541539-88-2|5-Methoxy-2-methyl-2H-indazole| Ambeed

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 541539-88-2 ] Purity: 95% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 541539-88-2 ]

CAS No. :	541539-88-2
Formula :	C₉H₁₀N₂O
M.W :	162.19
SMILES Code :	CN1N=C2C=CC(OC)=CC2=C1
MDL No. :	MFCD16620002
InChI Key :	RMHPLDTVLLYJAQ-UHFFFAOYSA-N
Pubchem ID :	11094954

Safety of [ 541539-88-2 ]

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

Computational Chemistry of [ 541539-88-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	9
Fraction Csp3	0.22
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	47.49
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	27.05 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.03
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	1.54
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.58
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.	1.16
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	1.4
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.54

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.3
Solubility	0.804 mg/ml ; 0.00496 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.	-1.72
Solubility	3.11 mg/ml ; 0.0192 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	-2.59
Solubility	0.417 mg/ml ; 0.00257 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.	-6.2 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)	1.51

Application In Synthesis of [ 541539-88-2 ]

* 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 [ 541539-88-2 ]

[ 541539-88-2 ] Synthesis Path-Downstream 1~14

1
[ 420-37-1 ]
[ 94444-96-9 ]
[ 541539-88-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	In ethyl acetate; at 20℃; for 3h;	To a solution of 5-methoxy-indazole (1.0 g, 6.7 mmol) in ethyl acetate (10 ml) was added BF40(CH3)3(1.3 g, 8.9 mmol). The solution was stirred at rt for 3 h. Sat. NaHC03aq. (10 ml) was added and extracted with ethyl acetate (20 ml). Organics were dried over Na2S04, concentrated, and purified by flash chromatography on silica gel (PE /EA = 2/1) to afford 0.64 g (59%) of the title compound as a yellow solid. [M+H] Calc'd for C9H10N2O, 163; Found, 163.
	In ethyl acetate; at 20℃; for 2h;	2-methyl-4-methoxyphenylamine (27.4 g, 200 mmol) was added to a solution of tetrafluoroboric acid (HBF4, 50% aqueous solution, 100 mL). The solution was stirred at room temperature for about 10 min, then cooled to 0~5C. A solution of sodium nitrite (13.9 g, 200 mmol) in water (20 mL) was dropped in. The mixture was warmed to room temperature and stirred 1 h. The reaction mixture was filtrated and the crude product was washed with diethyl ether (3 x 100 mL) and dried in air to provided 49.7 g of 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate. 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate (49.7 g, 21 1 mmol), 18-crown-6 (2.79 g, 10.6 mmol), potassium acetate (43.4 g, 422 mmol) were added to chloroform (300 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was washed with brine (3 x 30 mL), dried over sodium sulphate, and the solvents evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/petroleum ether 2:8 to 4:6) to provide 5-methoxy- lH-indazole (10.2 g). LC-MS (ESI) M+lfound= 149 (MWcalc= 148.1) To a stirred mixture of 5-methoxy-lH-indazole (9.5 g, 64.6 mmol) in ethyl acetate (200 mL), was added trimethyloxonium tetrafluoroborate (19.1 g, 129 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated NaHCO3 solution (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the solvents evaporated. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 2:3) gave 5-methoxy-2-methyl-2H-indazole (8.6 g). LC-MS (ESI) M+lfound= 163 (MWca,c= 162.1).To a mixture of 5-methoxy-2-methyl-2H-indazole (8.2 g, 50.6 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (9.01 g, 50.6 mmol). The mixture was stirred at room temperature for 4 h. The reaction was quenched with ethyl acetate (200 mL) and washed with saturated NaHCO3 aqueous solution until stopped bubbling. The organic layer was separated and washed with brine, then dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 1 :9) gave 3-bromo-5-methoxy- 2-methyl-2H-indazole (8.23 g). LC-MS (ESI) Mfound= 241 (MWcalc= 241.1) 3-Bromo-5-methoxy-2-methyl-2H-indazole (7.9 g, 32.7 mmol) was dissolved in dimethylacetamide (200 mL), and the following reagents were added: Pd2(dba)3 (1.2 g, 1.3 mmol, 4 mol%), Dppf (1.4 g, 2.6 mmol, 8 mol%), Zn powder (513 mg, 7.8 mmol, 24 mol%) and Zn(CN)2 (4.6 g, 39.2 mmol). The mixture was stirred at 170C for 6 h. The reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were dried over sodium sulphate and concentrated in vacuum. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 2:8) to give 5-methoxy-2-methyl-2H-indazole-3-carbonitrile as a white solid (5.9 g).5-Methoxy-2-methyl-2H-indazole-3-carbonitrile (4.67 g, 25 mmol) was dissolved in methanol (60 mL) and an aqueous solution of sodium hydroxide (10%, 60 mL) was added. The reaction mixture was refluxed for 4 h. Methanol was evaporated in vacuum. The residue was acidified to pH=4~5 EPO <DP n="72"/>and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried and evaporated to provide 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (4.3 g) as a white powder.To a dichloromethane (400 mL) solution of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid (4.3 g, 20.6 mmol) were added methy lam ine (hydrochloride salt, 2.8 g, 41.3 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (5.6 g, 41.3 mmol), 3-ethyl-l-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (11.9 g, 62 mmol) and triethylamine (17 mL, 124 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with diluted hydrochloric acid and brine, dried and evaporated to provide 5-methoxy-2-methyl-2H- indazole-3-carboxylic acid methylamide (3.03 g). LC-MS (ESI) Mfound= 219 (MWcalc= 219.2) To a solution of 5-methoxy-2-methyl-2H-indazole-3-carboxylic acid methylamide (2.9 g, 13.1 mmol) in dry dichloromethane (150 mL), Boron trifluoride-methyl sulfide complex (IM, 35 mL) was dropped in at O0C and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, the water phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were washed with brine, dried over sodium sulphate, and concentrated under vacuum to provide 5-hydroxy-2-methyl-2H-indazole-3- carboxylic acid methylamide (2.7 g). Yield from 2-methyl-4-methoxyphenylamine: 10%To a soluti...

References: [1]Journal of Organic Chemistry,2003,vol. 68,p. 4093 - 4095.
[2]Patent: WO2016/44138,2016,A1 .Location in patent: Paragraph 00116.
[3]Patent: WO2007/3419,2007,A1 .Location in patent: Page/Page column 69-72.

2
[ 557-21-1 ]
[ 541539-88-2 ]
[ 918946-36-8 ]

Yield	Reaction Conditions	Operation in experiment
		2-methyl-4-methoxyphenylamine (27.4 g, 200 mmol) was added to a solution of tetrafluoroboric acid (HBF4, 50% aqueous solution, 100 mL). The solution was stirred at room temperature for about 10 min, then cooled to 0~5C. A solution of sodium nitrite (13.9 g, 200 mmol) in water (20 mL) was dropped in. The mixture was warmed to room temperature and stirred 1 h. The reaction mixture was filtrated and the crude product was washed with diethyl ether (3 x 100 mL) and dried in air to provided 49.7 g of 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate. 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate (49.7 g, 21 1 mmol), 18-crown-6 (2.79 g, 10.6 mmol), potassium acetate (43.4 g, 422 mmol) were added to chloroform (300 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was washed with brine (3 x 30 mL), dried over sodium sulphate, and the solvents evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/petroleum ether 2:8 to 4:6) to provide 5-methoxy- lH-indazole (10.2 g). LC-MS (ESI) M+lfound= 149 (MWcalc= 148.1) To a stirred mixture of 5-methoxy-lH-indazole (9.5 g, 64.6 mmol) in ethyl acetate (200 mL), was added trimethyloxonium tetrafluoroborate (19.1 g, 129 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated NaHCO3 solution (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the solvents evaporated. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 2:3) gave <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong> (8.6 g). LC-MS (ESI) M+lfound= 163 (MWca,c= 162.1).To a mixture of <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong> (8.2 g, 50.6 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (9.01 g, 50.6 mmol). The mixture was stirred at room temperature for 4 h. The reaction was quenched with ethyl acetate (200 mL) and washed with saturated NaHCO3 aqueous solution until stopped bubbling. The organic layer was separated and washed with brine, then dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 1 :9) gave 3-bromo-5-methoxy- 2-methyl-2H-indazole (8.23 g). LC-MS (ESI) Mfound= 241 (MWcalc= 241.1) 3-Bromo-<strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong> (7.9 g, 32.7 mmol) was dissolved in dimethylacetamide (200 mL), and the following reagents were added: Pd2(dba)3 (1.2 g, 1.3 mmol, 4 mol%), Dppf (1.4 g, 2.6 mmol, 8 mol%), Zn powder (513 mg, 7.8 mmol, 24 mol%) and Zn(CN)2 (4.6 g, 39.2 mmol). The mixture was stirred at 170C for 6 h. The reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were dried over sodium sulphate and concentrated in vacuum. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 2:8) to give <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carbonitrile as a white solid (5.9 g).5-Methoxy-2-methyl-2H-indazole-3-carbonitrile (4.67 g, 25 mmol) was dissolved in methanol (60 mL) and an aqueous solution of sodium hydroxide (10%, 60 mL) was added. The reaction mixture was refluxed for 4 h. Methanol was evaporated in vacuum. The residue was acidified to pH=4~5 EPO <DP n="72"/>and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried and evaporated to provide <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carboxylic acid (4.3 g) as a white powder.To a dichloromethane (400 mL) solution of <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carboxylic acid (4.3 g, 20.6 mmol) were added methy lam ine (hydrochloride salt, 2.8 g, 41.3 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (5.6 g, 41.3 mmol), 3-ethyl-l-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (11.9 g, 62 mmol) and triethylamine (17 mL, 124 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with diluted hydrochloric acid and brine, dried and evaporated to provide 5-methoxy-2-methyl-2H- indazole-3-carboxylic acid methylamide (3.03 g). LC-MS (ESI) Mfound= 219 (MWcalc= 219.2) To a solution of <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carboxylic acid methylamide (2.9 g, 13.1 mmol) in dry dichloromethane (150 mL), Boron trifluoride-methyl sulfide complex (IM, 35 mL) was dropped in at O0C and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, the water phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were washed with brine, dried over sodium sulphate, and concentrated under vacuum to provide 5-hydroxy-2-methyl-2H-indazole-3- carboxylic acid methylamide (2.7 g). Yield from 2-methyl-4-methoxyphenylamine: 10%To a soluti...

References: [1]Patent: WO2007/3419,2007,A1 .Location in patent: Page/Page column 69-72.

3
[ 541539-88-2 ]
[ 918946-35-7 ]

Yield	Reaction Conditions	Operation in experiment
		2-methyl-4-methoxyphenylamine (27.4 g, 200 mmol) was added to a solution of tetrafluoroboric acid (HBF4, 50% aqueous solution, 100 mL). The solution was stirred at room temperature for about 10 min, then cooled to 0~5C. A solution of sodium nitrite (13.9 g, 200 mmol) in water (20 mL) was dropped in. The mixture was warmed to room temperature and stirred 1 h. The reaction mixture was filtrated and the crude product was washed with diethyl ether (3 x 100 mL) and dried in air to provided 49.7 g of 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate. 2-methyl-4-methoxyphenyldiazonium tetrafluoroborate (49.7 g, 21 1 mmol), 18-crown-6 (2.79 g, 10.6 mmol), potassium acetate (43.4 g, 422 mmol) were added to chloroform (300 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was washed with brine (3 x 30 mL), dried over sodium sulphate, and the solvents evaporated under vacuum. The residue was purified by flash chromatography (ethyl acetate/petroleum ether 2:8 to 4:6) to provide 5-methoxy- lH-indazole (10.2 g). LC-MS (ESI) M+lfound= 149 (MWcalc= 148.1) To a stirred mixture of 5-methoxy-lH-indazole (9.5 g, 64.6 mmol) in ethyl acetate (200 mL), was added trimethyloxonium tetrafluoroborate (19.1 g, 129 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated NaHCO3 solution (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the solvents evaporated. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 2:3) gave <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong> (8.6 g). LC-MS (ESI) M+lfound= 163 (MWca,c= 162.1).To a mixture of <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong> (8.2 g, 50.6 mmol) in acetic acid (100 mL) was added N-bromosuccinimide (9.01 g, 50.6 mmol). The mixture was stirred at room temperature for 4 h. The reaction was quenched with ethyl acetate (200 mL) and washed with saturated NaHCO3 aqueous solution until stopped bubbling. The organic layer was separated and washed with brine, then dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. Purification of the residue by flash chromatography (ethyl acetate/petroleum ether 1 :9) gave 3-bromo-5-methoxy- 2-methyl-2H-indazole (8.23 g). LC-MS (ESI) Mfound= 241 (MWcalc= 241.1) 3-Bromo-<strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong> (7.9 g, 32.7 mmol) was dissolved in dimethylacetamide (200 mL), and the following reagents were added: Pd2(dba)3 (1.2 g, 1.3 mmol, 4 mol%), Dppf (1.4 g, 2.6 mmol, 8 mol%), Zn powder (513 mg, 7.8 mmol, 24 mol%) and Zn(CN)2 (4.6 g, 39.2 mmol). The mixture was stirred at 170C for 6 h. The reaction mixture was quenched with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were dried over sodium sulphate and concentrated in vacuum. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 2:8) to give <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carbonitrile as a white solid (5.9 g).5-Methoxy-2-methyl-2H-indazole-3-carbonitrile (4.67 g, 25 mmol) was dissolved in methanol (60 mL) and an aqueous solution of sodium hydroxide (10%, 60 mL) was added. The reaction mixture was refluxed for 4 h. Methanol was evaporated in vacuum. The residue was acidified to pH=4~5 EPO <DP n="72"/>and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried and evaporated to provide <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carboxylic acid (4.3 g) as a white powder.To a dichloromethane (400 mL) solution of <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carboxylic acid (4.3 g, 20.6 mmol) were added methy lam ine (hydrochloride salt, 2.8 g, 41.3 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (5.6 g, 41.3 mmol), 3-ethyl-l-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (11.9 g, 62 mmol) and triethylamine (17 mL, 124 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with diluted hydrochloric acid and brine, dried and evaporated to provide 5-methoxy-2-methyl-2H- indazole-3-carboxylic acid methylamide (3.03 g). LC-MS (ESI) Mfound= 219 (MWcalc= 219.2) To a solution of <strong>[541539-88-2]5-methoxy-2-methyl-2H-indazole</strong>-3-carboxylic acid methylamide (2.9 g, 13.1 mmol) in dry dichloromethane (150 mL), Boron trifluoride-methyl sulfide complex (IM, 35 mL) was dropped in at O0C and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water, the water phase was extracted with dichloromethane (3 x 50 mL), and the combined organic phases were washed with brine, dried over sodium sulphate, and concentrated under vacuum to provide 5-hydroxy-2-methyl-2H-indazole-3- carboxylic acid methylamide (2.7 g). Yield from 2-methyl-4-methoxyphenylamine: 10%To a soluti...

References: [1]Patent: WO2007/3419,2007,A1 .Location in patent: Page/Page column 69-72.

4
[ 94444-96-9 ]
[ 2533-69-9 ]
[ 541539-88-2 ]