[ CAS No. 21203-68-9 ] {[proInfo.proName]}

Name: 21203-68-9|2-Methyl-5-nitropyridine|97%
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Quality Control of [ 21203-68-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 21203-68-9 ]

Product Details of [ 21203-68-9 ]

CAS No. :	21203-68-9	MDL No. :	MFCD04114179
Formula :	C₆H₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	USZINSZJSVMICC-UHFFFAOYSA-N
M.W :	138.12	Pubchem ID :	2794552
Synonyms :

Calculated chemistry of [ 21203-68-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.02
TPSA :	58.71 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.44 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.2
Log Po/w (XLOGP3) :	0.99
Log Po/w (WLOGP) :	1.3
Log Po/w (MLOGP) :	0.41
Log Po/w (SILICOS-IT) :	-0.35
Consensus Log Po/w :	0.71

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.7
Solubility :	2.77 mg/ml ; 0.02 mol/l
Class :	Very soluble
Log S (Ali) :	-1.81
Solubility :	2.13 mg/ml ; 0.0154 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.76
Solubility :	2.38 mg/ml ; 0.0172 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 21203-68-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 21203-68-9 ]

* 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.

Upstream synthesis route of [ 21203-68-9 ]
Downstream synthetic route of [ 21203-68-9 ]

[ 21203-68-9 ] Synthesis Path-Upstream 1~9

1
[ 21203-68-9 ]
[ 2364-75-2 ]

Reference： [1] Organic Letters, 2011, vol. 13, # 22, p. 6102 - 6105

2
[ 109-06-8 ]
[ 21203-68-9 ]
[ 18699-87-1 ]

Yield	Reaction Conditions	Operation in experiment
0.1 g	With oxygen; nitrogen(II) oxide In acetonitrile at 90℃; for 10 h;	Into the reactor, 0.93 g (10.0 mmol) of 2-methylpyridine, 5 mL of acetonitrile, 0.15 g of sulfonated graphene was added, and the reaction was stirred under an oxygen atmosphere at 5.0 MPa of nitrogen monoxide and a temperature of 90 ° C for 10 h. After the end of the reaction, nitrogen gas was introduced into the reaction mixture at a normal pressure until the nitrogen oxides completely escaped to the cold trap reaction receiver, and the catalyst was filtered off. The filtrate was washed with a 5percent (m/m) aqueous solution of sodium hydrogencarbonate to near neutral, and then washed with distilled water until the organic phase was neutral and concentrated by evaporation in vacuo. Separating the product components by column chromatography,The mass of 2-methylnitropyridine is 0.67g,Wherein 2-methyl-3-nitropyridine 0.10 g (mass fraction 16percent),2-methyl-5-nitropyridine 0.57 g (mass fraction 84percent), yield 49percent.

Reference： [1] Acta Chemica Scandinavica, 1994, vol. 48, # 2, p. 181 - 182
[2] Acta Chemica Scandinavica, 1994, vol. 48, # 12, p. 1001 - 1006
[3] Patent: CN108003029, 2018, A, . Location in patent: Paragraph 0043; 0044

3
[ 659742-21-9 ]
[ 109-06-8 ]
[ 21203-68-9 ]
[ 18699-87-1 ]
[ 57927-99-8 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 9, p. 4402 - 4413

4
[ 21203-68-9 ]
[ 35969-75-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With selenium(IV) oxide In 1,4-dioxane for 16 h; Reflux	To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1 ,4- dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulphate and evaporated to get 5-nitropicolinaldehyde (3.12g, 94 percent).
94%	With selenium(IV) oxide In 1,4-dioxane for 16 h; Reflux	Step 1 To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1,4-dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulfate and evaporated to get 5-nitropicolinaldehyde (3.12 g, 94percent).
35%	Stage #1: With selenium(IV) oxide; water In 1,4-dioxane for 4 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; diethyl ether; water	A mixture of 2-methyl-5-nitropyridine (3 g), selenium (IV) (2.9 g), 1,4- dioxane (25 mL) and water (0.5 mL) was refluxed for 4 hrs. The resulting black solid was filtered through Celite° bed and washed with ether. The filtrate was treated with saturate aqueous NaHC03 and filtered again. The filtrate was extracted with ether twice and the solvent was concentrated. The residue was purified with a short silica gel column eluted with 20percent ethyl acetate in hexane to give 1.0 g of orange precipitate 2 (35percent yield). ¹H NMR (CD2Cl2): 8 10.15 (s, 1H), 9.55 (s, 1H), 8.7 (d, 1H), 8.15 (s, 1H).

Reference： [1] Patent: WO2013/13815, 2013, A1, . Location in patent: Page/Page column 230; 231
[2] Patent: US2013/29962, 2013, A1, . Location in patent: Paragraph 1110
[3] Journal of Organic Chemistry, 2012, vol. 77, # 20, p. 8968 - 8979,12
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 20, p. 3672 - 3677
[5] Patent: WO2005/97752, 2005, A1, . Location in patent: Page/Page column 42
[6] Journal of Organic Chemistry, 1959, vol. 24, p. 1007
[7] Bulletin of the Chemical Society of Japan, 1993, vol. 66, # 3, p. 797 - 803

5
[ 21203-68-9 ]
[ 119830-47-6 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 20, p. 3681 - 3684

6
[ 56057-19-3 ]
[ 21203-68-9 ]
[ 39745-39-6 ]

Reference： [1] Journal of the American Chemical Society, 1954, vol. 76, p. 596,598

7
[ 21203-68-9 ]
[ 30651-24-2 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 20, p. 3681 - 3684
[2] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 2, p. 259 - 264
[3] Journal of the American Chemical Society, 1954, vol. 76, p. 3167

8
[ 21203-68-9 ]
[ 30563-98-5 ]

Reference： [1] Journal of Organic Chemistry, 1984, vol. 49, # 20, p. 3681 - 3684

9
[ 21203-68-9 ]
[ 36625-57-7 ]

Reference： [1] Patent: WO2013/13815, 2013, A1,
[2] Patent: US2013/29962, 2013, A1,

[ 21203-68-9 ] Synthesis Path-Downstream 1~88

1
[ 109-06-8 ]
[ 21203-68-9 ]

Reference： [1]Organic and Biomolecular Chemistry,2005,vol. 3,p. 538 - 541
[2]Acta Chemica Scandinavica,1999,vol. 53,p. 141 - 144
[3]Journal of Heterocyclic Chemistry,2005,vol. 42,p. 259 - 264
[4]Chemische Berichte,1939,vol. 72,p. 577,579
[5]Acta Chemica Scandinavica,1996,vol. 50,p. 556 - 557
[6]Synthesis,1997,p. 281 - 283
[7]Heterocycles,2002,vol. 58,p. 301 - 310

2
[ 21203-68-9 ]
[ 100-52-7 ]
5-nitro-2-<i>trans</i>(?)-styryl-pyridine [ No CAS ]

Reference： [1]Monatshefte fur Chemie,1949,vol. 80,p. 499,503

3
[ 21203-68-9 ]
[ 80287-53-2 ]

Yield	Reaction Conditions	Operation in experiment
98.3%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 3040.2 Torr; for 18h;Autoclave;	To a 250mL autoclave was added100mLMeOH, <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (15g, 0.lO9mol, 1.Oeq) and 10% Pd/C (0.5g,3.3wt%). The reaction mixture was stirred at RT under 4atm of hydrogen for 18h.TLC (PE: EA= 3: 1) showed the reaction was completed. The reaction mixture was filtered. The filtrate was concentrated in vacuum to afford the title compound 6- methyl-pyridin-3-ylamine (1 1.5g, HPLC: 97%) as a dark red solid. Yield: 98.3%.
95%	palladium; In methanol;	Step 3 5-Amino-2-picoline The product of Step 2, <strong>[21203-68-9]5-nitro-2-picoline</strong> (45.86, 0.332 mol), was dissolved in 200 mL of methanol and 1.15 g of 10% palladium on carbon was added to the resultant solution. The reaction mixture was hydrogenated at ambient temperature under 4 atmospheres of hydrogen. The palladium catalyst was removed by filtration through a 45 muMillipore filter and the filtrate was concentrated in vacuo to afford 33.96 g (95% yield) of the title compound as a tan solid; 1 H NMR (CDCl3) d 2.42 (s, 3H), 3.54 (brs, 2H), 6.91 (m, 2H), 8.00 (m, 1H).
77%	palladium-carbon; In methanol;	20a. 5-Amino-2-methylpyridine <strong>[21203-68-9]2-Methyl-5-nitropyridine</strong> (1.4 g, 10 mmol) and 10% Pd/C (200 mg) were combined in MeOH (40mL) and allowed to stir under a H2 atmosphere for 18 hours. The reaction mixture was filtered through celite and the filtrate concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford the title compound (845 mg, 77%): 1 H NMR (CD3 OD, 300 MHz) delta2.35 (s, 3H), 6.97-7.06 (m, 2H), 7.85 (d, J=2.5 Hz, 1H).

	With hydrogen;palladium 10% on activated carbon; In 1,4-dioxane; under 2585.81 Torr; for 24h;	A slurry of diethyl malonate (42 mL) and sodium (4.71 g) were warmed slowly to 90 C. and stirred at 90 C. for 2 hours and 120 C. for 30 minutes before being cooled to room temperature. Toluene (200 mL) and 2-chloro-5-nitropyridine (25.0 g) were added and the mixture was heated at 110 C. for 1.5 hours and ambient temperature for 17 h. After removal of the volatiles in vacuo, 6 N HCl (200 mL) was added and the mixture was heated to reflux for 4 h and cooled to room temperature. The solution was neutralized with solid sodium carbonate, extracted with ethyl acetate (6×100 mL), dried over solid magnesium sulfate, and concentrated to a dark solid. This material was purified by flash chromatography using 20% ethyl acetate in petroleum ether as the eluent. Concentration in vacuo of the product-rich fractions afforded <strong>[21203-68-9]2-methyl-5-nitropyridine</strong>. A mixture of <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenation at 50 psi for 24 hours and filtered over diatomaceous earth. Removal of the volatiles in vacuo provided 5-amino-2-methylpyridine. A solution of 5-amino-2-methylpyridine (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0 C., and vigorously stirred throughout the procedure. Sodium nitrite (6.32 g) in water (50 mL) was added. After 30 minutes, tin (II) chloride dihydrate (52.0 g) in 6 N HCl (100 mL) was added and the reaction slurry was stirred at 0 C. for 3 hours. The pH was adjusted to pH 14 with 40% aqueous potassium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and removal of the volatiles in vacuo provided 5-hydrazino-2-methylpyridine. A solution of 5-hydrazino-2-methylpyridine (8.0 g) and 4,4-dimethyl-3-oxopentanenitrile (10.0 g) in ethanol (200 mL) and 6 N HCl (6 mL) was refluxed for 17 hours and cooled to room temperature. Solid sodium hydrogen carbonate was added to neutralize the solution. The slurry was filtered and removal of the volatiles in vacuo provided a residue which was purified by column chromatography using ethyl acetate as the eluent. Concentration in vacuo of the product-rich fractions afforded 5-amino-3-t-butyl-1-(2-methylpyridin-5-yl)pyrazole. To a 0 C. mixture of 3 (0.40 g) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added phosgene (1.93 M in toluene, 1.50 mL). The mixture was stirred 15 min and the organic layer was dried (MgSO4) and most of the volatiles removed in vacuo. A solution of the 4-aminonaphthyl ether intermediate from Example 1 (0.30 g) in dichloromethane (10 mL) was added and the mixture stirred for 17 hours at ambient temperature. Removal of the volatiles in vacuo provided a residue that was purified by column chromatography using 10% methanol in ethyl acetate as the eluent. Concentration in vacuo of the product-rich fractions and recrystallization from warm tetrahydrofuran/petroleum ether afforded the title compound.
	With iron; acetic acid; for 24.5h;Heating / reflux;	Preparation 90; 6-methyl-pyridin-3-vlamine; Iron powder (10g) was added to a well-stirred solution of 2-methyl-5-nitro- pyridine, [ (46g, 330mmol) Monatshefte fur chemie, 1950 81 (4) 479] dissolved in acetic acid (500mL). The mixture was heated under reflux for 1.5 hours, cooled, and a further portion of iron powder (2g) was added. The reaction mixture was stirred under reflux for an additional 5 hours, cooled and left to stand for 18 hours. The iron powder was then filtered off and the filtrate was evaporated under reduced pressure. The residue was taken up in water and chloroform and was treated with potassium carbonate. The organic phase was washed with water, dried over magnesium sulfate and concentrated in vacuo to produce the title compound as a semi-solid (17. 2g). BPt. 130C 1 mmHg
	With 5%-palladium/activated carbon; hydrogen; at 50 - 60℃; under 3375.34 Torr;	In some specific embodiments, an isopropyl acetate (15 V) solution of 2-Methyl-5- nitropyridine (NPYR) is washed with a 1 N aqueous NaOH solution (2 V) and water (2 V). The solution is optionally circulated through charcoal capsules until the color-of-solution (COS) in-process control is met (COS 99 LC area%.

Reference： [1]Patent: WO2018/208630,2018,A1 .Location in patent: Page/Page column 55
[2]Patent: US5580872,1996,A
[3]Patent: US5733912,1998,A
[4]Chemische Berichte,1939,vol. 72,p. 577,579
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 4676 - 4686
[6]Patent: US2003/232865,2003,A1 .Location in patent: Page 35-36
[7]Patent: WO2005/82866,2005,A2 .Location in patent: Page/Page column 91-92
[8]Patent: WO2019/6231,2019,A1 .Location in patent: Paragraph 0038

4
[ 21203-68-9 ]
[ 35969-75-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With selenium(IV) oxide; In 1,4-dioxane; for 16h;Reflux;	To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1 ,4- dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulphate and evaporated to get 5-nitropicolinaldehyde (3.12g, 94 %).
94%	With selenium(IV) oxide; In 1,4-dioxane; for 16h;Reflux;	Step 1 To a stirred solution of 2-methyl-5-nitropyridine (3.0 g, 0.021 mol, 1 eq) in 1,4-dioxane (30 mL) at room temperature was added selenium dioxide (2.9 g, 0.026 mol, 1.2 eq) and stirred at reflux for 16 h. The reaction mixture was filtered, evaporated, diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over sodium sulfate and evaporated to get 5-nitropicolinaldehyde (3.12 g, 94%).
35%		A mixture of 2-methyl-5-nitropyridine (3 g), selenium (IV) (2.9 g), 1,4- dioxane (25 mL) and water (0.5 mL) was refluxed for 4 hrs. The resulting black solid was filtered through Celite bed and washed with ether. The filtrate was treated with saturate aqueous NaHC03 and filtered again. The filtrate was extracted with ether twice and the solvent was concentrated. The residue was purified with a short silica gel column eluted with 20% ethyl acetate in hexane to give 1.0 g of orange precipitate 2 (35% yield). ¹H NMR (CD2Cl2): 8 10.15 (s, 1H), 9.55 (s, 1H), 8.7 (d, 1H), 8.15 (s, 1H).

Reference： [1]Patent: WO2013/13815,2013,A1 .Location in patent: Page/Page column 230; 231
[2]Patent: US2013/29962,2013,A1 .Location in patent: Paragraph 1110
[3]Journal of Organic Chemistry,2012,vol. 77,p. 8968 - 8979,12
[4]Journal of Medicinal Chemistry,1992,vol. 35,p. 3672 - 3677
[5]Patent: WO2005/97752,2005,A1 .Location in patent: Page/Page column 42
[6]Journal of Organic Chemistry,1959,vol. 24,p. 1007
[7]Bulletin of the Chemical Society of Japan,1993,vol. 66,p. 797 - 803

5
[ 21203-68-9 ]
[ 217302-90-4 ]

Reference： [1]Monatshefte fur Chemie,1950,vol. 81,p. 473,479

6
[ 21203-68-9 ]
[ 30651-24-2 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684
[2]Journal of Heterocyclic Chemistry,2005,vol. 42,p. 259 - 264
[3]Journal of the American Chemical Society,1954,vol. 76,p. 3167

7
[ 60891-70-5 ]
[ 21203-68-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sulfuric acid; water; at 100℃; for 2h;	Reference Example 28: 5-Nitro-2-methyl pyridine. To 2-(5-nitro-pyridin-2-yl)-malonic acid diethyl ester (12.0 g, 42.5 mmol) was added cold aq. 20% sulfuric acid (120 mL) and the mixture was heated to 1000C for 2h. The cooled reaction was added to cold dilute sodium hydroxide solution and the pH adjusted to pH -10. The organics were extracted with dichloromethane (x 4), then the combined organic phases were dried over sodium sulfate. The filtrate was concentrated to afford 2-methyl-5-nitro pyridine (5.0 g, 83 %) as a brown solid.

Reference： [1]Patent: WO2008/62182,2008,A1 .Location in patent: Page/Page column 117
[2]Synthetic Communications,1990,vol. 20,p. 2965 - 2970
[3]Monatshefte fur Chemie,1950,vol. 81,p. 473,479
[4]Organic Letters,2011,vol. 13,p. 6102 - 6105
[5]Journal of Organic Chemistry,2012,vol. 77,p. 8968 - 8979,12

8
[ 56057-19-3 ]
[ 21203-68-9 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 3167

9
[ 109-06-8 ]
[ 21203-68-9 ]
[ 18699-87-1 ]

Yield	Reaction Conditions	Operation in experiment
0.57 g; 0.1 g	With oxygen; nitrogen(II) oxide; In acetonitrile; at 90℃; under 37503.8 Torr; for 10h;	Into the reactor, 0.93 g (10.0 mmol) of 2-methylpyridine, 5 mL of acetonitrile, 0.15 g of sulfonated graphene was added, and the reaction was stirred under an oxygen atmosphere at 5.0 MPa of nitrogen monoxide and a temperature of 90 C for 10 h. After the end of the reaction, nitrogen gas was introduced into the reaction mixture at a normal pressure until the nitrogen oxides completely escaped to the cold trap reaction receiver, and the catalyst was filtered off. The filtrate was washed with a 5% (m/m) aqueous solution of sodium hydrogencarbonate to near neutral, and then washed with distilled water until the organic phase was neutral and concentrated by evaporation in vacuo. Separating the product components by column chromatography,The mass of 2-methylnitropyridine is 0.67g,Wherein 2-methyl-3-nitropyridine 0.10 g (mass fraction 16%),2-methyl-5-nitropyridine 0.57 g (mass fraction 84%), yield 49%.

Reference： [1]Acta Chemica Scandinavica,1994,vol. 48,p. 181 - 182
[2]Acta Chemica Scandinavica,1994,vol. 48,p. 1001 - 1006
[3]Patent: CN108003029,2018,A .Location in patent: Paragraph 0043; 0044

10
[ 4548-45-2 ]
[ 996-82-7 ]
[ 21203-68-9 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684

11
[ 4548-45-2 ]
[ 105-53-3 ]
[ 21203-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; In N-methyl-acetamide; chloroform; water;	EXAMPLE 9 5-Nitro-2-picoline 206 g (1.29 mol) of diethyl malonate are added to 600 ml of dimethylformamide, and 51.2 g (1.28 mol) of freshly powdered NaOH are introduced, with cooling. The mixture is subsequently stirred after 15 minutes and a solution of 94.8 g (0.6 mol) of 5-nitro-2-chloropyridine in 600 ml of dimethylformamide is then added dropwise at room temperature. The deep red solution formed is stirred until the reaction is complete, 36% strength HCl is then added dropwise until the color changes to orange and the mixture is evaporated to dryness in vacuo. The residue is taken up in 400 ml of CHCl3, washed with 500 ml of water and evaporated again. The residue is now dissolved in a mixture of 1,200 ml of 36% strength HCl and 870 ml of water and the solution is boiled under reflux until the evolution of gas has ended. Thereafter, it is evaporated in vacuo, the residue is dissolved in 500 ml of water, the solution is extracted with methylene chloride and the organic phase is washed again with water. After the solvent has been stripped off, 72 g (87%) of 5-nitro-2-picoline remain. Melting point: 109-111 C.
		A slurry of diethyl malonate (42 mL) and sodium (4.71 g) were warmed slowly to 90 C. and stirred at 90 C. for 2 hours and 120 C. for 30 minutes before being cooled to room temperature. Toluene (200 mL) and 2-chloro-5-nitropyridine (25.0 g) were added and the mixture was heated at 110 C. for 1.5 hours and ambient temperature for 17 h. After removal of the volatiles in vacuo, 6 N HCl (200 mL) was added and the mixture was heated to reflux for 4 h and cooled to room temperature. The solution was neutralized with solid sodium carbonate, extracted with ethyl acetate (6×100 mL), dried over solid magnesium sulfate, and concentrated to a dark solid. This material was purified by flash chromatography using 20% ethyl acetate in petroleum ether as the eluent. Concentration in vacuo of the product-rich fractions afforded 2-methyl-5-nitropyridine. A mixture of 2-methyl-5-nitropyridine (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenation at 50 psi for 24 hours and filtered over diatomaceous earth. Removal of the volatiles in vacuo provided 5-amino-2-methylpyridine. A solution of 5-amino-2-methylpyridine (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0 C., and vigorously stirred throughout the procedure. Sodium nitrite (6.32 g) in water (50 mL) was added. After 30 minutes, tin (II) chloride dihydrate (52.0 g) in 6 N HCl (100 mL) was added and the reaction slurry was stirred at 0 C. for 3 hours. The pH was adjusted to pH 14 with 40% aqueous potassium hydroxide solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and removal of the volatiles in vacuo provided 5-hydrazino-2-methylpyridine. A solution of 5-hydrazino-2-methylpyridine (8.0 g) and 4,4-dimethyl-3-oxopentanenitrile (10.0 g) in ethanol (200 mL) and 6 N HCl (6 mL) was refluxed for 17 hours and cooled to room temperature. Solid sodium hydrogen carbonate was added to neutralize the solution. The slurry was filtered and removal of the volatiles in vacuo provided a residue which was purified by column chromatography using ethyl acetate as the eluent. Concentration in vacuo of the product-rich fractions afforded 5-amino-3-t-butyl-1-(2-methylpyridin-5-yl)pyrazole. To a 0 C. mixture of 3 (0.40 g) in dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added phosgene (1.93 M in toluene, 1.50 mL). The mixture was stirred 15 min and the organic layer was dried (MgSO4) and most of the volatiles removed in vacuo. A solution of the 4-aminonaphthyl ether intermediate from Example 1 (0.30 g) in dichloromethane (10 mL) was added and the mixture stirred for 17 hours at ambient temperature. Removal of the volatiles in vacuo provided a residue that was purified by column chromatography using 10% methanol in ethyl acetate as the eluent. Concentration in vacuo of the product-rich fractions and recrystallization from warm tetrahydrofuran/petroleum ether afforded the title compound.

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4676 - 4686
[2]Bulletin of the Chemical Society of Japan,1993,vol. 66,p. 797 - 803
[3]Patent: US4847382,1989,A
[4]Patent: US2003/232865,2003,A1 .Location in patent: Page 35-36

12
[ 123-54-6 ]
[ 14080-32-1 ]
[ 21203-68-9 ]
[ 1450-76-6 ]
[ 16475-85-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1987,vol. 23,p. 422 - 425
    Khimiya Geterotsiklicheskikh Soedinenii,1987,p. 508 - 512
[2]Chemistry of Heterocyclic Compounds,1987,vol. 23,p. 422 - 425
    Khimiya Geterotsiklicheskikh Soedinenii,1987,p. 508 - 512
[3]Chemistry of Heterocyclic Compounds,1987,vol. 23,p. 422 - 425
    Khimiya Geterotsiklicheskikh Soedinenii,1987,p. 508 - 512

13
[ 68906-00-3 ]
[ 75-04-7 ]
[ 67-64-1 ]
[ 21203-68-9 ]
[ 3665-80-3 ]

Reference： [1]Russian Chemical Bulletin,1994,vol. 43,p. 1041 - 1043
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1994,p. 1102 - 1104

14
[ 68906-00-3 ]
[ 67-64-1 ]
[ 21203-68-9 ]
[ 3665-80-3 ]

Reference： [1]Russian Chemical Bulletin,1994,vol. 43,p. 1041 - 1043
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1994,p. 1102 - 1104

15
[ 21203-68-9 ]
[ 27126-76-7 ]
5-nitro-2-tosyloxymethylpyridine [ No CAS ]

Reference： [1]Heterocycles,1994,vol. 38,p. 713 - 718

16
[ 17758-39-3 ]
[ 67-64-1 ]
[ 21203-68-9 ]

Reference： [1]Synthesis,1997,p. 1277 - 1280

Yield	Reaction Conditions	Operation in experiment
92%		Step 2 5-Nitro-2-picoline A suspension of 102.0 g (0.361 mol) of 2-(5-nitro-2-pyridyl)-1,3-propanedicarboxylate, from Step 1, in 600 mL of 20% aqueous sulfuric acid solution was heated at 95 C. for 24 hours. The resultant solution was poured onto 1 kg of ice and the aqueous mixture was adjusted to a pH within the range pH 10-12 with 50% aqueous sodium hydroxide solution. The precipitate was filtered and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated to a solid residue. The residue was washed with hexane. The hexane was removed by filtration and the solid was dried to afford 45.86 g (92% yield) of the title compound; 1 H NMR (CDCl3) d 2.71 (s, 3H), 7.36 (d, 1H, J=9.0 Hz), 8.37 (dd, 1H, J=3.0 Hz, 9.0 Hz), 9.33 (d, 1H, J=3.0 Hz).
		Production Example 159 Mixture of 2-methyl-5-aminopyridine with ethyl(5-aminopyridin-2-yl)acetate 3.131 g of diethyl 2-(5-nitropyridin-2-yl)malonate, 476 mg of lithium chloride and 0.2 ml of water were dissolved in 10 ml of N,N-dimethylformamide and heated at 120 C. for 3 hours. Then the reaction mixture was distilled under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane) to thereby give 803 mg of a mixture of 2-methyl-5-nitropyridine with ethyl(5-nitropyridin-2-yl)acetate as a reddish brown crystalline substance.

19
[ 65-85-0 ]
[ 56057-19-3 ]
copper-powder [ No CAS ]
[ 21203-68-9 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 3567

20
[ 21203-68-9 ]
[ 2999-46-4 ]
diethyl 5-methyl-8H-imidazo[1,5-a]pyrrolo[3,4-c]pyridine-1,7-dicarboxylate [ No CAS ]

Reference： [1]Heterocycles,2002,vol. 58,p. 301 - 310

21
[ 4487-59-6 ]
bis(μ-[2-(dimethylamino)ethanolato-N,O:O]tetramethyldiindium [ No CAS ]
[ 21203-68-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,2003,vol. 40,p. 565 - 567

22
[ 21203-68-9 ]
[ 852102-20-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,2005,vol. 42,p. 259 - 264

23
[ 21203-68-9 ]
[ 197516-48-6 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4676 - 4686

24
[ 21203-68-9 ]
[ 285984-51-2 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4676 - 4686

25
[ 21203-68-9 ]
1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4676 - 4686

26
[ 21203-68-9 ]
5-nitro-2-pyridinecarbaldehyde 2-pyridylhydrazone [ No CAS ]

Reference： [1]Bulletin of the Chemical Society of Japan,1993,vol. 66,p. 797 - 803

27
[ 21203-68-9 ]
[ 51984-34-0 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 3672 - 3677

28
[ 21203-68-9 ]
[ 143621-34-5 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 3672 - 3677

29
[ 21203-68-9 ]
[ 143621-32-3 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 3672 - 3677

30
[ 21203-68-9 ]
[ 143621-39-0 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 3672 - 3677

31
[ 21203-68-9 ]
[ 143621-36-7 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 3672 - 3677

32
[ 21203-68-9 ]
[ 119830-47-6 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684

33
[ 21203-68-9 ]
[ 90866-93-6 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684

34
[ 21203-68-9 ]
[ 90866-96-9 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684

35
[ 21203-68-9 ]
[ 90866-95-8 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684

36
[ 21203-68-9 ]
[ 30563-98-5 ]

Reference： [1]Journal of Organic Chemistry,1984,vol. 49,p. 3681 - 3684

37
[ 4548-45-2 ]
[ 21203-68-9 ]

Reference： [1]Synthetic Communications,1990,vol. 20,p. 2965 - 2970
[2]Monatshefte fur Chemie,1950,vol. 81,p. 473,479
[3]Journal of Organic Chemistry,2012,vol. 77,p. 8968 - 8979,12

38
[ 21203-68-9 ]
[ 29958-15-4 ]

Reference： [1]Chemische Berichte,1939,vol. 72,p. 577,579

39
[ 21203-68-9 ]
[ 7440-44-0 ]
[ 80287-53-2 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane;	A mixture of <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenated at 50 psi for 24 hours and filtered over celite. Removal of the volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution of this compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0 C., and vigorously stirred throughout the procedure.
	In 1,4-dioxane;	A mixture of <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenated at 50 psi for 24 hours and filtered over celite. Removal of the volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution of this compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0 C., and vigorously stirred throughout the procedure.
	In 1,4-dioxane;	A mixture of <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenated at 50 psi for 24 hours and filtered over celite. Removal of the volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution of this compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0 C., and vigorously stirred throughout the procedure.

In 1,4-dioxane;

A mixture of <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (13.0 g) and 10% Pd on activated carbon (0.1 g) in 1,4-dioxane (150 mL) was hydrogenated at 50 psi for 24 hours and filtered over celite. Removal of the volatiles in vacuo provided 2-methyl-5-aminopyridine. A solution of this compound (9.90 g) was dissolved in 6 N HCl (100 mL), cooled to 0 C., and vigorously stirred throughout the procedure.

Reference： [1]Patent: US2003/130309,2003,A1
[2]Patent: US6492529,2002,B1
[3]Patent: US6525046,2003,B1
[4]Patent: US6319921,2001,B1

40
[ 21203-68-9 ]
4-(5-nitro-pyridin-2-yl)butylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 7 Substitution of <strong>[21203-68-9]5-nitro-2-methylpyridine</strong> (414 g) for 3-methoxy-2-methylpyridine in the process of Example 3 gives 4-(5-nitro-2-pyridyl)butylamine. EXAMPLE 8

Reference： [1]Patent: US4526974,1985,A

41
[ 21203-68-9 ]
[ 887588-20-7 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃;Inert atmosphere;	100mL single-neck flask was added <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (10.0g, 72.40mmol), N- bromosuccinimide (13.2g, 74.20mmol), benzoyl peroxide (3.5g, 14.00 mmol) and carbon tetrachloride (100mL), under nitrogen, the reaction system was heated to 80 reaction overnight. Cooling to room temperature, the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 8/1), a yellow solid was obtained by 7.4g, yield: 47%.
31.19%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 12h;	To a solution of <strong>[21203-68-9]2-methyl-5-nitropyridine</strong> (5 g, 36.20 mmol) in CCl4 (75 mL) was added benzoyl peroxide (1.75 g, 7.24 mmol) and NBS (7.09 g, 39.82 mmol). The mixture was stirred at 80 C for 12 hr. The reaction mixture was concentrated and purified by column chromatography (Si02, petroleum ether/EtOAc = 1/0 to 10/1) to afford the product (2.45 g, 11.29 mmol, 31.19% yield) as a yellow oil.

Reference： [1]Patent: CN105524053,2016,A .Location in patent: Paragraph 0383; 0384
[2]Patent: WO2019/222173,2019,A1 .Location in patent: Page/Page column 152-153
[3]Journal of the American Chemical Society,2010,vol. 132,p. 13600 - 13603

42
[ 21203-68-9 ]
[ 2364-75-2 ]