179543-88-5|5-Hydrazinyl-2-methoxypyridine hydrochloride| Ambeed

Structure of 179543-88-5

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Quality Control of [ 179543-88-5 ] Purity: 97% SDS Specification

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Product Details of [ 179543-88-5 ]

CAS No. :	179543-88-5
Formula :	C₆H₁₀ClN₃O
M.W :	175.62
SMILES Code :	COC1=NC=C(NN)C=C1.[H]Cl
MDL No. :	MFCD23701461
InChI Key :	GNBNHMWUFAOTLY-UHFFFAOYSA-N
Pubchem ID :	23090203

Safety of [ 179543-88-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 179543-88-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	44.9
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	60.17 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.76
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.99
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.	0.24
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.15
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.57

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.31
Solubility	0.862 mg/ml ; 0.00491 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.	-2.64
Solubility	0.401 mg/ml ; 0.00228 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.82
Solubility	2.68 mg/ml ; 0.0152 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.	-6.12 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)	2.13

Application In Synthesis of [ 179543-88-5 ]

* 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 [ 179543-88-5 ]

[ 179543-88-5 ] Synthesis Path-Downstream 1~35

1
[ 160664-95-9 ]
[ 179543-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol;	[Referential Example 1] ;5-Hydrazino-2-methoxypyridine hydrochloride; [] A solution of sodium nitrite (3.795 g) in water (20 mL) was added dropwise to 5-amino-2-methoxypyridine (6.21 g) in concentrated hydrochloric acid (50 mL) over a period of 60 minutes with ice cooling, and the resultant mixture was stirred at a constant temperature for 30 minutes. Tin(II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 mL) was added dropwise to the reaction mixture at an internal temperature of about 10C for 30 minutes, followed by stirring for 2 hours at room temperature. Under cooling with ice, the reaction mixture was partitioned between sodium hydroxide (75 g) in water (300 mL) and diethyl ether. The aqueous layer was extracted with diethyl ether twice. Subsequently, the aqueous layer was saturated with sodium chloride, followed by extraction with diethyl ether. The organic layers were combined, and dried over sodium sulfate anhydrate, followed by filtration. 1M HCl in ethanol (50 mL) was added to the filtrate and the mixture was stirred. The solid that precipitated was collected by filtration, washed with diethyl ether, and dried, to thereby give the title compound (5.02 g, 57%).1H-NMR(400MHz,DMSO-d6)delta: 3.81(3H,s), 6.82(1H,d,J=8.8Hz), 7.57 (1H, dd, J=8.8,2.9Hz) , 7.97 (1H, d, J=2.9Hz) , 8.55-9.20 (1H, br) , 10.13-10.50(3H,br). MS(ESI)m/z: 140(M+H)+.

References: [1]Patent: EP1591443,2005,A1 .Location in patent: Page/Page column 24.

2
[ 179543-88-5 ]
[ 160664-95-9 ]

Yield	Reaction Conditions	Operation in experiment
60%		Referential Example 2];5-Hydrazino-2-methoxypyridine; [] Sodium nitrite (3.795 g) in water (20 mL) was added dropwise to 5-amino-2-methoxypyridine (6.207 g) in concentrated hydrochloric acid (50 mL) for 80 minutes with ice cooling, followed by stirring at a constant temperature for 30 minutes. Tin(II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 mL) was added dropwise to the reaction mixture at an internal temperature of about 10C for 60 minutes, followed by stirring at room temperature for 12.5 hours. Under cooling with ice, sodium hydroxide (54 g) in water (200 mL) and chloroform were added to the reaction mixture. After insoluble substances in the resultant mixture were removed by filtration, the mixture was partitioned. The aqueous layer was extracted with chloroform twice. The organic layers were combined, and dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, to thereby give the title compound as crystals (4.23 g, 60%) .1H-NMR (400MHz, CDCl3) delta: 3.50-3.68(2H,br), 3.88(3H,s), 4.86-5.03 (1H, br) , 6.66(1H,d,J=8.8Hz), 7.20 (1H, dd, J=8.8, 2.9Hz), 7.77 (1H, d, J=2.9Hz). MS(ESI)m/z: 140 (M+H)+.

References: [1]Patent: EP1591443,2005,A1 .Location in patent: Page/Page column 24.

3
[ 179543-88-5 ]
[ 741286-88-4 ]

Yield	Reaction Conditions	Operation in experiment
73%		Referential Example 44] ;5-(4-Methoxyphenyl)-1-(6-methoxy-3-pyridyl)pyrazole-3-carboxylic acid ethyl ester; [] 4-Methoxyacetophenone (300 mg) was dissolved in N,N-dimethylformamide (4 mL). 60% Sodium hydride (160 mg) was added to the resultant mixture at 0C, followed by stirring at room temperature for 0.5 hours. Under cooling with ice, diethyl oxalate (542 muL) was added to the reaction mixture, followed by stirring at room temperature for 14 hours. 5-Hydrazino-2-methoxypyridine hydrochloride (406 mg) obtained from Referential Example 1 was added to the reaction mixture, followed by stirring at 80C for 3 hours. The miture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine.Subsequently, the organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane - ethyl acetate), to thereby give the title compound as an oily substance (517 mg, 73%).1H-NMR(400MHz,CDCl3)delta: 1.42(3H,t,J=7.0Hz), 3.80(3H,s), 3.93(3H,s), 4.44(2H,q,J=7.0Hz), 6.73(1H,d,J=8.8Hz), 6.84(2H,d-like,J=8.8Hz), 6.97(1H,s), 7.13(2H,d-like,J=8.8Hz), 7.56(1H,dd,J=8.8,2.7Hz), 8.10(1H,d,J=2.7Hz) MS(ESI)m/z: 354(M+H)+.

References: [1]Patent: EP1591443,2005,A1 .Location in patent: Page/Page column 43.

4
[ 179543-88-5 ]
[ 741286-41-9 ]
[ 741291-47-4 ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine; In ethanol; at 20℃; for 14h;Heating / reflux;	2) The title compound; 5-Hydrazino-2-methoxypyridine hydrochloride (0.380 g) obtained from Referential Example 1 and triethylamine (0.30 mL) were added to a solution of the above-obtained 4-(3-methylphenyl)-2,4-dioxobutanoic acid ethyl ester (1.014 g) dissolved in ethanol (20 mL) at room temperature. The resultant mixture was refluxed under heat for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure, and the residue was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane - ethyl acetate: 20%), to thereby give the title compound as an oily substance (0.451 g, 62%).1H-NMR (400MHz, CDCl3) delta: 1.42(3H,t,J=7.1Hz), 2.30(3H,s), 3.92(3H,s), 4.45(2H,q,J=7.1Hz), 6.68-6.76(1H,m), 6.92-7.25(4H,m), 7.02(1H,s), 7.53-7.61(1H,m), 8.08-8.15 (1H, m) . MS (FAB)m/z: 338(M+H)+.

References: [1]Patent: EP1591443,2005,A1 .Location in patent: Page/Page column 27.

5
[ 179543-88-5 ]
[ 905730-11-2 ]
[ 905730-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; for 3h;Heating / reflux;	2-Hydroxy-4-oxo-4-(4-trifluoromethoxy-phenyl)-but-2-enoic acid methyl ester 12a (7.5 g, 25.8 mmol) and (6-Methoxy-pyridin-3-yl)-hydrazine hydrochloride (5.43 g, 31.0 mmol) are dissolved in methanol (100 mL), and heated at reflux for 3 hours. The mixture is evaporated and purified by silica gel chromatography (0% to 40% ethyl acetate in hexanes) to give 13a (4.70 g, 11.9 mmol) as a white powder: 1H-NMR (400MHz, CDCl3) delta = 8.09 (d, J = 2.8 Hz, IH), 7.57 (dd, J = 2.8, 8.8 Hz, IH)5 7.27 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.06 (s, IH), 6.76 (d, J = 8.8 Hz, IH), 3.98 (s, 3H), 3.95 (s, 3H); MS calculated for Ci8Hi5F3N3O4 (M+H1") 394.1, found 394.1.

References: [1]Patent: WO2006/84176,2006,A2 .Location in patent: Page/Page column 26.

6
[ 6628-77-9 ]
[ 179543-88-5 ]

Yield	Reaction Conditions	Operation in experiment
57%		[Referential Example 1] 5-hydrazino-2-methoxypyridine hydrochloride; [Show Image] A solution of sodium nitrite (3.795 g) in water (20 ml) was added dropwise to a solution of 5-amino-2-methoxypyridine (6.21 g) in conc. hydrochloric acid (50 ml) over 60 minutes under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. A solution of tin (II) chloride dihydrate (39.5 g) in conc. hydrochloric acid (30 ml) was added dropwise to the reaction liquid at an inner temperature of about 10C over 30 minutes, and the mixture was stirred at room temperature for 2 hours. To the reaction liquid were added a solution of sodium hydroxide (75 g) in water (300 ml) and diethylether under ice cooling, and the phases were separated. The aqueous layer was extracted twice with diethylether, and after saturating the aqueous layer with sodium chloride, the aqueous layer was again extracted with diethylether. The organic layers were combined, and dried over anhydrous sodium sulfate. After filtration, 1M solution of hydrochloric acid in ethanol (50 ml) was added to the filtrate, and the mixture was stirred. The resulting solid precipitate was collected by filtration, washed with diethylether, and dried to give the title compound (5.02 g, 57%). 1H-NMR (400 MHz, DMSO-d6)delta: 3.81 (3H, s), 6.82 (1H, d, J = 8.8 Hz), 7.57 (1H, dd, J = 8.8, 2.9 Hz), 7.97 (1H, d, J = 2.9 Hz), 8.55-9.20 (1H, br), 10.13-10.50 (3H, br). MS (ESI)m/z: 140 (M+H)+.
57%		[Reference Example 1] 5-Hydrazino-2-methoxypyridine hydrochloride [Show Image] A solution of sodium nitrite (3.795 g) in water (20 mL) was added dropwise to a solution of 5-amino-2-methoxypyridine (6.21 g) in concentrated hydrochloric acid (50 mL) for 60 minutes under ice cooling, and the resultant mixture was stirred at the same temperature for 30 minutes. A solution of tin(II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 mL) was added dropwise to the reaction solution at an internal temperature of about 10C over 30 minutes, and then the resultant mixture was stirred for 2 hours at room temperature. A solution of sodium hydroxide (75 g) in water (300 mL) and diethyl ether were added to the reaction solution under ice cooling, to partition the reaction solution. The aqueous layer was extracted twice with diethyl ether. Further, the aqueous layer was saturated with sodium chloride and then extracted with diethyl ether. The organic layers were combined, and dried over anhydrous sodium sulfate. After separation by filtration, a 1 M hydrochloric acid-ethanol solution (50 mL) was added to the filtrate, and the mixture was stirred. The solid that had precipitated was collected by filtration, washed with diethyl ether, and dried, thus to obtain the title compound (5.02 g, 57%). 1H-NMR(400MHz, DMSO-d6)delta: 3.81(3H, s), 6.82(1H, d, J=8.8Hz), 7.57(1H, dd, J=8.8, 2.9Hz), 7.97(1H, d, J=2.9Hz), 8.55-9.20(1H, br), 10.13-10.50(3H, br). MS(ESI)m/z: 140(M+H)+.

References: [1]Journal of the American Chemical Society,2017,vol. 139,p. 14833 - 14836.
[2]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 19-20.
[3]Patent: EP1785418,2007,A1 .Location in patent: Page/Page column 24.
[4]Patent: EP1591443,2005,A1 .

7
[ 179543-88-5 ]
[ 62124-77-0 ]
[ 741288-62-0 ]

Yield	Reaction Conditions	Operation in experiment
45%		[Referential Example 22] 1-(6-Methoxy-3-pyridyl)-5-(2-pyrazinyl)-1H-pyrazole-3-carboxylic acid; [Show Image] [Show Image] A 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (11.0 ml) was added to a solution of 1-(2-pyrazinyl)-1-ethanone (1.22g) intetrahydrofuran (10ml) at-78C, and the mixture was stirred for 55 minutes. Diethyl oxalate (2.05 ml) was then added to the solution and the temperature of the mixture was gradually elevated to room temperature. After stirring the mixture for 6.5 hours, 1N aqueous hydrochloric acid (11 ml), water, and diethylether were added to the reaction liquid and the phases were separated. The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate, and the combined organic layers were evaporated under reduced pressure to give crude ethyl 4-(2-pyrazinyl)-2,4-dioxobutanoate (1.83 g, 82%) as a solid. To a suspension of this crude product (1.58 g) in ethanol (20 ml) was added a solution prepared by adding triethylamine (1.9 ml) to a suspension of the <strong>[179543-88-5]5-hydrazino-2-methoxypyridine hydrochloride</strong> (1.50 g) of Referential Example 1 in ethanol (80 ml), and the mixture was heated under reflux for 19 hours. Acetic acid (5 ml) was added to the reaction liquid, and the mixture was heated under reflux for 1.5 days. After cooling with air, ethyl acetate and saturated aqueous sodium bicarbonate was added to the reaction liquid and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give ethyl 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)-1H-pyrazole-3-carboxylate (1.05 g, 45%) as a solid. 1N aqueous sodium hydroxide (10.0 ml) was added to a solution of this ethyl 1H-pyrazole-3-carboxylate derivative (1.05g) in ethanol (30 ml) at room temperature for 16 hours. 1N aqueous hydrochloric acid (15 ml), water, and ethyl acetate were added to the reaction liquid and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the crude product of the title compound (0.883 g, 92%) as a solid. This crude product was used in the subsequent reaction without further purification.

References: [1]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 39.

8
[ 179543-88-5 ]
[ 741288-24-4 ]
[ 741288-25-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine; In ethanol; for 2h;Heating / reflux;Product distribution / selectivity;	3) Ethyl 5-(4-methyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-carboxylate; Triethylamine (3.4 ml) was added to a suspension of the ethyl 4-(4-methyl-2-pyridyl)-2,4-dioxobutanoate (3.82 g) and the <strong>[179543-88-5]5-hydrazino-2-methoxypyridine hydrochloride</strong> (5.1 g) of Referential Example 1 in ethanol (70 ml), and the mixture was heated under reflux for 2 hours. After cooling with air, water and chloroform were added to the reaction liquid and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the solid precipitate was washed with a mixed solvent of hexane and ethyl acetate (3:1) to give ethyl 5-(4-methyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-carb oxylate. The solvent of the washing solution was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give ethyl 5-(4-methyl-2-pyridyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-carboxylate. This product combined with the solid as described above yielded 1.20 g (26%). 1H-NMR (400 MHz, CDCl3)delta: 1.43 (3H, t, J = 7.08 Hz), 2.35 (3H, s), 3.94 (3H, s), 4.45 (2H, q, J = 7.08 Hz), 6.75 (1H, dd, J = 8.79, 0.61 Hz), 7.05 (1H, ddd, J = 5.13, 1.59, 0.73 Hz), 7.23 (1H, t, J = 0.73 Hz), 7.24 (1H, s), 7.67 (1H, dd, J = 2.81, 8.79Hz), 8.09 (1H, dd, J=2.81, 0.49 Hz), 8.35 (1H, d, J = 0.49, 5.13 Hz). ESI-MSm/z: 339 (M+H)+.

References: [1]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 44.

9
[ 741288-60-8 ]
[ 179543-88-5 ]
[ 741288-62-0 ]

Yield	Reaction Conditions	Operation in experiment
45%		[Reference Example 6] 1-(6-Methoxy-3-pyridyl)-5-(2-pyrazinyl)-1H-pyrazole-3-carboxylic acid [Show Image] [Show Image] Lithium bis(trimethylsilyl)amide (a 1.0 M solution in tetrahydrofuran, 11.0 mL) was added to a solution of 1-(2-pyrazinyl)-1-ethanone (1.22 g) in tetrahydrofuran (10 mL) under cooling to -78C, and the resultant mixture was stirred for 55 minutes. Diethyl oxalate (2.05 mL) was added thereto, and the mixture was slowly returned to room temperature, and stirred for 6.5 hours. An aqueous 1 N hydrochloric acid solution (11 mL), water and diethyl ether were added to the reaction solution, and the mixture was partitioned. Then, sodium chloride was added to the aqueous layer to be saturated, and then ethyl acetate was added for extraction. The organic layers were combined, and the solvent was evaporated under reduced pressure, to obtain a crude product of 4-(2-pyrazinyl)-2, 4-dioxobutanoic acid ethyl ester (1.83 g, 82%) as a solid. To a suspension of this crude product (1.58 g) in ethanol (20 mL), a solution formed from a suspension of <strong>[179543-88-5]5-hydrazino-2-methoxypyridine hydrochloride</strong> (1.50 g) of Reference Example 1 in ethanol (80 mL) conditioned with triethylamine (1.9 mL), was added, and the mixture was heated to reflux for 19 hours. Acetic acid (5 mL) was further added to the reaction solution, and the mixture was heated to reflux for 1.5 days. After air cooling, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 1-(6-methoxy-3-pyridyl)-5-(2-pyrazinyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1.05 g, 45%) as a solid. To a solution of this obtained 1H-pyrazole-3-carboxylic acid ethyl ester product (1.05 g) in ethanol (30 mL), an aqueous 1 N sodium hydroxide solution (10.0 mL) was added, and the mixture was stirred for 16 hours at room temperature. An aqueous 1 N hydrochloric acid solution (15 mL), water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, to obtain a crude product of the title compound (0.883 g, 92%) as a solid. This product was supplied to the subsequent reaction without being purified.

References: [1]Patent: EP1785418,2007,A1 .Location in patent: Page/Page column 28-29.

10
[ 179543-88-5 ]
[ 95-92-1 ]
[ 2124-31-4 ]
[ 858598-10-4 ]

Yield	Reaction Conditions	Operation in experiment
58%		[Referential Example 17] 5-(4-Dimethylaminophenyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-carboxylic acid; [Show Image] 1) Ethyl 5-(4-dimethylaminophenyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-carboxylate; To a solution of sodium ethoxide (1.36 g) in ethanol (50 ml) was added a solution of diethyl oxalate (2.72 ml) and 4'-dimethylaminoacetophenone (1.632 g) in ethanol (50 ml), and the mixture was heated under reflux for 16 hours. After cooling with air, <strong>[179543-88-5]5-hydrazino-2-methoxypyridine hydrochloride</strong> (2.102 g) of Referential Example 1 was added to the solution and the mixture was heated under reflux for 3 hours. After cooling with air, the reaction solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue and the phases were separated, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give ethyl 5-(4-dimethylaminophenyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-c arboxylate (2.134 g, 58%) as an oily product. 1H-NMR (400 MHz, CDCl3)delta: 1.42 (3H, t, J = 7.1 Hz), 2.97 (6H, s), 3.94 (3H, s), 4.45 (2H, q, J = 7.1 Hz), 6.62 (2H, d, J= 8.8 Hz), 6.73 (1H, d, J = 8.8 Hz), 6.94 (1H, s), 7.06 (2H, d, J = 8.8 Hz), 7.58 (1H, dd, J = 8.8, 2.7 Hz), 8.16 (1H, d, J = 2.7 Hz). ESI-MSm/z: 367 (M+H)+.

References: [1]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 35.

11
[ 179543-88-5 ]
[ 18992-80-8 ]
[ 95-92-1 ]
[ 858598-00-2 ]

Yield	Reaction Conditions	Operation in experiment
90%		[Referential Example 15] 5-(3-Dimethylaminophenyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-c arboxylic acid; [Show Image] 1) Ethyl 5-(3-dimethylaminophenyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-carboxylate; A solution of 1-(3-dimethylaminophenyl)-1-ethanone (1.63 g) in ethanol (20 ml) and diethyl oxalate (3.10 ml) were added to a solution of sodium ethoxide (1.63 g) in ethanol (20 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction liquid was added the <strong>[179543-88-5]5-hydrazino-2-methoxypyridine hydrochloride</strong> (2.52 g) of Referential Example 1, and the mixture was heated under reflux for 14.5hours. After cooling with air, the reaction solvent was evaporated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium bicarbonate, and the phases were separated, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give ethyl 5-(3-dimethylaminophenyl)-1-(6-methoxy-3-pyridyl)-1H-pyrazole-3-c arboxylate (3.30 g, 90%) as an oily product. 1H-NMR (400 MHz, CDCl3)delta: 1.43 (3H, t, J = 7.1 Hz), 2.87 (6H, s), 3.93 (3H, s), 4.46 (2H, q, J = 7.1 Hz), 6.50 (1H, d, J = 7.6 Hz), 6.54-6.55 (1H, m), 6.69 (1H, dd, J = 8.3, 2.4 Hz), 6.73 (1H, d, J = 8.8 Hz), 7.03 (1H, s), 7.16 (1H, dd, J = 8.1, 7.8 Hz), 7.59 (1H, dd, J = 8.8, 2.7 Hz), 8.15 (1H, d, J = 2.7 Hz). ESI-MSm/z: 367 (M+H)+.

References: [1]Patent: EP1698626,2006,A1 .Location in patent: Page/Page column 33.

12
[ 179543-88-5 ]
[ 86688-88-2 ]
[ 95-92-1 ]
[ 741288-81-3 ]

Yield	Reaction Conditions	Operation in experiment
72%		[Reference Example 5] 1-(6-Methoxy-3-pyridyl)-5-(1H-pyrrol-2-yl)pyrazole-3-carboxylic acid [Show Image] Diethyl oxalate (3.10 mL) and 1-[1-(phenylsulfonyl)-1H-pyrrol-2-yl]-1-ethanone (2.49 g) were added to a solution of sodium ethoxide (1.63 g) in ethanol (20 mL) under ice cooling, and the resultant mixture was stirred for 5 hours at room temperature. To this reaction solution, <strong>[179543-88-5]5-hydrazino-2-methoxypyridine hydrochloride</strong> (2.52 g) of Reference Example 1 and ethanol (20 mL) were added, and the mixture was heated to reflux for 14.5 hours. After air cooling, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to a residue obtained by evaporating the reaction solvent under reduced pressure, and the mixture was partitioned. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 1-(6-methoxy-3-pyridyl)-5-[1-(phenylsulfonyl)-1H-pyrrol-2-yl]pyrazole-3-carboxylic acid ethyl ester (3.28 g, 72%) as an oily product. To a solution of this ethyl ester product (3.28 g) in ethanol (22 mL), an aqueous 1 N sodium hydroxide solution (22 mL) was added, and the mixture was stirred for 2 days at room temperature. An aqueous 1 N hydrochloric acid solution was added to the reaction solution, and the precipitated solid was filtered, to obtain the title compound (1.40 g, 68%) as a solid. 1H-NMR(400MHz, DMSO-d6)delta: 3.94(3H, s), 5.49-5.51(1H, m), 5.98-6.00(1H, m), 6.87-6.89(1H, m), 6.98(1H, dd, J=8.8, 0.5Hz), 7.08(1H, s), 7.80(1H, dd, J=8.8, 2.7Hz), 8.25(1H, dd, J=2.7, 0.5Hz), 11.39(1H, br s). ESI-MSm/z: 285(M+H)+.

References: [1]Patent: EP1785418,2007,A1 .Location in patent: Page/Page column 28.

13
[ 179543-88-5 ]
[ 19718-92-4 ]
[ 1432472-65-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sulfuric acid; In water; for 2h;Reflux;	[0489] Scheme 3: synthesis of 2-(5-methoxy-lH-indol-3-yl)-N,N-dimethylethanamine (KD19) and 2-(5-methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylethanamine (KD20)[0490] A reported procedure was followed to prepare the compounds(i).

References: [1]Patent: WO2013/63492,2013,A1 .Location in patent: Paragraph 0489-0490.

14
[ 179543-88-5 ]
[ 1432473-11-4 ]

References: [1]Patent: WO2013/63492,2013,A1 .

15
[ 179543-88-5 ]
[ 1432472-68-8 ]

References: [1]Patent: WO2013/63492,2013,A1 .

16
[ 179543-88-5 ]
[ 1432472-69-9 ]

References: [1]Patent: WO2013/63492,2013,A1 .

17
[ 179543-88-5 ]
[ 32464-55-4 ]
[ 1432472-67-7 ]