3998-88-7|Ethyl 2-chloro-6-methylisonicotinate| Ambeed

Structure of 3998-88-7

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Quality Control of [ 3998-88-7 ] Purity: 98% SDS Specification

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Product Details of [ 3998-88-7 ]

CAS No. :	3998-88-7
Formula :	C₉H₁₀ClNO₂
M.W :	199.63
SMILES Code :	O=C(OCC)C1=CC(C)=NC(Cl)=C1
MDL No. :	MFCD09842151
InChI Key :	UMAAIDIASQFLTF-UHFFFAOYSA-N
Pubchem ID :	22625009

Safety of [ 3998-88-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 3998-88-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	50.3
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.43
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	2.43
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.22
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.	1.55
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.64
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.25

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.75
Solubility	0.353 mg/ml ; 0.00177 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.9
Solubility	0.254 mg/ml ; 0.00127 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.51
Solubility	0.0611 mg/ml ; 0.000306 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	Yes
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.	-5.79 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	1.0 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)	1.98

Application In Synthesis of [ 3998-88-7 ]

* 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.

Downstream synthetic route of [ 3998-88-7 ]

[ 3998-88-7 ] Synthesis Path-Downstream 1~35

2
[ 25462-85-5 ]
[ 64-17-5 ]
[ 3998-88-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sulfuric acid; at 0 - 80℃;	Step 1: Ethyl 2-chloro-6-methylisonicotinate (97). To a stirred solution of 96 (7.0 g, 40.79 mmol) in ethanol (70 mL) was added conc H2SO4 (2 mL) at 0 C. dropwise followed by heating at 80 C. for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and washed with water, sodium bicarbonate solution and sat. NaCl. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford 97 (7 g, 86%) as a white solid.
		a) A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 equivalent) in EtOH (200 ml.) and a few drops of concentrated sulfuric acid is stirred at 75C for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 ml.) and washed with a solution of sat. aq. NaHCO3 (70 ml.) and water (2x70 ml_). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR = 0.92 min, [M+1]+ = 200.17.
		A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 eq.) in ethanol (200 mL) and a few drops of concentrated sulfuric acid is stirred at 75C for24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 mL) and washed with a solution of sat. aq. NaHCO3 (70 mL) and water (2x70 mL). <n="40"/>The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6- methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR = 0.92 min, [M+1]+ = 200.17; A solution of 2-chloro-6-methyl-isonicotinic acid (15.5 g, 90.3 mmol) in ethanol (200 mL) and H2SO4 (0.5 mL) is stirred at 75C for 24 h. The solvent is evaporated and the residue is dissolved in EA (200 mL). The solution is washed with sat. aq. NaHCO3-solution (70 mL) and water (70 mL), dried over MgSO4, filtered, concentrated and dried under HV to give 2-chloro-6-methyl-isonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR = 0.92 min; [M+1]+ = 200.17.

		A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 equivalent) in EtOH (200 mL) and a few drops of concentrated sulfuric acid is stirred at 75 C. for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 mL) and washed with a solution of sat. aq. NaHCO3 (70 mL) and water (2×70 mL). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR=0.92 min, [M+1]+=200.17.
		a) To a solution of 2-chloro-6-methylisonicotinic acid (50 g, 291.4 mmol) in ethanol (750 mL), a few drops of concentrated sulfuric acid are added and the mixture is stirred at 75 C. for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (300 mL) and washed with a solution of sat. aq. NaHCO3 (100 mL) followed with brine (2*70 mL). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (54.9 g) as a white solid after recrystallization from heptane; LC-MS: tR=0.92 min, [M+1]+=200.17.
		a) Concentrated H2SO4 (1.16 mL, 21.6 mmol) is added dropwise to a suspension of 2-chloro-6-methylpyridine-4-carboxylic acid (11.58 g, 67.49 mmol) in ethanol (100 mL). The reaction mixture is then stirred at 70 C. for 24 h. Sat. NaHCO3 is added slowly to reach pH 8 and the aq. solution is extracted with EA three times. The org. extracts are collected, dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylpyridine-4-carboxylic acid ethyl ester (11.81 g) as an off white solid; LC-MS: tR=0.91 min, [M+H]+=199.93.
	With sulfuric acid; In ethanol; at 75℃; for 24h;Product distribution / selectivity;	a) A solution of 2-chloro-6-methylisonicotinic acid (15.5 g, 90.3 mmol, 1 eq.) in ethanol (200 mL) and a few drops of concentrated sulfuric acid is stirred at 75 C. for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (200 mL) and washed with a solution of sat. aq. NaHCO3 (70 mL) and water (2*70 mL). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6-methylisonicotinic acid ethyl ester (16.3 g) as a pink powder; LC-MS: tR=0.92 min, [M+1]+=200.17.
		To a solution of 2-chloro-6-methylisonicotinic acid (50 g, 291.4 mmol) in ethanol (750 ml_), a few drops of concentrated sulfuric acid are added and the mixture is stirred at 75C for 24 h. The solvent is evaporated and the residue is dissolved in ethyl acetate (300 ml.) and washed with a solution of sat. aq. NaHCO3 (100 ml.) followed with brine (2x70 ml_). The org. extract is dried over MgSO4, filtered and evaporated to give 2-chloro-6- methylisonicotinic acid ethyl ester (54.9 g) as a white solid after recrystallization from heptane; LC-MS: tR = 0.92 min, [M+1]+ = 200.17.

References: [1]Patent: US2010/249071,2010,A1 .Location in patent: Page/Page column 63-64.
[2]Patent: WO2008/29371,2008,A1 .Location in patent: Page/Page column 41.
[3]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 38-39; 49.
[4]Patent: US2010/63108,2010,A1 .Location in patent: Page/Page column 16.
[5]Patent: US2011/46170,2011,A1 .Location in patent: Page/Page column 17.
[6]Patent: US2011/46170,2011,A1 .Location in patent: Page/Page column 18.
[7]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 14.
[8]Patent: WO2009/109907,2009,A1 .Location in patent: Page/Page column 42.

3
[ 6336-44-3 ]
[ 3998-88-7 ]
[ 1122089-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 15h;	b) To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (2.0 g, 10.0 mmol), and trans-propenyl boronic acid (1.30 g, 15.13 mmol) in DME (20 mL), a solution of 2 M aq.K2CO3 (3 mL) followed by Pd(PPh3)4 (150 mg, 0.205 mmol) and PPh3 (265 mg, 0.99 mmol) is added. The mixture is stirred at 1000C for 15 h before it is cooled to rt, diluted with ether and washed with sat. aq. Na2CO3 (2x30 mL). The org. extract is dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-propenyl-6-methylisonicotinic acid ethyl ester (2.25 g) as a colourless oil; LC- MS: tR =0.65 min, [M+1]+ = 206.33.
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In 1,2-dimethoxyethane; water; at 100℃; for 15h;	To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (2.0 g, 10.0 mmol), and trans-propenyl boronic acid (1.30 g, 15.13 mmol) in DME (20 ml_), a solution of 2 M aq. K2CO3 (3 ml_) followed by Pd(PPh3)4 (150 mg, 0.205 mmol) and triphenylphosphine (265 mg, 0.99 mmol) is added. The mixture is stirred at 100C for 15 h before it is cooled to rt, diluted with diethyl ether and washed with sat. aq. Na2CO3 (2x30 ml_). The org. extract is dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-propenyl-6-methylisonicotinic acid ethyl ester (2.25 g) as a colourless oil; LC-MS: tR =0.65 min, [M+1]+ = 206.33.
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In 1,2-dimethoxyethane; water; at 100℃; for 15h;	To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (2.0 g, 10.0 mmol), and trans-propenyl boronic acid (1.30 g, 15.13 mmol) in DME (20 mL), a solution of 2 M aq. K2CO3 (3 mL) followed by Pd(PPh3)4 (150 mg, 0.205 mmol) and PPh3 (265 mg, 0.99 mmol) is added. The mixture is stirred at 100 C. for 15 h before it is cooled to rt, diluted with ether and washed with sat. aq. Na2CO3 (2×30 mL). The org. extract is dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-propenyl-6-methylisonicotinic acid ethyl ester (2.25 g) as a colourless oil; LC-MS: tR=0.65 min, [M+1]+=206.33.

With potassium carbonate; triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 15h;

b) To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (2.0 g, 10.0 mmol), and trans-propenyl boronic acid (1.30 g, 15.13 mmol) in DME (20 mL), a solution of 2 M aq. K2CO3 (3 mL) followed by Pd(PPh3)4 (150 mg, 0.205 mmol) and triphenylphosphine (265 mg, 0.99 mmol) is added. The mixture is stirred at 100 C. for 15 h before it is cooled to rt, diluted with diethyl ether and washed with sat. aq. Na2CO3 (2*30 mL). The org. extract is dried over Na2SO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-propenyl-6-methylisonicotinic acid ethyl ester (2.25 g) as a colourless oil; LC-MS: tR=0.65 min, [M+1]+=206.33.

References: [1]Patent: WO2008/29371,2008,A1 .Location in patent: Page/Page column 35; 41.
[2]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 39.
[3]Patent: US2010/63108,2010,A1 .Location in patent: Page/Page column 16.
[4]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 14.

4
[ 1177015-14-3 ]
[ 3998-88-7 ]
[ 1011263-95-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 20h;	a) To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (9.92 g, 49.7 mmol), 2,4,6- tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (13.0 g, 49.7 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968- 4971 ), and PPh3 (1.39 g, 8.60 mmol) in DME (120 ml_), a solution of 2 M aq. K2CO3 (40 ml.) is added. The mixture is degassed and flushed with N2 before Pd(PPh3)4 (580 mg, 0.793 mmol) is added. The mixture is stirred at 1000C for 20 h before it is cooled to rt, diluted with EA and washed with sat. aq. NaHCO3 (2x200 ml_). The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 15:1 to give 2-methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g) as a yellow oil; LC-MS: tR = 0.44 min, 1H NMR (CDCI3): delta 1.43 (m, 3 H), 1.98 (s, 3 H), 2.09 (s, 3 H), 2.63 (s, 3 H), 4.34-4.46 (m, 2 H), 6.39 (s, 1 H), 7.50 (s, 1 H), 7.56 (s, 1 H).
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In 1,2-dimethoxyethane; water; at 100℃; for 20h;	To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (9.92 g, 49.7 mmol), 2,4,6-tris-(2-methyl-propenyl)-cycloboroxane pyridine complex (13.0 g, 49.7 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971 ), and triphenylphosphine (1.39 g, 8.60 mmol) in DME (120 ml_), a solution of 2 M aq. K2CO3 (40 ml_) is added. The mixture is degassed and flushed with N2 before Pd(PPh3)4 (580 mg, 0.793 mmol) is added. The mixture is stirred at 100C for 20 h before it is cooled to rt, diluted with EA and washed with sat. aq. NaHCOs (2x200 ml_). The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 15:1 to give 2-methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g) as a yellow oil; LC-MS: tR = 0.44 min; 1H NMR (CDCI3): delta 1.43 (m, 3 H), 1.98 (s, 3 H), 2.09 (s, 3 H), 2.63 (s, 3 H), 4.34-4.46 (m, 2 H), 6.39 (s, 1 H), 7.50 (s, 1 H), 7.56 (s, 1 H).
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In 1,2-dimethoxyethane; water; at 100℃; for 20h;	To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (9.92 g, 49.7 mmol), 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (13.0 g, 49.7 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971), and PPh3 (1.39 g, 8.60 mmol) in DME (120 mL), a solution of 2 M aq. K2CO3 (40 mL) is added. The mixture is degassed and flushed with N2 before Pd(PPh3)4 (580 mg, 0.793 mmol) is added. The mixture is stirred at 100 C. for 20 h before it is cooled to rt, diluted with EA and washed with sat. aq. NaHCO3 (2×200 mL). The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 15:1 to give 2-methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g) as a yellow oil; LC-MS: tR=0.44 min, 1H NMR (CDCl3): delta 1.43 (m, 3H), 1.98 (s, 3H), 2.09 (s, 3H), 2.63 (s, 3H), 4.34-4.46 (m, 2H), 6.39 (s, 1H), 7.50 (s, 1H), 7.56 (s, 1H).

With potassium carbonate; triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 100℃; for 20h;Inert atmosphere;

a) To a solution of <strong>[3998-88-7]2-chloro-6-methylisonicotinic acid ethyl ester</strong> (9.92 g, 49.7 mmol), 2,4,6-tris-(2-methyl-propenyl)-cycloboroxane pyridine complex (13.0 g, 49.7 mmol, prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea J. Org. Chem. 67 (2002) 4968-4971), and triphenylphosphine (1.39 g, 8.60 mmol) in DME (120 mL), a solution of 2 M aq. K2CO3 (40 mL) is added. The mixture is degassed and flushed with N2 before Pd(PPh3)4 (580 mg, 0.793 mmol) is added. The mixture is stirred at 100 C. for 20 h before it is cooled to rt, diluted with EA and washed with sat. aq. NaHCO3 (2*200 mL). The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 15:1 to give 2-methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g) as a yellow oil; LC-MS: tR=0.44 min; 1H NMR (CDCl3): delta 1.43 (m, 3H), 1.98 (s, 3H), 2.09 (s, 3H), 2.63 (s, 3H), 4.34-4.46 (m, 2H), 6.39 (s, 1H), 7.50 (s, 1H), 7.56 (s, 1H).

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 110 - 130.
[2]Patent: WO2008/29371,2008,A1 .Location in patent: Page/Page column 35; 42.
[3]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 40.
[4]Patent: US2010/63108,2010,A1 .Location in patent: Page/Page column 17.
[5]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 15.

5
[ 3998-88-7 ]
C₉H₁₇NO₂*ClH [ No CAS ]

References: [1]Patent: EP1221441,2002,A2 .Location in patent: Page 197.

6
[ 3998-88-7 ]
[ 152815-18-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With acetic acid; In tetrahydrofuran;	Lithium aluminium hydride (350 mg, 9.26 mmol) was added in portions to a solution of <strong>[3998-88-7]ethyl 2-chloro-6-methyl-4-pyridinecarboxylate</strong> (1.85 g, 9.26 mmol) in THF (40 ml) cooled at 0 C. The mixture was stirred for 15 minutes at 0 C. and acetic acid (2 ml) was added. The mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 5 % aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (35/65) to give 2-chloro-4-hydroxymethyl-6-methylpyridine (1.28 g, 88%). 1 H NMR Spectrum: (CDCl3) 1.92(t, 1H); 2.53(s, 3H); 4.70(d, 2H); 7.06(s, 1H); 7.16(s, 1H) MS - ESI: 157 [MH]+ Elemental Analysis: Found C 53.1 H 5.3 N 8.7 C7 H8 NOCl Requires C 53.3 H 5.1 N 8.9%

References: [1]Patent: US5962458,1999,A .
[2]Patent: US6362336,2002,B1 .Location in patent: Example 43.

7
[ 25462-85-5 ]
[ 3998-88-7 ]

References: [1]Patent: US6362336,2002,B1 .Location in patent: Example 43.

8
[ 25462-85-5 ]
[ 7664-93-9 ]
[ 3998-88-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	In ethanol; dichloromethane;	The starting material was prepared as follows: A solution of 2-chloro-6-methyl-4-pyridinecarboxylic acid (2 g, 12 mmol) in ethanol (100 ml) and concentrated sulphuric acid (10 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methylene chloride. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (1/9) to give ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (2 g, 86%). 1 H NMR Spectrum: (CDCl3) 1.41(t, 3H); 2.6(s, 3H); 4.40(q, 2H); 7.63(s, 1H); 7.69(s, 1H) MS - ESI: 200 [MH]+ Elemental Analysis: Found C 54.4 H 5.3 N 7.0 C9 H10 NO2 Cl Requires C 54.1 H 5.0 N 7.0%

References: [1]Patent: US5962458,1999,A .

9
[ 3998-88-7 ]
1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-pyridin-4-yl)pyrazolo[3,4-d]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		EXAMPLE 117 1-Cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one Following a procedure substantially similar to that described in Example 16, part c, but substituting <strong>[3998-88-7]ethyl 2-chloro-6-methyl-4-pyridinecarboxylate</strong> for 6-carboethoxy-imidazo[1,2-a]pyridine there was obtained 1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid in 73% yield, m.p. 277-278 C. when recrystallized from DMF.

References: [1]Patent: US5294612,1994,A .

10
[ 3998-88-7 ]
[ 75-31-0 ]
[ 1122089-69-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 85℃; for 20h;Sealed tube; Inert atmosphere;	Step 1: Ethyl 2-(isopropylamino)-6-methylisonicotinate (9). Ethyl 2-chloro-6- methylpyridine-4-carboxylate 8 (550 mg, 2.75 mmol), Pd(OAc)2 (28 mg, 0.13 mmol), BINAP (156 mg, 0.25 mmol), Cs2C03 (2.4 g, 7.5 mmol) and 1,4-dioxane (25 mL) were combined in a sealed tube. N2 was bubbled into the mixture for a few minutes and isopropylamine (885 mg, 15 mmol) was added. The sealed mixture was heated to 85 C for 20 h. The mixture was filtered through Celite and washed with EtOAc. The solvents were removed in vacuo. Purification by flash column chromatography gave 9 (530 mg, 86%).
86%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 85℃; for 20h;Sealed tube; Inert atmosphere;	Ethyl 2-chloro-6- methylpyridine-4-carboxylate 8 (550 mg, 2.75 mmol), Pd(OAc)2 (28 mg, 0.13 mmol), BINAP (156 mg, 0.25 mmol), Cs2C03 (2.4 g, 7.5 mmol) and 1 ,4-dioxane (25 mL) were combined in a sealed tube. N2 was bubbled into the mixture for a few minutes and isopropylamine (885 mg, 15 mmol) was added. The sealed mixture was heated to 85 C for 20 h. The mixture was filtered through Celite and washed with EtOAc. The solvents were removed in vacuo. Purification by flash column chromatography gave 9 (530 mg, 86%).
21%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 14h;Inert atmosphere; Sealed tube;	Step 2: Ethyl 2-(isopropylamino)-6-methylisonicotinate (98). To a stirred solution of ester 97 (5.0 g, 25.1 mmol) in dry dioxane (100 mL), Cs2CO3 (24.5 g, 75.3 mmol) and isopropylamine (12.6 mL, 8.8 g, 150.01 mmol) was added. The mixture was degassed and kept under nitrogen atmosphere and Xantphos (4.36 g, 7.53 mmol) and Pd(II) acetate (1.12 g, 5.02 mmol) were added. The reaction mixture was stirred in a sealed vessel at 85 C. for 14 h. The reaction mixture was cooled to room temperature, filtered and concentrated. The crude compound was purified by column chromatography to give ester 98 (1.2 g, 21%).

	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 18h;sealed vessel;	To a solution of <strong>[3998-88-7]2-chloro-6-methyl-isonicotinic acid ethyl ester</strong> (5.20 g, 26.0 mmol) in dioxane (200 mL), CS2CO3 (25.5 g, 78.1 mmol) and isopropylamine (9.24 g, 156.3 mmol) is added. The mixture is degassed and put under N2 before <n="51"/>Xantphos (5.43 g, 9.38 mmol) and Pd(II) acetate (1.17 g, 5.26 mmol) are added. The mixture is stirred in a sealed vessel at 85C for 18 h. The mixture is cooled to rt, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 2-isopropylamino-6-methyl-isonicotinic acid ethyl ester (3.91 g) as an orange solid; LC-MS: tR = 0.67 min; [IVM]+ = 223.10.
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 85℃; for 18h;Inert atmosphere; Sealed;	b) To a solution of <strong>[3998-88-7]2-chloro-6-methyl-isonicotinic acid ethyl ester</strong> (5.20 g, 26.0 mmol) in dioxane (200 mL), Cs2CO3 (25.5 g, 78.1 mmol) and isopropylamine (9.24 g, 156.3 mmol) is added. The mixture is degassed and put under N2 before Xantphos (5.43 g, 9.38 mmol) and Pd(II) acetate (1.17 g, 5.26 mmol) are added. The mixture is stirred in a sealed vessel at 85 C. for 18 h. The mixture is cooled to rt, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 2-isopropylamino-6-methyl-isonicotinic acid ethyl ester (3.91 g) as an orange solid; LC-MS: tR=0.67 min; [M+1]+=223.10.

References: [1]Patent: WO2017/4608,2017,A1 .Location in patent: Paragraph 0123.
[2]Patent: WO2017/4609,2017,A1 .Location in patent: Paragraph 0119.
[3]Patent: US2010/249071,2010,A1 .Location in patent: Page/Page column 63-64.
[4]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 49-50.
[5]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 18.

11
[ 3998-88-7 ]
[ 1193489-24-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2215 - 2219.

12
[ 3998-88-7 ]
[ 124-40-3 ]
C₁₁H₁₆N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;palladium diacetate; In tetrahydrofuran; at 110℃;Inert atmosphere;	Under argon, a solution of 2-chloro-6-methylpyridine-4-carboxylic acid ethyl ester (3.42 g 16.74 mmol), Na tert.-butylate (1.77 g, 18.4 mmol), Xantphos (967 mg, 1.67 mmol) and Pd(OAc)2 (376 mg, 1.67 mmol) in 2 M dimethylamine in THF (20 ml.) is stirred at 1 10C for 18 h. Another 10 ml. of 2 M dimethylamine in THF is added and the mixture is stirred for another 24 h. The dark reaction mixture is cooled to rt, diluted with 6 N aq. HCI and extracted with diethyl ether (4 times). The org. extracts are concentrated, the residue is dissolved in 6 N aq. HCI and heated to 1000C for 18 h. The orange suspension is concentrated, dissolved in 1 N aq. NaOH and concentrated again. The residue is dissolved in 1 N aq. NaOH and methanol and separated by MPLC on RP-Ci8 silica gel to give 2- dimethylamino-6-methyl-isonicotinic acid (0.871 g) as a beige solid; LC-MS: tR = 0.44 min, [M+H]+ = 181.07.

References: [1]Patent: WO2009/109907,2009,A1 .Location in patent: Page/Page column 44.

13
[ 3998-88-7 ]
2,4,6-trivinylcyclotriboroxane*pyridine complex [ No CAS ]
[ 1186513-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 15h;	To a solution of <strong>[3998-88-7]2-chloro-6-methyl-isonicotinic acid ethyl ester</strong> (15 g, 75.1 mmol) in DME (100 mL), vinylboroxine (18.1 g, 75.1 mmol) is added, followed by 2M aq. K2CO3 (15 mL), Pd(PPh3)4 (750 mg, 0.65 mmol), and PPh3 (1.0 g, 6.17 mmol). The mixture is stirred at 1000C for 15 h before it is cooled to rt, diluted with diethyl ether (300 mL) and washed with 1 N aq. NaOH and brine. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 6-methyl-2- vinylisonicotinic acid ethyl ester (10.1 g) as a yellow oil; LC-MS: tR =0.67 min, [M+1]+ = 192.07.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 110 - 130.
[2]Patent: WO2009/109907,2009,A1 .Location in patent: Page/Page column 42.

14
[ 3998-88-7 ]
[ 226917-15-3 ]

References: [1]Patent: WO2009/109907,2009,A1 .

15
[ 3998-88-7 ]
[ 124-40-3 ]
[ 226917-15-3 ]

Yield	Reaction Conditions	Operation in experiment
		b) Under argon, a solution of 2-chloro-6-methylpyridine-4-carboxylic acid ethyl ester (3.42 g 16.74 mmol), Na tert.-butylate (1.77 g, 18.4 mmol), Xantphos (967 mg, 1.67 mmol) and Pd(OAc)2 (376 mg, 1.67 mmol) in 2 M dimethylamine in THF (20 mL) is stirred at 110 C. for 18 h. Another 10 mL of 2 M dimethylamine in THF is added and the mixture is stirred for another 24 h. The dark reaction mixture is cooled to rt, diluted with 6 N aq. HCl and extracted with diethyl ether (4 times). The org. extracts are concentrated, the residue is dissolved in 6 N aq. HCl and heated to 100 C. for 18 h. The orange suspension is concentrated, dissolved in 1 N aq. NaOH and concentrated again. The residue is dissolved in 1 N aq. NaOH and methanol and separated by MPLC on RP-C18 silica gel to give 2-dimethylamino-6-methyl-isonicotinic acid (0.871 g) as a beige solid; LC-MS: tR=0.44 min, [M+H]+=181.07.

References: [1]Patent: US2011/46170,2011,A1 .Location in patent: Page/Page column 18.

16
[ 3998-88-7 ]
[ 1122091-59-1 ]

References: [1]Patent: US2011/46170,2011,A1 .

17
[ 92988-08-4 ]
[ 3998-88-7 ]
[ 1186513-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In 1,2-dimethoxyethane; water; at 100℃; for 15h;	b) To a solution of <strong>[3998-88-7]2-chloro-6-methyl-isonicotinic acid ethyl ester</strong> (15 g, 75.1 mmol) in DME (100 mL), vinylboroxine (18.1 g, 75.1 mmol) is added, followed by 2M aq. K2CO3 (15 mL), Pd(PPh3)4 (750 mg, 0.65 mmol), and PPh3 (1.0 g, 6.17 mmol). The mixture is stirred at 100 C. for 15 h before it is cooled to rt, diluted with diethyl ether (300 mL) and washed with 1N aq. NaOH and brine. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluding with heptane:EA 4:1 to give 6-methyl-2-vinylisonicotinic acid ethyl ester (10.1 g) as a yellow oil; LC-MS: tR=0.67 min, [M+1]+=192.07.

References: [1]Patent: US2011/46170,2011,A1 .Location in patent: Page/Page column 17.

18
[ 3998-88-7 ]
[ 1011263-91-4 ]

References: [1]Patent: US2011/212998,2011,A1 .

19
[ 3998-88-7 ]
[ 1011263-93-6 ]

References: [1]Patent: US2011/212998,2011,A1 .

20
[ 3998-88-7 ]
[ 1122089-71-7 ]

References: [1]Patent: US2011/212998,2011,A1 .

21
[ 3998-88-7 ]
[ 1011264-12-2 ]