dioxane; methanol; chloroform; ethyl acetate;	Step A 3-Benzyloxycarbonylamino-6-methyl-2-pyridinone DPPA (35.6 ml, 165 mmol) was added to a stirred solution of <strong>[38116-61-9]2-hydroxy-6-methylpyridine-3-carboxylic acid</strong> (22.97 g, 150 mmol) and triethylamine (23.0 ml, 165 mmol) in dry dioxane (300 ml) and the resulting solution was heated to reflux. After 16 h more triethylamine (23.0 ml, 165 mmol) and benzyl alcohol (17.1 ml, 150 mmol) were added and the solution was refluxed for a further 24 h. The reaction was concentrated in vacuo to remove most of the volatiles. The residue was partitioned between methylene chloride and brine, acidified to pH 1 with 1M HCl. The organic layer was washed with sodium hydrogen carbonate solution and brine, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexanes gradient 70-80% ethyl acetate, followed by 5% methanol/chloroform). The resulting solid was recrystallized from methanol, to give the title compound (21.15 g, 55%): 1 H NMR (CDCl3) delta 2.29 (s, 3H, CH3), 5.20 (s, 2H, PhCH2), 6.06 (d, J=7.6 Hz, pyridinone-5-H), 7.32-7.43 (m, 5H, Ph), 7.67 (br s, 1H, CbzNH), 8.03 (br d, pyridinone-4-H).

References: [1]Patent: US5668289,1997,A .
[2]Patent: US6420397,2002,B1 .
[3]Patent: US5668289,1997,A .

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• Appel Reaction • Arndt-Eistert Homologation • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chugaev Reaction • Corey-Kim Oxidation • Dess-Martin Oxidation • Hunsdiecker-Borodin Reaction • Hydride Reductions • Jones Oxidation • Martin's Sulfurane Dehydrating Reagent • Mitsunobu Reaction • Moffatt Oxidation • Oxidation of Alcohols by DMSO • Passerini Reaction • Preparation of Alcohols • Preparation of Amines • Preparation of Carboxylic Acids • Reactions of Alcohols • Reactions of Amines • Reactions of Carboxylic Acids • Reactions with Organometallic Reagents • Ritter Reaction • Schmidt Reaction • Sharpless Olefin Synthesis • Specialized Acylation Reagents-Ketenes • Swern Oxidation • Ugi Reaction

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CAS No.: 38116-61-9

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CAS No.: 38116-61-9

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