7584-05-6|3-Methylisonicotinonitrile| Ambeed

CAS No. :	7584-05-6
Formula :	C₇H₆N₂
M.W :	118.14
SMILES Code :	CC1=C(C=CN=C1)C#N
MDL No. :	MFCD09261048
InChI Key :	SFNWPKSTEHBXSY-UHFFFAOYSA-N
Pubchem ID :	82063

Safety of [ 7584-05-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 7584-05-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	33.92
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	36.68 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.44
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.94
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.26
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.	0.13
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	1.78
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.11

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.66
Solubility	2.6 mg/ml ; 0.022 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.3
Solubility	5.96 mg/ml ; 0.0505 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.45
Solubility	0.423 mg/ml ; 0.00358 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.35 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.42

Application In Synthesis of [ 7584-05-6 ]

* 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 [ 7584-05-6 ]

[ 7584-05-6 ] Synthesis Path-Downstream 1~55

1
[ 1003-73-2 ]
[ 77-78-1 ]
[ 1620-77-5 ]
[ 7584-05-6 ]
[ 20970-75-6 ]

References: [1]Journal of the American Chemical Society,1959,vol. 81,p. 4004,4005.

2
[ 1003-73-2 ]
[ 74-88-4 ]
[ 7584-05-6 ]
[ 20970-75-6 ]

References: [1]Chemical and pharmaceutical bulletin,1959,vol. 7,p. 925,928.

3
[ 1681-36-3 ]
[ 7584-05-6 ]

References: [1]Pharmaceutical bulletin,1957,vol. 5,p. 78 - 79.

4
[ 7584-05-6 ]
phenylmagnesium bromide [ No CAS ]
[ 20002-31-7 ]

References: [1]Pharmaceutical bulletin,1957,vol. 5,p. 78 - 79.

5
[ 7584-05-6 ]
[ 4021-12-9 ]

References: [1]Pharmaceutical bulletin,1957,vol. 5,p. 78 - 79.

6
[ 151-50-8 ]
[ 86488-30-4 ]
[ 7584-05-6 ]
[ 20970-75-6 ]

References: [1]Chemical and pharmaceutical bulletin,1959,vol. 7,p. 925,928.

7
[ 1003-73-2 ]
[ 151-50-8 ]
[ 7584-05-6 ]

Yield	Reaction Conditions	Operation in experiment
34%		Example 1; A. 3-Methyl-isonicotinonitrile.; To 3-methyl-pyridine 1 -oxide (15.90 g, 150 mmol) is added at 0 0C during 30 min. dimethylsulfate (15.60 mL). The resulting reaction mixture is stirred overnight at 40 0C. A solution of KCN (10.75 g, 165 mmol) in a mixture of EtOH/water 1 : 1 (120 mL) is added and the reaction mixture is stirred overnight at 40 0C. The reaction mixture is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by flash column chromatography (silica gel, cyclohexane / EtOAc 85 : 15) affords the title compound as orange crystals (6.00 g, 50.80 mmol, 34%). 1H NMR (400 MHz, DMSO-(Z6) delta ppm 8.76 (s, 1 H), 8.64 (d, J = 4.9 Hz, 1 H), 7.80 (d, J = 4.9 Hz, 1 H).
34%		3-Methyl-isonicotinonitrile; To 3-methyl-pyridine 1 -oxide (15.9 g, 150 mmol) is added at 0 0C during 30 min. dimethylsulfate (15.6 ml_). The resulting reaction mixture is stirred overnight at 40 0C. A solution of KCN (10.75 g, 165 mmol) in a mixture of EtOH / water 1 : 1 (120 mL) is added and the reaction mixture is stirred overnight at 40 0C. The reaction mixture is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated at reduced pressure. Purification by FCC (silica gel, cyclohexane / EtOAc 85 : 15) affords the title compound as orange crystals (6.0 g, 50.8 mmol, 34%). 1H NMR (400 MHz, DMSO-d6, 298 K): delta = 8.76 (s, 1 H), 8.64 (d, J = 4.9 Hz, 1 H), 7.80 (d, J = 4.9 Hz, 1 H).
		A. A mixture of 3-methyl-pyridine 1-oxide (20 g, 0.183 mol) and iodoethane (32 mL, 0.403 mmol) is stirred 16 h. 200 mL water is added, the aqueous layer is separated and washed with Et2O. The collected aqueous layer is warmed to 50 C. and a solution of KCN (24 g, 0.366 mol) in 60 mL of water is added slowly in one hour. After an additional one hour stirring, the mixture is extracted with Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes:EtOAc=4:1 as eluent to provide 3-methyl-isonicotinonitrile.

References: [1]Patent: WO2008/122615,2008,A1 .Location in patent: Page/Page column 49.
[2]Patent: WO2008/122614,2008,A1 .Location in patent: Page/Page column 19.
[3]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.
[4]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1751 - 1755.
[5]Patent: US2006/116368,2006,A1 .Location in patent: Page/Page column 55.

8
[ 3230-65-7 ]
[ 7584-05-6 ]
[ 131250-24-3 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 705 - 717.

9
[ 67-56-1 ]
[ 7584-05-6 ]
3-Methyl-isonicotinimidic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1230 - 1241.

10
[ 7584-05-6 ]
[ 917-54-4 ]
[ 82352-00-9 ]

References: [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1751 - 1755.

11
[ 7584-05-6 ]
[ 4637-24-5 ]
[ 80935-76-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; for 120h;	B. To a solution of <strong>[7584-05-6]3-methyl-isonicotinonitrile</strong> (12.25 g, 0.104 mmol) in 100 mL of DMF is added dimethylformamide dimethyl acetal (22 mL, 0.166 mol) portionwise in 5 days. The solvent is evaporated to dryness. The residue is purified by silica gel column chromatography with hexanes:EtOAc=4:1 as eluent to provide 3-(2-dimethylamino-vinyl)-isonicotinonitrile.

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.
[2]Patent: US2006/116368,2006,A1 .Location in patent: Page/Page column 55.

12
[ 7584-05-6 ]
[ 2365-48-2 ]
[ 116986-03-9 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1987,vol. 329,p. 557 - 562.

13
[ 7584-05-6 ]
[ 103-63-9 ]
[ 113003-47-7 ]

References: [1]Archiv der Pharmazie,1987,vol. 320,p. 385 - 393.

14
[ 151-50-8 ]
[ 87117-12-2 ]
[ 1620-77-5 ]
[ 7584-05-6 ]
[ 20970-75-6 ]

References: [1]Heterocycles,1984,vol. 22,p. 1121 - 1124.

15
[ 222191-28-8 ]
[ 7584-05-6 ]

References: [1]Organic Preparations and Procedures International,1999,vol. 31,p. 120 - 123.
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 6942 - 6990.

Yield	Reaction Conditions	Operation in experiment
		The process in claim 63 in which the selected quaternary salt or its acid salt is of a first pyridine base from the group consisting of 4-cyanopyridine; 3-methyl-4-cyanopyridine; and 3-methylpyridine.

18
[ 151-50-8 ]
[ 86488-30-4 ]
aqueous dioxane [ No CAS ]
[ 7584-05-6 ]
[ 20970-75-6 ]

References: [1]Chemical and pharmaceutical bulletin,1959,vol. 7,p. 925,928.

19
[ 151-50-8 ]
[ 87117-12-2 ]
aqueous dioxane [ No CAS ]
[ 1620-77-5 ]
[ 7584-05-6 ]
[ 20970-75-6 ]

References: [1]Journal of the American Chemical Society,1959,vol. 81,p. 4004,4005.

20
[ 583-58-4 ]
[ 7584-05-6 ]

References: [1]Organic Preparations and Procedures International,1999,vol. 31,p. 120 - 123.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 1682 - 1697.
[3]Russian Journal of General Chemistry,2012,vol. 82,p. 1987 - 1993.
Zh. Obshch. Khim.,2012,vol. 82,p. 2033 - 2039,7.
[4]Patent: US2014/18360,2014,A1 .
[5]Chemistry - A European Journal,2016,vol. 22,p. 8301 - 8308.
[6]Journal of Medicinal Chemistry,2017,vol. 60,p. 6942 - 6990.

21
[ 74663-96-0 ]
[ 7584-05-6 ]

References: [1]Organic Preparations and Procedures International,1999,vol. 31,p. 120 - 123.
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 6942 - 6990.

22
[ 7584-05-6 ]
[ 113003-48-8 ]

References: [1]Archiv der Pharmazie,1987,vol. 320,p. 385 - 393.

23
[ 7584-05-6 ]
1,3-Dimethyl-4-(3-phenyl)-propylpyridiniumiodid [ No CAS ]

References: [1]Archiv der Pharmazie,1987,vol. 320,p. 385 - 393.

24
[ 7584-05-6 ]
[ 113018-67-0 ]

References: [1]Archiv der Pharmazie,1987,vol. 320,p. 385 - 393.

25
[ 7584-05-6 ]
3,4-Dihydro-1',3'-dimethylspiro<naphthalin-1(2H),4'-piperidin> [ No CAS ]

References: [1]Archiv der Pharmazie,1987,vol. 320,p. 385 - 393.

26
[ 7584-05-6 ]
3,4-Dihydro-1',3'-dimethylspiro<naphthalin-1(2H),4'-piperidin> [ No CAS ]

References: [1]Archiv der Pharmazie,1987,vol. 320,p. 385 - 393.

27
[ 7584-05-6 ]
[ 117007-12-2 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1987,vol. 329,p. 557 - 562.

28
[ 7584-05-6 ]
[ 80935-77-9 ]

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3559 - 3572.
[3]Patent: WO2009/158396,2009,A1 .

29
[ 7584-05-6 ]
[ 80935-81-5 ]

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.
[2]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.

30
[ 7584-05-6 ]
[ 80935-78-0 ]

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.

31
[ 7584-05-6 ]
[ 253-50-9 ]

References: [1]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 1349 - 1352.

32
[ 7584-05-6 ]
[ 83402-08-8 ]

References: [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1751 - 1755.

33
[ 7584-05-6 ]
[ 131895-53-9 ]

References: [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1751 - 1755.

34
[ 7584-05-6 ]
[ 131250-25-4 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 705 - 717.

35
[ 7584-05-6 ]
[ 131250-26-5 ]

References: [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 705 - 717.

36
[ 7584-05-6 ]
[ 125903-80-2 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1230 - 1241.

37
[ 1003-73-2 ]
[ 7584-05-6 ]

References: [1]Chemical and pharmaceutical bulletin,1959,vol. 7,p. 925,928.

38
[ 7584-05-6 ]
[ 58997-11-8 ]

References: [1]Pharmaceutical bulletin,1957,vol. 5,p. 78 - 79.

39
[ 7584-05-6 ]
[ 106-47-8 ]
[ 698395-73-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 3-picoline (50 g, 0.48 mol) in glacial acetic acid (150 ml) was added hydrogen peroxide (25 ML) at RT. The mixture was heated to 90C for 3 hr. The mixture was cooled to RT and more hydrogen peroxide (18.5 ml) was added slowly. The mixture was again heated to 90OC for 19 hr. The excess peroxide was carefully decomposed using Pd-C (2.5 g) at 0C. Pd-C was removed by filtration, and the filtrate was concentrated and crude 3-methyl pyridine-1-oxide was purified by fractional distillation in vacuo. [00144] A solution of 3-methyl pyridine-1-oxide (10 g, 0.092 mol) in methyl iodide (15 ml) was left at rt for 18 hr and the solid was filtered. The filtrate was diluted with diethyl ether and extracted with water (40 ML). The solid was re-dissolved in the aqueous extract, 1,4-dioxane (50 ml) was added, followed by potassium cyanide (15 g, 0.23 mol) and the mixture was stirred at RT for 3 hr. The product was extracted with chloroform. The chloroform layer was washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by fractional distillation (61-62C/0. 2 mm) to yield a white low melting solid. [00145] BC13 (24 ml, 1 M in DCM, 0.024 mol) was added slowly to a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of trichloroethylene over a period of 15 min. at 0C and stirred at this temperature for an additional 10 min. 4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AIC13 (3 g, 0.022 mol) were added at 0C. The solution was allowed to warm to RT and stirred for 30 min. The solution was then heated at 80-90C for 1 hr. and the DCM was distilled off. The resulting solution was REFLUXED at 115C for 4 hr and stirred at RT overnight. 3N HCI (20 ML) was added and the mixture REFLUXED at 100C for 2 hr. The reaction mixture was cooled to 0C and adjusted to pH-12 with 6N NaOH. The reaction mixture was extracted with DCM., and the DCM layer washed with water, brine and dried over NA2SO4. The solvent was removed, and the crude was purified by column chromatography over silica gel to yield a yellow solid.

References: [1]Patent: WO2004/46092,2004,A2 .Location in patent: Page 46-47.

40
[ 931-19-1 ]
[ 7584-05-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 3-picoline (50 g, 0.48 mol) in glacial acetic acid (150 ml) was added hydrogen peroxide (25 ML) at RT. The mixture was heated to 90C for 3 hr. The mixture was cooled to RT and more hydrogen peroxide (18.5 ml) was added slowly. The mixture was again heated to 90OC for 19 hr. The excess peroxide was carefully decomposed using Pd-C (2.5 g) at 0C. Pd-C was removed by filtration, and the filtrate was concentrated and crude 3-methyl pyridine-1-oxide was purified by fractional distillation in vacuo. [00144] A solution of 3-methyl pyridine-1-oxide (10 g, 0.092 mol) in methyl iodide (15 ml) was left at rt for 18 hr and the solid was filtered. The filtrate was diluted with diethyl ether and extracted with water (40 ML). The solid was re-dissolved in the aqueous extract, 1,4-dioxane (50 ml) was added, followed by potassium cyanide (15 g, 0.23 mol) and the mixture was stirred at RT for 3 hr. The product was extracted with chloroform. The chloroform layer was washed with water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by fractional distillation (61-62C/0. 2 mm) to yield a white low melting solid. [00145] BC13 (24 ml, 1 M in DCM, 0.024 mol) was added slowly to a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of trichloroethylene over a period of 15 min. at 0C and stirred at this temperature for an additional 10 min. 4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AIC13 (3 g, 0.022 mol) were added at 0C. The solution was allowed to warm to RT and stirred for 30 min. The solution was then heated at 80-90C for 1 hr. and the DCM was distilled off. The resulting solution was REFLUXED at 115C for 4 hr and stirred at RT overnight. 3N HCI (20 ML) was added and the mixture REFLUXED at 100C for 2 hr. The reaction mixture was cooled to 0C and adjusted to pH-12 with 6N NaOH. The reaction mixture was extracted with DCM., and the DCM layer washed with water, brine and dried over NA2SO4. The solvent was removed, and the crude was purified by column chromatography over silica gel to yield a yellow solid.

References: [1]Patent: WO2004/46092,2004,A2 .Location in patent: Page 46-47.

41
[ 7584-05-6 ]
[ 58515-46-1 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	1-Amino-3-(3-methyl-4-pyridyl)2,6-naphthyridine To 5.9 g. of <strong>[7584-05-6]4-cyano-3-methylpyridine</strong> dissolved in 30 ml. of dimethylformamide, gradually add 6.7 g. of potassium t-butoxide at about 5 C. Maintain the mixture at 5 C for 4 - t hours and quench the reaction in ice water. Collect the crystalline precipitate and recrystallize from toluene to yield 1-amino-3-(3-methyl-4-pyridyl)-2,6-naphthyridine.

References: [1]Patent: US4017500,1977,A .

42
[ 7584-05-6 ]
[ 58481-11-1 ]
[ 1071017-80-5 ]
[ 1071017-84-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In 1,2-dimethoxyethane; at 95℃;	Example 18; A. 3-[2-(2-chloropyridin-4-yl)-2-oxoethyl]isonicotinonitrile and 3-[2-(2-methoxypyridin- 4-yl)-2-oxoethyl]isonicotinonitrile.; In a three-necked round-bottomed flask equipped with a reflux cooler, 60 % NaH in mineral oil (1.35 g, 33.9 mmol) is added to DME (70 ml_). The suspension is heated to 95 0C and a solution of <strong>[7584-05-6]3-methylisonicotinonitrile</strong> (1.00 g, 8.47 mmol) and 2-chloroisonicotinic acid methyl ester (2.18 g, 12.71 mmol) in DME (15 mL) is added. The resulting reaction mixture is stirred overnight at 95 0C. After cooling down to room temperature the reaction mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to afford <n="182"/>a 1 : 2 mixture of 3-[2-(2-chloropyridin-4-yl)-2-oxoethyl]isonicotinonitrile and 3-[2-(2- methoxypyridin-4-yl)-2-oxoethyl]isonicotinonitrile as a brown solid (2.25 g, 8.47 mmol, 100%). 3-[2-(2-chloropyridin-4-yl)-2-oxoethyl]isonicotinonitrile: MS (ES+): 258 (M(C13H8CIN3OHH)+; 3-[2-(2-methoxy-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile: MS (ES+): 254 (M(C14H11N3O2HH)+ .
	With sodium hydride; In 1,2-dimethoxyethane; at 95℃;	3-[2-(2-chloro-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile and 3-[2-(2-methoxy-pyridin-4-yl)-2- oxo-ethyl]-isonicotinonitrile; In a three-necked round-bottomed flask equipped with a reflux cooler, 60 % NaH in mineral oil (1.35 g, 33.9 mmol) is added to DME (70 ml_). The suspension is heated to 95 0C and a solution of <strong>[7584-05-6]3-methyl-isonicotinonitrile</strong> (1.00 g, 8.47 mmol) and 2-chloro-isonicotinic acid methyl ester (2.18 g, 12.71 mmol) in DME (15 ml_) is added. The resulting reaction mixture is stirred overnight at 95 0C. After cooling down to room temperature the reaction mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to afford a 1 : 2 mixture of 3-[2-(2-chloro-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile and 3-[2-(2- methoxy-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile as a brown solid (2.25 g, 8.47 mmol, 100%). 3-[2-(2-chloro-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile: MS (ES+): 258 (M(C13H8CIN3O)H-H)+; 3-[2-(2-methoxy-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile: MS (ES+): 254 (M(C14H11N3O2)H-H)+ .

References: [1]Patent: WO2008/122615,2008,A1 .Location in patent: Page/Page column 180-181.
[2]Patent: WO2008/122614,2008,A1 .Location in patent: Page/Page column 34.

43
[ 7584-05-6 ]
[ 2459-09-8 ]
[ 1071017-66-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydride; In 1,2-dimethoxyethane; at 95℃;	3-(2-Oxo-2-pyridin-4-yl-ethyl)-isonicotinonitrile; <n="20"/>In a three-necked round-bottomed flask equipped with reflux cooler, 60 % NaH in mineral oil (4.06 g, 102 mmol) is added to DME (80 ml_). The suspension is heated to 95 0C and a solution of <strong>[7584-05-6]3-methyl-isonicotinonitrile</strong> (3.00 g, 25.4 mmol) and isonicotinic acid methyl ester (3.48 g, 25.4 mmol) in DME (20 ml_) is added. The resulting reaction mixture is stirred overnight at 95 0C. After cooling down to room temperature, the reaction mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to afford an orange solid (5.67 g, 25.4 mmol, 100%). 1H NMR (400 MHz, DMSO-d6, 298 K): delta = 9.19 (s, 1 H), 8.72 (d, J = 6.2 Hz, 2H), 8.65 (d, J = 5.1 Hz, 1 H), 7.95 (d, J = 5.1 Hz, 1 H), 7.84 (d, J = 6.2 Hz, 2H), 4.84 (s, 2H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7367 - 7372.
[2]Patent: WO2008/122614,2008,A1 .Location in patent: Page/Page column 18-19.

44
[ 7584-05-6 ]
[ 540-88-5 ]
[ 1071017-64-5 ]

Yield	Reaction Conditions	Operation in experiment
95%		C. lambda/-f-Butyl-3-methy]isonicotinamide.; To the solution of the <strong>[7584-05-6]3-methyl-isonicotinonitrile</strong> (18.90 g, 159.92 mmol) in DCM (50 mL) is added f-BuOAc (72.63 mL, 538.84 mmol), followed by concentrated H2SO4 (12.32 mL, 874.46 mmol). The reaction is stirred for 8 h at rt, then diluted with a solution of saturated aqueous NaHCO3 and DCM (50 mL). The organic layer is washed with H2O, brine, dried over anhydrous Na2SO4 and then evaporated under reduced pressure to provide a white solid (29.30 g, 152.44 mmol, 95%).

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 5400 - 5421.
[2]Patent: WO2008/122615,2008,A1 .Location in patent: Page/Page column 50.

45
[ 7584-05-6 ]
[ 20970-75-6 ]
[ 4637-24-5 ]
[ 80935-76-8 ]

Yield	Reaction Conditions	Operation in experiment
	With pyrrolidine; In N,N-dimethyl-formamide; at 130℃; for 16h;Inert atmosphere;	[00305] A round bottom flask was charged with <strong>[7584-05-6]3-methylpyridine-4-carbonitrile</strong> (52 g, 440 mmol), anhydrous NN-dimethylformamide (100 niL), NN-dimethylformamide dimethylacetal (; 314 g,2644 mmol) and pyrrolidine (31 g, 440 mmol) under an inert atmosphere and heated at 130 C for 16 hours. After completion of the reaction (TLC), the reaction was treated with ice-cold water (300 mL) and then extracted with ethylacetete (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed to get 72 g of the desired product (mixture of 2- and 4- isomers) which was used as such in the next step without further purification. MS: 174 [M+H]+ = 174

References: [1]Patent: WO2009/11904,2009,A1 .Location in patent: Page/Page column 57.

46
[ 773837-37-9 ]
[ 1104027-41-9 ]
[ 7584-05-6 ]
[ 20970-75-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; at 50℃;	[00304] A round bottom flask was charged with N-ethoxy-3-methylpyridinium iodide (74.00 g,536 mmol), potassium carbonate (148.00 g, 1072 mmol) and water (350 mL). To this was slowly added a solution of sodium cyanide (49.9 g, 1018 mmol) in water (200 mL) over a period of 30 min. The resultant reaction mixture was heated to 50 0C for 2 hours. After completion of the reaction (TLC), the reaction mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 28.5 g of the <n="58"/>product (mixture of 2- and 4- isomers) which was used in the next step without further purification. MS:[M+H]+= 1 19

References: [1]Patent: WO2009/11904,2009,A1 .Location in patent: Page/Page column 56-57.

47
[ 7584-05-6 ]
[ 4637-24-5 ]
[ 601514-61-8 ]

Yield	Reaction Conditions	Operation in experiment
54.4%	In N,N-dimethyl-formamide;Reflux;	Preparation of (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile; [00150] To a solution of <strong>[7584-05-6]3-methylisonicotinonitrile</strong> (10 g, 85 mmol) in DMF (100 mL) was added l,l-dimethoxy-N,N-dimethylmethanamine (18.05 mL, 135 mmol). The mixture was heated to reflux overnight. The mixture was cooled to rt and an additional 3.0 mL of l,l-dimethoxy-N,N-dimethylmethanamine was added to the mixture, and it was again heated to reflux. After heating the mixture overnight, it was cooled to rt and an additional 3.0 mL of l,l-dimethoxy-N,N-dimethylmethanamine was added to the mixture. The mixture was heated overnight at reflux. The mixture was cooled to rt and an additional 3.0 mL of 1 , 1 -dimethoxy-N,N- dimethylmethanamine were added. The mixture was again heated to reflux. After heating the mixture overnight, it was cooled to rt. To the mixture was added 3.0 mL of l,l-dimethoxy-N,N-dimethylmethanamine. The mixture was heated to reflux overnight. The mixture was cooled to rt and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and was loaded onto a BIOTAGE 65 + M cartridge and was purified using a 10-70% EtOAc in hexanes gradient. The expected product, (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (7.97 g, 46.0 mmol, 54.4 % yield), was isolated as a bright-yellow solid. LC/MS: m/z 174.11 (M+H)+ , 1.690 min (method 1). 1H NMR (500 MHz, chloroform-^) I ppm 1H NMR (500 MHz, chloroform-^ I ppm 8.69 (s, 1 H) 8.14 (d, J= 5.19 Hz, 1 H) 7.23 (d, J= 4.88 Hz, 1 H) 7.15 (d, J= 13.43 Hz, 1 H) 5.21 (d, J= 13.73 Hz, 1 H) 2.95 (s, 6 H)
20%	In N,N-dimethyl-formamide;Reflux;	To a solution of <strong>[7584-05-6]3-methylisonicotinonitrile</strong> (26, 168 mg, 1.4 mmol)in DMF (3 mL) was added 1,1-dimethoxyl-N,N-dimethylmethanamine(400 muL, 2.8 mmol). The mixture was heated to reflux overnight. Thenthe mixture was cooled to RT and additional 200 muL of 1,1-dimethoxyl-N,N-dimethylmethanamine was added to the mixture. The mixture washeated to reflux overnight. Then repeated addition of 200 muL 1,1-dimethoxyl-N,N-dimethylmethanamine to the mixture. The mixture washeated to reflux overnight. After completion of the reaction, the mixturewas cooled to RT and concentrated in vacuo to give a brown oil,the residue was purified by flash column chromatography on silica(EtOAc/Petroleum ether 1:2) to yield the yellow solid (20%). 1H NMR(400 MHz, CDCl3) delta 8.69 (s, 1H), 8.14-8.11 (m, 1H), 7.25-7.23 (m,1H), 7.16 (d, J=13.6 Hz, 1H), 5.21 (d, J=13.6 Hz, 1H), 2.95 (s, 6H).
	In N,N-dimethyl-formamide; for 18h;Reflux;	Step B: To a solution of <strong>[7584-05-6]4-cyano-3-methylpyridine</strong> 1 (123 g, 1.0 mol) inN,N-dimethylformamide (800 mL) is added N,N-dimethylformamide dimethyl acetal (800 mL). The mixture is heated at reflux for 18 h. After cooling and concentration in <n="31"/>vacuo, the residue is dissolved in dichloromethane (400 rnL) and precipitated with n- pentane. Filtration and washing with n-pentane, followed by drying under high vacuum, yielded 3-[(E)-2-(dimehtylamino)ethenyl]-4-cyanopyridine 2 as a light-green solid: 1H NMR (400 MHz, CDCl3) delta = 8.69 (s, IH), 8.13 (d, J = 6.8 Hz, IH), 7.23 (dd, J = 6.8, 1.0 Hz, IH), 7.16 (d, J = 17.6 Hz, IH), 5.21 (d, J = 17.6 Hz, IH), 2.96 (s, 6H).

References: [1]Patent: WO2009/158396,2009,A1 .Location in patent: Page/Page column 82-83.
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3559 - 3572.
[3]Patent: WO2009/105717,2009,A1 .Location in patent: Page/Page column 29-30.

48
[ 1003-73-2 ]
[ 773837-37-9 ]
[ 7584-05-6 ]

Yield	Reaction Conditions	Operation in experiment
		Step A: To a solution of 3-methylpyridine-N-oxide (240 g, 2.2 mol) in dichloromethane (4 L) is added ethyl iodide (530 mL, 6.6 mol). The mixture is stirred at reflux overnight. Then the suspension is cooled. The resulting precipitate is collected by filtration and washed with diethyl ether (500 mL) to give a white solid. The solid is dissolved in water (2.4 L) and warmed to 500C. A solution of sodium cyanide (200 g, 4 mol) in water (600 mL) is slowly added over 1 h, keeping the internal temperature below 600C. The reaction mixture is stirred at 55C for another 1 h. The reaction mixture is extracted with diethyl ether (3 x 1.5 L). The combined extracts are dried over MgSO4 and concentrated to yield 4-cyano-3-methylpyridine 1 as a brown oil: 1H NMR (400 MHz, CDCl3) delta = 8.66 (s, IH), 8.58 (dd, J = 6.8, 1.0 Hz, IH), 7.46 (d, J= 6.8 Hz, IH), 2.54 (s, 3H).

References: [1]Patent: WO2009/105717,2009,A1 .Location in patent: Page/Page column 29.

49
[ 1003-73-2 ]
potassium cyanide [ No CAS ]
[ 7584-05-6 ]

Yield	Reaction Conditions	Operation in experiment
49%		Preparation 62 3-Methylisonicotinonitrile To a solution of 3-methylpyridine 1-oxide (10,59g, 0.1 mol) in ACN (22ml) was added iodoethane (17.5m1, 0.22mol) dropwise and the mixture stirred at r.t. for 2h. The solid formed was filtered off, redissolved in water (48ml) and warm up to 55C. At this temperature KCN (12.3g, 0.1 9mol) in water (32ml) was added dropwise over 3.5h. Then the reaction mixture was stirred at this temperature for 2h and at r.t. overnight. The desired product was extracted with ether, washed with brine and concentrated. The solid obtained was recrystallized in diisopropyl ether. Yield=49% LRMS: m/z 119 (M+1)+ Retention time: 3.77 min (Method B)

References: [1]Patent: EP2202232,2010,A1 .Location in patent: Page/Page column 50.
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 5400 - 5421.
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7367 - 7372.

50
[ 7584-05-6 ]
[ 22926-86-9 ]

Yield	Reaction Conditions	Operation in experiment
47%	With hydroxylamine hydrochloride; potassium hydrogencarbonate; In tetrahydrofuran; water; at -25 - 20℃;	-(3-methylpyridin-4-yl)-5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)- 1,2,4-oxadiazoleHydroxylamine hydrochloride (23.53g, 339 mmol) was dissolved in water (120ml) and potassium bicarbonate (33.9g, 3339 mmol) was added cautiously. The mixture was stirred slowly until complete solution. The mixture was added to a solution of 3-methyl isonicotinonitrile (2g, 16.9 mmol) in THF (30 mL) at -25 0C (ice methanol bath) and the reaction was stirred at room temperature for 16h. The reaction mixture was extracted with EtOAc (3XlOOmL) and the combined organic phases were washed with brine (80ml). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography using hexanes/EtOAc (1 :1) to yield 7V-hydroxyimidamide in 47% yield (1.2 g).

References: [1]Patent: WO2009/151529,2009,A1 .Location in patent: Page/Page column 156.

51
[ 7584-05-6 ]
[ 116986-14-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2h;Reflux;	3-Methylisonicotinonitrile (123, 590 mg, 5.0 mmol), NBS (1.2 g, 7.0 mmol) and AIBN (50 mg, 0.3 mmol) were diluted with carbon tetrachloride (20 mL); and the mixture was heated at reflux for 2 h. The reaction mixture was concentrated to one-half its original volume, filtered, and the filtrate was evaporated to dryness under reduced pressure.

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 262 - 266.
[2]Patent: US2014/18360,2014,A1 .Location in patent: Paragraph 0155.

52
[ 7584-05-6 ]
[ 1201445-66-0 ]

References: [1]Patent: WO2009/151529,2009,A1 .

53
[ 7584-05-6 ]
[ 1360557-69-2 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1682 - 1697.
[2]Patent: US2014/18360,2014,A1 .

54
[ 7584-05-6 ]
[ 1360557-71-6 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1682 - 1697.
[2]Patent: US2014/18360,2014,A1 .

55
[ 7584-05-6 ]
[ 1360557-73-8 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1682 - 1697.
[2]Patent: US2014/18360,2014,A1 .

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Technical Information

• Blaise Reaction • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Hydride Reductions • Preparation of Aldehydes and Ketones • Preparation of Amines • Ritter Reaction • Thorpe-Ziegler Reaction

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CAS No.: 7584-05-6

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