1211537-09-5|5-Bromo-3-fluoro-1H-indazole| Ambeed

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Quality Control of [ 1211537-09-5 ] Purity: 98% SDS Specification

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Product Details of [ 1211537-09-5 ]

CAS No. :	1211537-09-5
Formula :	C₇H₄BrFN₂
M.W :	215.02
SMILES Code :	FC1=NNC2=C1C=C(Br)C=C2
MDL No. :	MFCD23381339
InChI Key :	YGAXEFQRZVEQAZ-UHFFFAOYSA-N
Pubchem ID :	66793399

Safety of [ 1211537-09-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 1211537-09-5 ]

* 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 [ 1211537-09-5 ]

[ 1211537-09-5 ] Synthesis Path-Downstream 1~35

1
[ 110-87-2 ]
[ 1211537-09-5 ]
[ 1365889-96-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 1h;	Step-2: Synthesis of 5-bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole Into a 2-L 3-necked round-bottom flask was placed <strong>[1211537-09-5]5-bromo-3-fluoro-1H-indazole</strong> (70 g, 325.55 mmol, 1.00 equiv), DCM (700 mL), and TsOH (5.6 g, 32.52 mmol, 0.10 equiv). This was followed by the drop-wise addition of DHP (82.4 g, 979.55 mmol, 3.01 equiv) while stirring at 0 C. The resulting solution was stirred at 0 C. until completion. The reaction was monitored by LCMS. The resulting mixture was washed with 2*500 mL of H2O, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:100-10:90). The collected fractions were combined and concentrated under vacuum to deliver the title compound in 96.3 g (99%) as yellow oil. 1H NMR (300 MHz, DMSO-d6) delta 8.02 (d, J=1.8 Hz, 1H), 7.78-7.74 (m, 1H), 7.67-7.63 (m, 1H), 5.88-5.71 (m, 1H), 3.95-3.79 (m, 1H), 3.75-3.71 (m, 1H), 2.31-2.13 (m, 1H), 2.11-1.86 (m, 2H), 1.74-1.70 (m, 1H), 1.58-1.50 (m, 2H). LCMS: 299 [M+H]+.
99%	With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 1h;	Into a 2-L 3-necked round-bottom flask was placed <strong>[1211537-09-5]5-bromo-3-fluoro-1H-indazole</strong> (70 g, 325.55 mmol, 1.00 equiv), DCM (700 mL), and TsOH (5.6 g, 32.52 mmol, 0.10 equiv). This was followed by the drop-wise addition of DHP (82.4 g, 979.55mmol, 3.01 equiv) while stirring at 0oC. The resulting solution was stirred at 0oC until completion. The reaction was monitored by LCMS. The resulting mixture was washed with 2x500 mL of H2O, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:100-10:90). The collected fractions were combined and concentrated under vacuum to deliver the title compound in 96.3 g (99%) as yellow oil.1H NMR (300 MHz, DMSO-d6) delta 8.02 (d, J = 1.8 Hz, 1H), 7.78-7.74 (m, 1H), 7.67-7.63 (m, 1H), 5.88-5.71 (m, 1H), 3.95-3.79 (m, 1H), 3.75-3.71 (m, 1H), 2.31-2.13 (m, 1H), 2.11-1.86 (m, 2H), 1.74-1.70 (m, 1H), 1.58-1.50 (m, 2H). LCMS: 299 [M+H]+.
60%	With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 12h;	10265] The reaction was carried out according to Scheme1, Step-i to give a crude product, which was purified over230-400 mesh silica column chromatography using 1% ethylacetate in n-hexane to afford the title compound of Ex. 2Step-2 (5 g, 60%) as a brown oil

60%	With toluene-4-sulfonic acid; In dichloromethane; at 23℃; for 12h;	General procedure: To a stuffed solution of 5-bromo- 1H-indazole (23.5 mmol) in dry dichloromethane (50 mL) at 23C was added dihydro pyran (9.9 g, 118 mmol) followed by addition of pyridinium p-toluene sulfonate (0.6 g, 2.4 mmol). The resulting mixture was stuffed at room 23C temperature for 16 h. Upon completion by TLC, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulphate and concentrated. The crude material was purified by column chromatography over 230-400 mesh silica using 4-5% ethyl acetate in hexane to afford5-bromo-i-(tetrahydro-2H-pyran-2-yl)-1H-indazole (20 mmol, 86%) as a pale yellow oil.
	With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 18h;	Step 2: 5-Bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole A mixture of <strong>[1211537-09-5]5-bromo-3-fluoro-1H-indazole</strong> (6.0 g, 27.9 mmol), PTSA (530.7 mg, 2.79 mmol) and DHP (3.05 g, 36.3 mmol) in dichloromethane (80 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane (370 mL) and washed with water (230 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:100 to 1:15) to afford the title compound as a yellow solid (6.2 g, yield 74.3%). 1H NMR (DMSO-d6, 400 MHz): delta 7.96 (s, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.76 (dd, 1H), 3.84-3.80 (m, 1H), 3.71-3.64 (m, 1H), 2.20-2.15 (m, 1H), 1.97-1.87 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.47 (m, 2H).
11 g	With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 18h;	A mixture of 5 -bromo-3 -fluoro- 1H-indazole (9.5 g, 44.2 mmol), p-toluenesulfonic acid (840 mg, 4.4 mmol), 3,4-dihydro-2H-pyran (4.83 g, 57.5 mmol), and dichloromethane (150 mL) was stirred at rt for 18 h, diluted with dichloromethane (200 mL), and then washed with water (150 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (1: 100-1 :50; ethyl acetate/petroleum ether) to give 11 g of 5-bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a yellow solid. 1H NMR (400 MHz, DMSO-d6): oe 7.96 (s, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.76 (dd, 1H), 3.84-3.80 (m, 1H), 3.71-3.64 (m, 1H), 2.20-2.15 (m, 1H), 1.97-1.87 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.47 (m, 2H).

References: [1]Patent: US2018/141913,2018,A1 .Location in patent: Paragraph 0226; 0227.
[2]Patent: WO2019/225552,2019,A1 .Location in patent: Paragraph 0059.
[3]Patent: US2016/347717,2016,A1 .Location in patent: Paragraph 0264; 0265.
[4]Patent: WO2018/97273,2018,A1 .Location in patent: Paragraph 0055; 0060.
[5]Patent: US2012/71535,2012,A1 .Location in patent: Page/Page column 59.
[6]Patent: WO2013/142266,2013,A1 .Location in patent: Paragraph 00485.

2
[ 53857-57-1 ]
[ 1211537-09-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With acetic acid; Selectfluor; In acetonitrile; at 80℃; for 12h;	Step-1: Synthesis of 5-bromo-3-fluoro-1H-indazole Into a 500-mL round-bottom flask was placed 5-bromo-1H-indazole (20 g, 101.51 mmol, 1.00 equiv), selectfluor (71.6 g, 2.00 equiv), AcOH (30 mL), and CH3CN (300 mL). The resulting solution was stirred at 80 C. in an oil bath until completion. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3*100 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). The collected fractions were combined and concentrated under vacuum to deliver the title compound in 11 g (50%) as a white solid. LCMS: 215.1 [M+H]+.
33%	With acetic acid; Selectfluor; In acetonitrile; at 80℃; for 16h;	Into a 5-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5-bromo-1H-indazole (200 g, 1.0204mol, 1.00 equiv), CH3CN (3.5L), acetic acid (120 mL), and selectfluoro (544 g, 1.5367mol, 1.51 equiv). The resulting solution was stirred at 80oC until completion. The reaction progress was monitored by LCMS. The resulting solution was diluted with 8 L of ethyl acetate and washed with 3x4000 mL of H2O. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:100-15:85). The collected fractions were combined and concentrated under vacuum to deliver the title compound in 72 g (33%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) delta 12.77 (s, 1H), 8.03-7.90 (m, 1H), 7.59-7.48 (m, 2H). LCMS: 215 [M+H]+.
9 g	With Selectfluor; In N,N-dimethyl acetamide; at 60℃; for 18h;Inert atmosphere;	Selectfluor (72 g, 203 mmol) was added to a solution of 5-bromo-lH-indazole (20.0 g, 102 mmol) and N,N-dimethylacetamide (500 mL) under N2. The mixture was heated at 60 C for 18 h, allowed to cool to rt, diluted with ethyl acetate ( 1.5 L), and washed with water (150 mL x The organic layer was dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (1 : 10; ethyl acetate :petroleum ether) to give 10.8 g of an impure product. Repurification by silica gel chromatography (1 :20; ethyl acetate:petroleum ether) gave 9 g of 5-bromo-3-fluoro-1H-indazole as a light yellow solid. 1H NMR (400 MHz; DMSO-d6): delta 12.77 (s 1H), 7.96 (s, 1H), 7.54 (d, IH), 7.48 (d, 1H).

References: [1]Patent: US2018/141913,2018,A1 .Location in patent: Paragraph 0194; 0195.
[2]Patent: WO2019/225552,2019,A1 .Location in patent: Paragraph 0058.
[3]Patent: US2012/71535,2012,A1 .
[4]Patent: WO2013/142266,2013,A1 .Location in patent: Paragraph 00484.
[5]Patent: US2016/347717,2016,A1 .
[6]Patent: WO2018/97273,2018,A1 .

3
5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]
[ 1211537-09-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid; Selectfluor; In acetonitrile; for 1h;Reflux;	10263] To a stirred solution of 5-bromo-i-(tetrahydro-2H- pyran-2-yl)-iH-indazole (10 g, 35.7 mmol, as prepared in Example 1, Step-i) in 100 mE of acetonitrile, were added acetic acid (4 mE) and selectfluor (25.2 g, 71.4 mmol) at room temperature. Reaction mixture was refluxed for 1 h. Upon completion by TEC, the reaction mixture was diluted with water (100 mE) and extracted with ethyl acetate (200 mE). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over 230-400 mesh silica column chromatography using 1% ethyl acetate in n-hexane to afford 5-bromo-3- fluoro-iH-indazole (6 g, 78%) as a brown oil
78%	With acetic acid; Selectfluor; In acetonitrile; for 1h;Reflux;	To a stirred solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10 g, 35.7 mmol, as prepared in Production Example la) in 100 mL of acetonitrile, were added acetic acid (4 mL) and selectfluor (25.2 g, 71.4 mmol) at room temperature. Reaction mixture was refluxed for 1 h. Upon completion by TLC, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over 230-400 mesh silica column chromatography using 1% ethyl acetate in n-hexane to afford 5-bromo-3-fluoro-1H-indazole (6 g, 78%) as a brown oil.
	With acetic acid; Selectfluor; In acetonitrile; for 2h;Reflux; Inert atmosphere;	Example 23; Preparation of 5-Bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate 39)Step 1: 5-Bromo-3-fluoro-1H-indazole A mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 35.7 mmol; Intermediate 1), acetic acid (4 mL), Selectfluor (25.3 g, 71.4 mmol), and acetonitrile (100 mL) was refluxed under N2 for 2 h. The reaction was allowed to cool to rt, diluted with ethyl acetate (420 mL), and then washed with water (270 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as yellow solids (6.0 g, yield 78.1%). 1H NMR (DMSO-d6, 400 MHz): delta 12.77 (s, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H).

References: [1]Patent: US2016/347717,2016,A1 .Location in patent: Paragraph 0262; 0263.
[2]Patent: WO2018/97273,2018,A1 .Location in patent: Paragraph 0059.
[3]Patent: US2012/71535,2012,A1 .Location in patent: Page/Page column 58-59.

4
[ 110-87-2 ]
[ 1211537-09-5 ]
[ 1365889-97-9 ]