[ CAS No. 20348-16-7 ] {[proInfo.proName]}

Name: 20348-16-7|2-Amino-6-methylpyridin-3-ol|97%
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Quality Control of [ 20348-16-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 20348-16-7 ]

Product Details of [ 20348-16-7 ]

CAS No. :	20348-16-7	MDL No. :	MFCD09839245
Formula :	C₆H₈N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WJRVHFJZHFWCMS-UHFFFAOYSA-N
M.W :	124.14	Pubchem ID :	88500
Synonyms :

Calculated chemistry of [ 20348-16-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	35.63
TPSA :	59.14 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.93
Log Po/w (XLOGP3) :	0.55
Log Po/w (WLOGP) :	0.69
Log Po/w (MLOGP) :	-0.07
Log Po/w (SILICOS-IT) :	0.62
Consensus Log Po/w :	0.54

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.45
Solubility :	4.41 mg/ml ; 0.0355 mol/l
Class :	Very soluble
Log S (Ali) :	-1.36
Solubility :	5.37 mg/ml ; 0.0433 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.43
Solubility :	4.57 mg/ml ; 0.0368 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 20348-16-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 20348-16-7 ]

* 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.

Upstream synthesis route of [ 20348-16-7 ]
Downstream synthetic route of [ 20348-16-7 ]

[ 20348-16-7 ] Synthesis Path-Upstream 1~2

1
[ 15128-90-2 ]
[ 20348-16-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen In ethanol at 50℃; for 1 h;	3-Hydroxy-6-methyl-2-nitropyridine (30 g, 194.6 mmol) was hydrogenated in ethanol solution at 50° C. using H2 at 5 psi and 20percent Pd(OH)2/C catalyst for 1 hour. Upon completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to get the desired product 1 as a brown solid (23.68 g, 98percent). NMR data was consistent with the proposed structure.
97%	for 20 h;	2-amino-6-methylpyridin-3-ol; A mixture of 3-hydroxy-6-methyl-2-nitropyridine (20 g, 0.129 mol) and 10percent Pd/C (4 g) was stirred vigorously in a flow of hydrogen for 20 h. The catalyst was filtered off, washed with methanol, and the filtrate was evaporated to dryness to provide 15.5 g (97percent) of a brown crystalline solid. ¹H-NMR-data (DMSO-d6): 9.0 (1H), 6.72 (1H)₁ 6.21 (1H), 5.29 (2H), 2.15 (3H).
95%	With hydrogen In acetic acid for 13 h;	To a solution of 6-methyl-2-nitropyridin-3-ol (25.0 g, 162 mmol) in acetic acid (400 mL) was added 10percent palladium on carbon (50percent wet, 2.50 g) . The reaction mixture was purged with hydrogen and stirred under balloon pressure hydrogen for 13 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound (19.1 g, 153 mmol, 95percent) as a colorless powder. ¹H NMR (DMSO-d₆) δ 2.14 (s, 3H), 5.31 (s, 2H), 6.20 (d, J EPO <DP n="83"/>= 7.5 Hz, IH), 6.70 (d, J = 7.5 Hz, IH), 9.09 (s, IH).

93%	With palladium 10% on activated carbon; hydrogen; acetic acid In ethanol at 20℃; for 6 h;	First Step Synthesis of 2-Amino-6-methyl pyridin-3-ol To a solution (20 mL) of 6-methyl-2-nitropyridin-3-ol (1.6 g, 10 mmol) in ethanol, Pd/C (10percent wet, 0.40 g, 0.38 mmol) and acetic acid (0.050 mL, 0.87 mmol) were added, and the resulting mixture was stirred under hydrogen atmosphere at room temperature. Six hours later, the reaction solution was filtered with Celite and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, Fuji Silysia Chemical Ltd., chloroform alone to chloroform/methanol=88/12) to obtain the title compound (1.2 g; 93percent) as a yellow liquid. ¹H-NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 6.38 (1H, d, J=8.0 Hz), 6.82-6.86 (1H, m).
80%	With hydrogen In ethanol at 20℃; for 24 h;	A mixture of 3-hydroxy-6-methyl-2-nitropyridine (4.2 g, 27 mmol) and 10percent palladium on carbon (0.25 g, 0.24 mmol) in ethanol (75 mL) was stirred at rt under an atmosphere of hydrogen for 24 hr. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness under vacuum. The residue was subjected to chromatography on silica gel using Biotage SP1 employing a 40+M cartridge and eluting with MeOH/DCM 10percent 2 CV, 10-35percent in 10 CV, 35percent 2 CV. The purified product 2-amino-6-methyl-3- pyridinol (D145, 2.72 g, 80percent) was isolated as pale brown solid.[M+H]⁺ 125

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2679 - 2684
[2] Patent: US2002/169200, 2002, A1,
[3] Patent: US2004/92538, 2004, A1, . Location in patent: Page 41-42
[4] Patent: WO2006/51410, 2006, A1, . Location in patent: Page/Page column 40
[5] Patent: WO2008/51533, 2008, A2, . Location in patent: Page/Page column 81-82
[6] Patent: US2014/128606, 2014, A1, . Location in patent: Paragraph 0108; 0109; 0110; 0111
[7] Patent: US5409943, 1995, A,
[8] Chemistry - A European Journal, 2004, vol. 10, # 8, p. 1944 - 1955
[9] Patent: WO2009/37294, 2009, A1, . Location in patent: Page/Page column 145
[10] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[11] Patent: US2002/77321, 2002, A1,
[12] Patent: US5155116, 1992, A,
[13] Patent: US5084456, 1992, A,
[14] Patent: WO2007/146066, 2007, A2, . Location in patent: Page/Page column 94
[15] Patent: US6921767, 2005, B2,
[16] Patent: EP1219622, 2002, A2, . Location in patent: Page 23
[17] Patent: US4038396, 1977, A,

2
[ 1121-78-4 ]
[ 20348-16-7 ]

Reference： [1] Patent: US2008/138656, 2008, A1,
[2] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[3] Patent: US4038396, 1977, A,

[ 20348-16-7 ] Synthesis Path-Downstream 1~79

1
[ 696-59-3 ]
[ 20348-16-7 ]
[ 104697-41-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

2
[ 100-44-7 ]
[ 20348-16-7 ]
[ 81066-67-3 ]

Reference： [1]Synthesis,1981,p. 971 - 973

3
[ 52238-17-2 ]
[ 20348-16-7 ]
C₂₈H₂₄N₄O₄ [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1980,vol. 63,p. 413 - 419

4
[ 140-89-6 ]
[ 20348-16-7 ]
[ 55656-32-1 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610
[2]Patent: EP1219622,2002,A2 .Location in patent: Page 23

5
[ 20348-16-7 ]
3-ethoxy-2-nitro-acrylic acid ethyl ester [ No CAS ]
[ 131694-46-7 ]

Reference： [1]Journal of Chemical Research, Miniprint,1990,p. 2411 - 2433

6
[ 20348-16-7 ]
[ 445-29-4 ]
[ 134377-98-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 899 - 906

7
[ 20348-16-7 ]
[ 530-62-1 ]
[ 55656-25-2 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 497 - 503

8
[ 15128-90-2 ]
[ 20348-16-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	palladium on activated carbon; In ethyl acetate;	a 2-Amino-6-methyl-pyridin-3-ol A mixture of 6-methyl-2-nitro-pyridin-3-ol (18.5 g, 0.120 mmol), 10% palladium on activated carbon (1.35 g), and ethyl acetate (240 mL) was hydrogenated for 3 days. The mixture was filtered through Celite and washed with methanol/ethylacetate (5%). The filtrate and washing were combined and concentrated to give the title compound (14.7 g, 99% yield) as a pale brown solid. 1H NMR (DMSO-d6) delta9.19 (bs, 1H), 6.73 (d, 1H, J=7.6 Hz), 6.12 (d, 1H, J=7.6 Hz), 5.36 (bs, 2H), 2.15 (s, 3H).
98%	With hydrogen;palladium(II) hydroxide/carbon; In ethanol; at 50℃; under 258.58099999999996 Torr; for 1h;	<strong>[15128-90-2]3-Hydroxy-6-methyl-2-nitropyridine</strong> (30 g, 194.6 mmol) was hydrogenated in ethanol solution at 50 C. using H2 at 5 psi and 20% Pd(OH)2/C catalyst for 1 hour. Upon completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to get the desired product 1 as a brown solid (23.68 g, 98%). NMR data was consistent with the proposed structure.
97%	With hydrogen;palladium 10% on activated carbon; for 20h;	2-amino-6-methylpyridin-3-ol; A mixture of <strong>[15128-90-2]3-hydroxy-6-methyl-2-nitropyridine</strong> (20 g, 0.129 mol) and 10% Pd/C (4 g) was stirred vigorously in a flow of hydrogen for 20 h. The catalyst was filtered off, washed with methanol, and the filtrate was evaporated to dryness to provide 15.5 g (97%) of a brown crystalline solid. 1H-NMR-data (DMSO-d6): 9.0 (1H), 6.72 (1H)1 6.21 (1H), 5.29 (2H), 2.15 (3H).

95%	With hydrogen;palladium 10% on activated carbon; In acetic acid; for 13h;	To a solution of <strong>[15128-90-2]6-methyl-2-nitropyridin-3-ol</strong> (25.0 g, 162 mmol) in acetic acid (400 mL) was added 10% palladium on carbon (50% wet, 2.50 g) . The reaction mixture was purged with hydrogen and stirred under balloon pressure hydrogen for 13 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound (19.1 g, 153 mmol, 95%) as a colorless powder. 1H NMR (DMSO-d6) delta 2.14 (s, 3H), 5.31 (s, 2H), 6.20 (d, J EPO <DP n="83"/>= 7.5 Hz, IH), 6.70 (d, J = 7.5 Hz, IH), 9.09 (s, IH).
93%	With palladium 10% on activated carbon; hydrogen; acetic acid; In ethanol; at 20℃; for 6h;	First Step Synthesis of 2-Amino-6-methyl pyridin-3-ol To a solution (20 mL) of <strong>[15128-90-2]6-methyl-2-nitropyridin-3-ol</strong> (1.6 g, 10 mmol) in ethanol, Pd/C (10% wet, 0.40 g, 0.38 mmol) and acetic acid (0.050 mL, 0.87 mmol) were added, and the resulting mixture was stirred under hydrogen atmosphere at room temperature. Six hours later, the reaction solution was filtered with Celite and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, Fuji Silysia Chemical Ltd., chloroform alone to chloroform/methanol=88/12) to obtain the title compound (1.2 g; 93%) as a yellow liquid. 1H-NMR (400 MHz, CDCl3) delta: 2.32 (3H, s), 6.38 (1H, d, J=8.0 Hz), 6.82-6.86 (1H, m).
92%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20 - 25℃; for 24h;	A mixture of <strong>[15128-90-2]6-methyl-2-nitropyridine-3-ol</strong> (5.0 g, 32.4 mmol, 1.0 eq.) and 10% palladium on carbon (500 mg) in ethanol (30 mL) was vigorously stirred under a hydrogen atmosphere at room temperature for one day. The mixture was filtered on Celite 545 and washed with ethanol (100 mL).The filtrate was concentrated under reduced pressure and the residue was washed with diethyl ether (50 mL) to give the desired product (3.7 g, 29.8 mmol, 92%) as a yellow solid.
91%	palladium-charcoal; In ethanol;	(a) 2-Amino-3-hydroxy-6-methylpyridine <strong>[15128-90-2]3-Hydroxy-6-methyl-2-nitropyridine</strong> (25 g, 0.162 g) was dissolved in ethanol (600 ml) and hydrogenated over 10% palladium-charcoal (3.3 g) at 50 p.s.i. Removal of the catalyst and evaporation of the solvent gave the product (36.4 g, 91%), m.p. 147-149 C.
80%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 24h;	A mixture of <strong>[15128-90-2]3-hydroxy-6-methyl-2-nitropyridine</strong> (4.2 g, 27 mmol) and 10% palladium on carbon (0.25 g, 0.24 mmol) in ethanol (75 mL) was stirred at rt under an atmosphere of hydrogen for 24 hr. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness under vacuum. The residue was subjected to chromatography on silica gel using Biotage SP1 employing a 40+M cartridge and eluting with MeOH/DCM 10% 2 CV, 10-35% in 10 CV, 35% 2 CV. The purified product 2-amino-6-methyl-3- pyridinol (D145, 2.72 g, 80%) was isolated as pale brown solid.[M+H]+ 125
	With H2;Pd(OH)2/C; In ethanol;	Step 1 2-amino-6-methyl-3-pyridinol <strong>[15128-90-2]3-Hydroxy-6-methyl-2-nitropyridine</strong> (30 g, 194.6 mmol) was hydrogenated in ethanol solution at 50 C. using H2 at 5 psi and 20% Pd(OH)2/C catalyst for 1 hour. Upon completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to get the desired product 1 as a brown solid (23.68 g, 98%). NMR data was consistent with the proposed structure.
	In methanol; pyrographite;	Stage B: 2-Amino-3-Hydroxy-6- Methylpyridine 3.5 g of <strong>[15128-90-2]2-nitro-3-hydroxy-6-methylpyridine</strong> are placed under a hydrogen pressure in 50 ml of methanol in the presence of 1 gram of palladinized charcoal. The mixture is stirred and filtered. The methanol is evaporated off.
	In methanol; pyrographite;	Stage B: 2-AMINO-3-HYDROXY-6-METHYLPYRIDINE 3.5 g of <strong>[15128-90-2]2-nitro-3-hydroxy-6-methylpyridine</strong> in 50 ml of methanol are placed under hydrogen pressure in the presence of one gram of palladinized charcoal. The mixture is stirred and filtered. The methanol is evaporated.
	With ammonium formate;palladium hydroxide on carbon; In ethanol; at 70℃; for 1h;	Ammonium formate (1.64 g, 26 mmol) was added to a suspension OfPd(OH)2 on carbon (-20% Pd, 0.73 g, 1.0 mmol) and <strong>[15128-90-2]2-nitro-3-hydroxy-6-methylpyridine</strong> (2.0 g, 13 mmol) in EtOH (20 mL). The reaction mixture was heated to 70 0C for 1 h at which point the reaction mixture was allowed to cool to rt and was filtered through Celite. The filtrate was concentrated under reduced pressure, yielding a thick orangish oil. The material was dissolved in EtOH (25 mL) and potassium hydroxide (0.875 g, 15.6 mmol) and carbon disulfide (15 mL) were added. The reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was acidified with 1 N HCl5 and the resulting solid was collected by filtration. The solid was washed with water (2 x) and air dried followed by drying in a 35 0C vacuum oven. LC-MS: RT = 5.58 min, [M+H]+ = 167.0.
	With H2;Pd(OH)2/C; In ethanol;	Step 1 2-amino-6-methyl-3-pyridinol <strong>[15128-90-2]3-Hydroxy-6-methyl-2-nitropyridine</strong> (30 g, 194.6 mmol) was hydrogenated in ethanol solution at 50 C. using H2 at 5 psi and 20% Pd(OH)2/C catalyst for 1 hour. Upon completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to get the desired product 1 as a brown solid (23.68 g, 98%). NMR data was consistent with the proposed structure.
	palladium; In methanol;	Step B Preparation of 2-amino-3-hydroxy-6-methylpyridine <strong>[15128-90-2]3-Hydroxy-6-methyl-2-nitropyridine</strong> (3.5 g.) in 75 ml. of methanol was reduced over 1 g. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 2-amino-3-hydroxy-6-methylpyridine which was used directly in the next stop.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684
[2]Patent: US2002/169200,2002,A1
[3]Patent: US2004/92538,2004,A1 .Location in patent: Page 41-42
[4]Patent: WO2006/51410,2006,A1 .Location in patent: Page/Page column 40
[5]Patent: WO2008/51533,2008,A2 .Location in patent: Page/Page column 81-82
[6]Patent: US2014/128606,2014,A1 .Location in patent: Paragraph 0108; 0109; 0110; 0111
[7]Bioorganic Chemistry,2019,vol. 86,p. 346 - 362
[8]Patent: US5409943,1995,A
[9]Chemistry - A European Journal,2004,vol. 10,p. 1944 - 1955
[10]Patent: WO2009/37294,2009,A1 .Location in patent: Page/Page column 145
[11]Journal of Medicinal Chemistry,1987,vol. 30,p. 2031 - 2046
[12]Patent: US2002/77321,2002,A1
[13]Patent: US5155116,1992,A
[14]Patent: US5084456,1992,A
[15]Patent: WO2007/146066,2007,A2 .Location in patent: Page/Page column 94
[16]Patent: US6921767,2005,B2
[17]Patent: EP1219622,2002,A2 .Location in patent: Page 23
[18]Patent: US4038396,1977,A

Yield	Reaction Conditions	Operation in experiment
8.40 g (99%)		117b. 2-Amino-3-hydroxy-6-methylpyridine 3-Hydroxy-6-methyl-2-nitropyridine from Example 117a (10.5 g, 68 mmole) was combined with 10% Pd/C (100 mg) in EtOH (100 mL), and the mixture was stirred under a H2 atmosphere for 16 hours. The mixture was filtered and concentrated to yield 8.40 g (99%) of the title compound. mp 141-145 C. 1 H NMR (DMSO-d6, 300 MHz) δ: 2.14 (s, 3H), 6.22 (d, J=7.5 Hz, 1H), 6.71 (d J=7.5 Hz, 1H). MS (DCI/NH3) m/e 125 (M+H)+, 142 (M+NH4)+.

11
[ 89-95-2 ]
[ 20348-16-7 ]
2-[(2-hydroxyphenyl)methyl]imino}-6-methylpyridin-3-ol [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 1944 - 1955

12
[ 51731-17-0 ]
[ 20348-16-7 ]
4-[(3-hydroxy-6-methylpyridin-2-yl)amino]but-3-en-2-one [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 1944 - 1955

13
[ 20348-16-7 ]
[ 79-04-9 ]
[ 20348-10-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium hydrogencarbonate; In water; butanone;	b) 6-Methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one L. Savelon, et. al, Bioorganic & Medicinal Chemistry, 6, 133, (1998). To a suspension of 2-amino-6-methyl-pyridin-3-ol (18.3 g, 148 mmol), sodium bicarbonate (30 g, 354 mmol), H2O (100 mL), and 2-butanone (100 mL) in an ice-water bath was added a solution of chloroacetyl chloride (13.3 mL. 167 mmol) in 2-butanone (30 mL) over 1.5 h, controlling the temperature below 10 C. After the addition was complete, the ice-water bath was removed and the mixture was stirred at ambient temperature for 30 minutes, followed by refluxing for 1.5 h. The solvents were evaporated, and the resulting solid was washed with H2O (3 times), and dried under high vacuum overnight, giving the title compound (19.2 g, 79% yield) as a pale yellow solid. 1H NMR (CDCl3) δ10.45 (bs, 1H), 7.17 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.1 Hz), 4.62 (s, 2H), 2.52 (s, 3H). Mass spectrum (LCMS, ESI) calculated for C8H9N2O2 165.1 (M+1); found 165.1.
38%	With sodium hydrogencarbonate; In water; butanone; at 20 - 75℃; for 2.5h;	chloroacetyl chloride (0.37 mL) was added dropwise to a stirred, cooled (0 C.) mixture of 1 (0.500 g), 0.810 g NaHCO3, and 4 mL 2-butanone in 4 mL water. Once the addition was complete, the reaction mixture was warmed to room temp. and stirred for 30 minutes, then heated to 75 C. for 2 hours. The reaction mixture was cooled to room temp. and the 2-butanone was stripped off under reduced pressure. 1 mL water was added and the solids were filtered off and washed with water to get the crude product. The solid was dissolved in warmed (50 C.) ethyl acetate and filtered through a small plug of silica gel. The silica gel was washed with more warm ethyl acetate, combined with the filtrate, and concentrated under reduced pressure to get the desired product 2 (0.250 g, 38%) as a deep orange solid. NMR data was consistent with the proposed structure

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684
[2]Patent: US2002/169200,2002,A1
[3]Patent: US2004/92538,2004,A1 .Location in patent: Page 41-42

14
[ 75-15-0 ]
[ 20348-16-7 ]
[ 55656-32-1 ]

Yield	Reaction Conditions	Operation in experiment
		Ammonium formate (1.64 g, 26 mmol) was added to a suspension OfPd(OH)2 on carbon (-20% Pd, 0.73 g, 1.0 mmol) and 2-nitro-3-hydroxy-6-methylpyridine (2.0 g, 13 mmol) in EtOH (20 mL). The reaction mixture was heated to 70 0C for 1 h at which point the reaction mixture was allowed to cool to rt and was filtered through Celite. The filtrate was concentrated under reduced pressure, yielding a thick orangish oil. The material was dissolved in EtOH (25 mL) and potassium hydroxide (0.875 g, 15.6 mmol) and carbon disulfide (15 mL) were added. The reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was acidified with 1 N HCl5 and the resulting solid was collected by filtration. The solid was washed with water (2 x) and air dried followed by drying in a 35 0C vacuum oven. LC-MS: RT = 5.58 min, [M+H]+ = 167.0.

Reference： [1]Patent: WO2007/146066,2007,A2 .Location in patent: Page/Page column 94

15
[ 20348-16-7 ]
[ 381226-84-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

16
[ 20348-16-7 ]
[ 445490-28-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

17
[ 20348-16-7 ]
[ 381226-85-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

18
[ 20348-16-7 ]
[ 855313-36-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

19
[ 20348-16-7 ]
[ 855313-34-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

20
[ 20348-16-7 ]
3-benzo[1,3]dioxol-5-yl-3-{5-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-ethoxy]-indol-1-yl}-propionic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

21
[ 20348-16-7 ]
[ 855313-42-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

22
[ 20348-16-7 ]
[ 855313-40-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

23
[ 20348-16-7 ]
6-{2-[1-(1-benzo[1,3]dioxol-5-yl-2-ethoxycarbonyl-vinyl)-1H-indol-5-yloxy]-ethyl}-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

24
[ 20348-16-7 ]
[ 20567-67-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2679 - 2684

25
[ 1121-78-4 ]
[ 20348-16-7 ]

Yield	Reaction Conditions	Operation in experiment
26%		Synthesis Example 3 Synthesis of Exemplified Compound No. 2 6-methyl-2-amino-pyridin-3-ol [8] was obtained from 6-methyl-pyridin-3-ol [6] in a total yield of 26% by a known method described in a document.

Reference： [1]Patent: US2008/138656,2008,A1
[2]Journal of Medicinal Chemistry,1987,vol. 30,p. 2031 - 2046
[3]Patent: US4038396,1977,A

26
[ 20348-16-7 ]
5-methyl-3-<2-(4-phenyl-1-piperazinyl)ethyl>oxazolo<4,5-b>pyridin-2(3H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 497 - 503

27
[ 20348-16-7 ]
[ 104697-49-6 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

28
[ 20348-16-7 ]
[ 104697-42-9 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

29
[ 20348-16-7 ]
[ 104697-43-0 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

30
[ 20348-16-7 ]
[ 104697-44-1 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

31
[ 20348-16-7 ]
[ 104697-45-2 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

32
[ 20348-16-7 ]
[ 104697-46-3 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 4242 - 4246

33
[ 20348-16-7 ]
[ 134377-94-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 899 - 906

34
[ 20348-16-7 ]
[ 78757-30-9 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610

35
[ 20348-16-7 ]
[ 78757-31-0 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610

36
[ 20348-16-7 ]
[ 78757-32-1 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610

37
[ 20348-16-7 ]
[ 78757-33-2 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610

38
[ 20348-16-7 ]
[ 78757-34-3 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610

39
[ 20348-16-7 ]
[ 78771-20-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1981,vol. 17,p. 441 - 442
Khimiya Geterotsiklicheskikh Soedinenii,1981,p. 608 - 610

40
[ 358-23-6 ]
[ 20348-16-7 ]
[ 320774-07-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; In dichloromethane; at -78 - -20℃;	To a stirred suspension of <strong>[20348-16-7]2-amino-6-methylpyridin-3-ol</strong> (2g) in DCM (50 ml) containing triethylamine (2.2g), trifluoromethanesulfonic anhydride (5.3g) was added under N2 at -78C. After the mixture became homogeneous, it was allowed to warm to -20C and then quenched with aqueous NaHCO3. Work-up by extraction into chloroform purification on silica gel using 40% ethyl acetate in heptane as an eluent afforded the title compound (86%).

Reference： [1]Patent: EP1202994,2004,B1 .Location in patent: Page 19

41
[ 20348-16-7 ]
[ 209328-87-0 ]

Yield	Reaction Conditions	Operation in experiment
42%	With tetrafluoroboric acid; sodium nitrite; at 0 - 5℃; for 5.0h;	To a solution of 10-2 (7.7 g, 62.1 mmol, 1.0 eq.) dissolved in a 49.5-50.5% tetrafluoroboric acid solution (80 mL), sodium nitrite (10.85 g, 0.16 mol, 2.5 eq.) was portion-wise added at 0C under stirring over 3 hours. The resulting mixture was stirred at 0-5C for further 2 hours. Afterwards, aqueous 1M sodium hydroxide solution (550 mL) was added slowly to adjust pH 6-7 while keeping the temperature below 10C. The resulting mixture was extracted with ethyl acetate (4 × 300 mL).The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate/cyclohexane, 3/7, v/v) to give the desired product (3.3 g,26.0 mmol, 42%) as a light yellow solid.
4.68g (54.7%)	With sodium hydroxide; sodium nitrite; In HF;	117c. 2-Fluoro-3-hydroxy-6-methylpyridine 2-Amino-3-hydroxy-6-methylpyridine from Example 117b (8.35 g, 67.25 mmol) was dissolved in aquious HF (48% 100 mL) and cooled to -5 C. NaNO2 (5.2 g, 75.4 mmol) was added at a rate that maintained the temperature below 0 C. After the addition was complete, the solution was heated to 30 C. After 30 minutes, the solution was cooled to 0 C., and the solution was neutralized by addition of NaOH (20% aq) The aqueous mixture was extracted with ethyl acetate. The organic extracts were dried (MgSO4), and the solvent was evaporated. The crude product was chromatographed (silica gel; hexane/EtOAc 1:1) to yield 4.68g (54.7%) of the title compound. mp 133-135 C. 1 H NMR (DMSO-d6, 300 MHz) delta: 2.29 (s, 3H), 6.98 (d, J=8 Hz, 1H), 7.26 (dd J=8 Hz, 1H). MS (DCI/NH3) m/e 128 (M+H)+, 145 (M+NH4)+. Anal. calcd. for C6 H6 FNO C, 56.69; H, 4.76 N, 11.02. Found: C, 56.72; H, 4.73; N, 11.03.

Reference： [1]Bioorganic Chemistry,2019,vol. 86,p. 346 - 362
[2]Patent: US6133253,2000,A

42
[ 85118-00-9 ]
[ 20348-16-7 ]
2-Amino-3-(2,6-difluorobenzyloxy)-6-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	In sodium hydroxide; dichloromethane; water;	(a) 2-Amino-3-(2,6-difluorobenzyloxy)-6-methylpyridine A mixture of 2,6-difluorobenzyl bromide (25 g, 0.12 1 mol) and 2-amino-3-hydroxy-6methylpyridine (13.6 g, 0.11 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (10 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (25.8 g, 94%), m.p. 121-123 C.

Reference： [1]Patent: US5409943,1995,A

43
[ 20348-16-7 ]
[ 20443-98-5 ]
2-Amino-3-(2,6-dichlorobenzyloxy)-6-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In sodium hydroxide; dichloromethane; water;	(b) 2-Amino-3-(2,6-dichlorobenzyloxy)-6-methylpyridine A mixture of 2,6-dichlorobenzyl bromide (26.3 g, 0.11 mol) and 2-amino-3-hydroxy-6methylpyridine (12.4 g, 0.1 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (10 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product (21.4 g, 7 6%), m.p. 135-137 C.

Reference： [1]Patent: US5409943,1995,A

44
[ 55117-15-2 ]
[ 20348-16-7 ]
2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In dichloromethane;	(a) 2-Amino- 3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine A mixture of <strong>[20348-16-7]2-amino-3-hydroxy-6-methylpyridine</strong> (4.3 g, 0.035 mol), dichloromethane (26 ml) and 40% aqueous sodium hydroxide solution (26 ml) was stirred for five minutes at room temperature, then 2-chloro-6-fluorobenzyl chloride (6.8 g, 0.038 mol) and Adogen 464 (2.5 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts and trituration with ethanol gave the desired product. Yield 6.3 g (67%), m.p. 108-109 C.

Reference： [1]Patent: US5409943,1995,A

45
[ 75-15-0 ]
[ 20348-16-7 ]
[ 55656-32-1 ]

Yield	Reaction Conditions	Operation in experiment
85%		Methviri.31oxazolor4.5-bipyridine-2-thiol; KOH (14 g, 0.25 mol) was added to a stirred mixture of <strong>[20348-16-7]2-amino-6-methylpyridin-3-ol</strong> (15.5 g, 0.125 mol) in absolute EtOH (500 mL) under an argon atmosphere. Carbon disulfide (16 mL, 0.25 mol) was added and the reaction mixture was heated to reflux in argon for 16 h. The reaction mixture was evaporated to dryness, water (250 mL) was added followed by acetic acid (20 mL) until the pH was ~5. The formed precipitate was separated by filtration, washed with water, and dried to afford 17.7 g (85%) of 5-methyl[1,3]oxazolo[4,5-b]pyridine-2- thiol as a yellow crystalline solid. 1H-NMR-data (DMSO-d6): 7.70 (1H), 7.07 (1H), 2.46 (3H).

Reference： [1]Patent: WO2006/51410,2006,A1 .Location in patent: Page/Page column 39

46
[ 20348-16-7 ]
[ 55656-25-2 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	Stage C: 5-METHYL-3H-OXAZOLO[4,5-b]PYRIDIN-2-ONE 1.24 g (10 mmol) of <strong>[20348-16-7]2-amino-3-hydroxy-6-methylpyridine</strong> are introduced into a three-necked round-bottomed flask. The system is placed under argon. 20 ml of anhydrous tetrahydrofuran and then 2.43 g (15 mmol) of 1,1'-carbonyldimidazole are added. The mixture is heated to reflux for 6 hours. The reaction medium is evaporated. The crystals obtained are washed with water, filtered off and redissolved in hot methanol. The solution is filtered and re-evaporated. Yield: 75%. Melting point 243 C. Spectral characteristics: 1 H NMR; solvent CDCl3: δ ppm; δ: 12.3 1H, complex, NH; δ: 7.5 1H, doublet; H7; J=8 Hz; δ: 6.9 1H, doublet; H6; J=8 Hz; δ: 2.4 3H; singlet; CH3. Infrared: 1750 cm-1, γ(C=O); 1610 cm-1, γ(C=C).

Reference： [1]Patent: US5084456,1992,A

47
[ 50-00-0 ]
[ 20348-16-7 ]
[ 1022250-52-7 ]

Yield	Reaction Conditions	Operation in experiment
77%		To a solution of <strong>[20348-16-7]2-amino-6-methylpyridin-3-ol</strong> (19.1 g, 153 mmol) in methanol (200 mL) were added formaldehyde (36- 38% solution in water; 130 mL) , sodium cyanoborohydride (29.0 g, 459 mmol) and acetic acid (2.0 mL) . The mixture was stirred at room temperature for 4 h. The mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (400 mL) , concentrated in vacuo and extracted with ethyl acetate (400 mL X 3) . The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound (17.9 g, 118 mmol, 77%) as a colorless powder .1H NMR (DMSO-d<j) δ 2.23 (s, 3H), 2.83 (s, 6H), 6.47 (d, J = 8.4 Hz, IH), 6.85 (d, J = 8.4 Hz, IH), 9.17 (s, IH). MS Calcd.: 152; MS Found: 153 (M+H) .

Reference： [1]Patent: WO2008/51533,2008,A2 .Location in patent: Page/Page column 82

48
[ 20348-16-7 ]
[ 52833-94-0 ]
[ 1146951-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	With PPA;	The 5-bromo-3-(5-methyloxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine used as starting material was prepared as follows: A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-methyl-pyridin-3-ol (1.4 g) and polyphosphoric acid (10 g) was stirred at 200 C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The reaction mixture was extracted with dichloromethane/acetonitrile, the organic phase was washed with water, a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated to afford the crude product 5-bromo-3-(5-methyloxazolo[4,5-b]pyridin-2-yl)pyridin-2-amine (0.500 g) as a solid. NMR Spectrum: (DMSOd6) 2.60 (s, 3H), 7.35 (d, 1H), 7.85 (bs, 2H), 8.10 (d, 1H), 8.35 (d, 1H), 8.37 (d, 1H); Mass spectrum: M+H+ 304-306.

Reference： [1]Patent: US2009/118305,2009,A1

49
[ 950772-15-3 ]
[ 20348-16-7 ]
[ 1134198-37-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With acetic acid; In tetrahydrofuran; at 100℃; for 1h;Microwave;	Polymer supported sodium cyanoborohydride (99 mg, 0.43 mmol) was added to a solution of 1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 51 mg, 0.21 mmol), 2- amino-6-methyl-3-pyridinol (D145, 26 mg, 0.21 mmol) and acetic acid (0.061 mL, 1.07 <n="147"/>mmol) in THF (2.5 ml_). The mixture was heated by microwave at 100 0C for 30 min and then for a further 30 min before being filtered and concentrated by rotary evaporation to give 2-({1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-6-methyl-3-pyridinol (D146, 82 mg, 100%) as a yellow oil, which was used without further purification.1H NMR (CDCI3) δ: 1.16-1.24 (4 H, m), 1.45-1.74 (6 H, m), 1.82-1.96 (3 H, m), 2.32 (3 H, s), 2.43 (3 H, m), 2.85 (3 H, m), 3.41 (1 H, m), 3.45-3.52 (3 H, m), 6.24 (1 H, d, J 8.1), 6.99 (1 H, d, J 8.1 ).

Reference： [1]Patent: WO2009/37294,2009,A1 .Location in patent: Page/Page column 145-146

50
[ 20348-16-7 ]
[ 96-34-4 ]
[ 20348-10-1 ]

Yield	Reaction Conditions	Operation in experiment
62%		A solution of 2-amino-6-methyl-pyridin-3-ol (5.7g, 46 mmol) (prepared by reduction of 6-methyl-2-nitro-pyridin-3-ol according to the procedure of J. Kaminski et al, [J. Med. Chem, 30 (11), 2031 (1987)] in dimethylsulphoxide (60 ml) was treated with sodium hydride (44 mmol) under argon. After 0.25 hours methyl chloroacetate (4 mL, 5g, 46 mmol) was added and the mixture heated at 100C for 3.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), then partitioned between dichloromethane and water. The organic extracts were dried and evaporated and the residue was chromatographed eluting with 0-20% ethyl acetate in dichloromethane affording the product as a white crystalline solid (4.7g, 62%). MS (+ve ion electrospray) m/z 165 (MH+).

Reference： [1]Patent: WO2003/87098,2003,A1 .Location in patent: Page/Page column 72

51
[ 94-75-7 ]
[ 20348-16-7 ]
[ 1355026-63-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 537 - 542

52
[ 6954-77-4 ]
[ 20348-16-7 ]
[ 1355026-42-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 537 - 542

53
[ 1645-65-4 ]
[ 20348-16-7 ]
[ 1564284-01-0 ]