[ CAS No. 885588-14-7 ] {[proInfo.proName]}

Name: 885588-14-7|Methyl 2-bromo-5-fluoropyridine-4-carboxylate|98%
Brand: Ambeed
SKU: A204547
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Quality Control of [ 885588-14-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 885588-14-7 ]

Product Details of [ 885588-14-7 ]

CAS No. :	885588-14-7	MDL No. :	MFCD09951945
Formula :	C₇H₅BrFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HLTNRIWFYBDWKA-UHFFFAOYSA-N
M.W :	234.02	Pubchem ID :	46311206
Synonyms :

Safety of [ 885588-14-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 885588-14-7 ]

* 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.

Upstream synthesis route of [ 885588-14-7 ]
Downstream synthetic route of [ 885588-14-7 ]

[ 885588-14-7 ] Synthesis Path-Upstream 1~3

1
[ 67-56-1 ]
[ 885588-12-5 ]
[ 885588-14-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	at 0 - 20℃; for 16 h;	To a stirred solution of 2-bromo-5-fluoroisonicotinic acid (2.8 g, 12.78 mmol) in MeOH (30 ml), SOCI2 (7.54 g,63.9 mmol) was added at ooc and it was allowed to stir at rt for 16h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved in water (100 ml), basified to pH-8 using saturated NaHC03 solution, and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried overanhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (2.2 g, 73percent)as a pale yellow solid;LC-MS (method 8): Rt = 2.41 min; m/z = 234.07 (M+H+).

Reference： [1] Patent: WO2006/45514, 2006, A1, . Location in patent: Page/Page column 38
[2] Patent: WO2017/207813, 2017, A1, . Location in patent: Page/Page column 150

2
[ 885588-12-5 ]
[ 18107-18-1 ]
[ 885588-14-7 ]

Yield	Reaction Conditions	Operation in experiment
88.4%	for 1.5 h; Cooling	a) methyl 2-bromo-5-fluoroisonicotinate To a cooled solution of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) by chromatography on a 50 g Silicycle silica cartridge using a heptane/ethyl acetate 10-50percent gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4percent) as a light yellow solid. mp.: 43-6° C. MS: m/z=233.9 (M+H⁺).
88.4%	for 1.75 h; Cooling	To a cooled solution of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) bychromatography on a 50 g Silicycle silica cartridge using a heptane / ethyl acetate 10-50percent gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4percent) as a light yellow solid, mp.: 43 - 6°C. MS: m/z= 233.9 (M+H⁺).

Reference： [1] Patent: US2012/142665, 2012, A1, . Location in patent: Page/Page column 27-28
[2] Patent: WO2012/76430, 2012, A1, . Location in patent: Page/Page column 76-77

3
[ 885588-14-7 ]
[ 1380331-29-2 ]

Reference： [1] Patent: US2012/142665, 2012, A1,
[2] Patent: WO2012/76430, 2012, A1,

[ 885588-14-7 ] Synthesis Path-Downstream 1~81

1
[ 67-56-1 ]
[ 885588-12-5 ]
[ 885588-14-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With thionyl chloride;	Methyl 2-bromo-5-fluoroisonicotinate:; To a solution of <strong>[885588-12-5]2-bromo-5-fluoroisonicotinic acid</strong> (1.5 g, 6.82 mmol) in methanol (75 ml), thionyl dichloride (2.5 ml, 34.09 mmol) was added drop-wise. The reaction mixture was stirred overnight. The solvent was removed under high vacuum. The residual solid was distilled at 90 0C under vacuum to get 1.3g (81 %) of pure methyl 2-bromo-5- fluoroisonicotinate:
73%	With thionyl chloride; at 0 - 20℃; for 16.0h;	To a stirred solution of <strong>[885588-12-5]2-bromo-5-fluoroisonicotinic acid</strong> (2.8 g, 12.78 mmol) in MeOH (30 ml), SOCI2 (7.54 g,63.9 mmol) was added at ooc and it was allowed to stir at rt for 16h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved in water (100 ml), basified to pH-8 using saturated NaHC03 solution, and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried overanhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (2.2 g, 73%)as a pale yellow solid;LC-MS (method 8): Rt = 2.41 min; m/z = 234.07 (M+H+).
10.3 g	With thionyl chloride; In methanol; at 0 - 20℃; for 24.5h;	To a solution of 2-bromo-5-fluoro-pyridine-4-carboxylic acid (10.0 g, 45.5 mmol) in methanol (300 mL) cooled to 0C was added thionyl chloride (16.5 mL, 227.3 mmol) dropwise over 30 minutes. The reaction mixture was stirred at ambient temperature for 24 hours. Toluene (40 mL) was added to the reaction mixture. After evaporation of methanol, thionyl chloride was distilled out. The remaining toluene was evaporated on rotary evaporator affording the cmde product, which was dissolved in dichloromethane (30 mL) evaporated under reduced pressure affording methyl 2-bromo-5 -fluoropyridine-4-carboxylate (10.3 g). LCMS: MW (calcd): 232.9; MS (ES, m/z): 234, 236 (M+H).

Reference： [1]Patent: WO2006/45514,2006,A1 .Location in patent: Page/Page column 38
[2]Patent: WO2017/207813,2017,A1 .Location in patent: Page/Page column 150
[3]Patent: WO2019/12284,2019,A1 .Location in patent: Paragraph 0149

2
[ 885588-14-7 ]
[ 1380330-05-1 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

3
[ 885588-14-7 ]
[ 1380331-29-2 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

4
[ 885588-14-7 ]
[ 1380331-31-6 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

5
[ 885588-14-7 ]
[ 1380331-32-7 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

6
[ 885588-14-7 ]
[ 1380331-33-8 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

7
[ 885588-14-7 ]
[ 1380331-34-9 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

8
[ 885588-14-7 ]
[ 1380331-35-0 ]

Reference： [1]Patent: US2012/142665,2012,A1
[2]Patent: WO2012/76430,2012,A1

9
[ 885588-12-5 ]
[ 18107-18-1 ]
[ 885588-14-7 ]

Yield	Reaction Conditions	Operation in experiment
88.4%	In methanol; benzene; for 1.5h;Cooling;	a) methyl 2-bromo-5-fluoroisonicotinate To a cooled solution of <strong>[885588-12-5]2-bromo-5-fluoroisonicotinic acid</strong> (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) by chromatography on a 50 g Silicycle silica cartridge using a heptane/ethyl acetate 10-50% gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4%) as a light yellow solid. mp.: 43-6 C. MS: m/z=233.9 (M+H+).
88.4%	In methanol; benzene; for 1.75h;Cooling;	To a cooled solution of <strong>[885588-12-5]2-bromo-5-fluoroisonicotinic acid</strong> (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) bychromatography on a 50 g Silicycle silica cartridge using a heptane / ethyl acetate 10-50% gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4%) as a light yellow solid, mp.: 43 - 6C. MS: m/z= 233.9 (M+H+).
10.46 g	In methanol; diethyl ether; toluene; at 0 - 20℃; for 2.5h;	To a solution of 2-bromo-5-fluoro-pyridine-4-carboxylic acid (10.0 g, 45.5 mmol) in methanol (35 mL) and toluene (65 mL) cooled to 0C was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether; 45.5 mL, 90.9 mmol) dropwise over 30 minutes. The reaction mixture was stirred at ambient temperature. After 2h, the reaction mixture was evaporated under reduced pressure affording the cmde product, which was dissolved in ethyl acetate (50 mL), washed with water (100 mL) and brine (50 mL) respectively, filtered through phase separator filter and evaporated under reduced pressureaffording methyl 2-bromo-5-fluoro-pyridine-4-carboxylate (10.46g). LCMS: MW (calcd): 232.9; MS (ES, m/z): 234, 236 (M+H).

In methanol; hexane; toluene; at 20℃; for 1.0h;

2-Bromo-5-fluoroisonicotinic acid(1.1 g) was mixed in toluene (15 mL) and methanol (5 mL).To this mixture was added 2M trimethylsilyldiazomethane / hexane solution at room temperature.The reaction mixture was stirred at room temperature for 1 hour.By concentrating the reaction mixture under reduced pressure,The title compound (1.17 g) was obtained as a crude product.

Reference： [1]Patent: US2012/142665,2012,A1 .Location in patent: Page/Page column 27-28
[2]Patent: WO2012/76430,2012,A1 .Location in patent: Page/Page column 76-77
[3]Patent: WO2019/12284,2019,A1 .Location in patent: Paragraph 0150
[4]Patent: JP2019/131544,2019,A .Location in patent: Paragraph 0450-0453

10
[ 885588-14-7 ]
[ 4248-19-5 ]
[ 1380331-28-1 ]

Yield	Reaction Conditions	Operation in experiment
56%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In 1,4-dioxane; at 100℃; for 6.0h;Inert atmosphere;	A mixture of <strong>[885588-14-7]methyl 2-bromo-5-fluoropyridine-4-carboxylate</strong> (6.64 g, 28.4 mmol), tert- Butyl carbamate (4.0 g, 34.1 mmol), cesium carbonate (13.0 g, 39.8 mmol), X-phos (657 mg, 1.1 mmol) and Pd(dba)2 (520 mg, 0.9 mmol) in 1,4-dioxane (100 mL) was purged with nitrogen and then stirred at 100 C under nitrogen for 6 h. The mixture was cooled to RT, diluted with water (100 mL), and extracted with EA (150 mL x 2). The combined organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed, eluting with 0- 30% EA in hexane to give methyl 2-((tert-butoxycarbonyl)amino)-5-fluoropyridine-4- carboxylate as a white solid (4.5 g, 56%). MS (ESI+) m/z 271.1 (M+H)+, retention time: 1.81 min. (Method A). 1H NMR (400 MHz, CDCl3) δ 1.52 (s, 9H), 3.96 (s, 3H), 8.24 (s, 1H), 8.40 (d, 1H), 9.00 (s, 1H).
56%	With caesium carbonate; bis(dibenzylideneacetone)-palladium(0); XPhos; In 1,4-dioxane; at 100℃; for 6.0h;Inert atmosphere;	A mixture of <strong>[885588-14-7]methyl 2-bromo-5-fluoropyridine-4-carboxylate</strong> (6.64 g, 28.4 mmol), tert-Butyl carbamate (4.0 g, 34.1 mmol), cesium carbonate (13.0 g, 39.8 mmol), X-phos (657 mg, 1.1 mmol) and Pd(dba)2 (520 mg, 0.9 mmol) in 1,4-dioxane (100 mL) was purged with nitrogen and then stirred at 100 C under nitrogen for 6 h. The mixture was cooled to RT, diluted with water (100 mL), and extracted with EA (150 mL x 2). The combined organic phase was washed with brine, dried over MgS04, and concentrated. The residue was chromatographed, eluting with 0-30% EA in hexane to give methyl 2-((tert-butoxycarbonyl) amino)-5-fluoropyridine-4-carboxylate as a white solid (4.5 g, 56%). MS (ESI+) m/z 271.1 (M+H)+, retention time: 1.81 min. (Method A). 'H NMR (400 MHz, CDCl3) d 1.52 (s, 9H), 3.96 (s, 3H), 8.24 (s, 1H), 8.40 (d, 1H), 9.00 (s, 1H).
55.7%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 5.5h;Inert atmosphere;	b) methyl 2-(tert-butoxycarbonylamino)-5-fluoroisonicotinate To an nitrogen purged suspension of <strong>[885588-14-7]methyl 2-bromo-5-fluoroisonicotinate</strong> (2.8 g, 12 mmol) in dioxane (55 ml) is added successively tert-butyl carbamate (1.68 g, 14.4 mmol), tris(dibenzylidene-acetone)dipalladium(0) (219 mg, 239 umol), 4,5-bis(diphenylphos-phino)-9,9-dimethylxanthene (277 mg, 479 mmol) and cesium carbonate (5.46 g, 16.8 mmol). The mixture is then stirred for 5.5 hrs at 100 C. under nitrogen atmosphere. After 5 min at 100 C. the redbrown suspension has turned green. The mixture is diluted with ethyl acetate, washed twice with water, once with brine, dried with magnesium sulfate and the solvent is removed in vacuo. The product is isolated by chromatography of the residue (3.85 g) on a 70 g Silicycle silica cartridge using a heptane/ethyl acetate 10-40% gradient affording methyl 2-(tert-butoxycarbonylamino)-5-fluoroisonicotinate (1.8 g, 55.7%) as a light yellow solid. MS: m/z=271.2 (M+H+).

55.7%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 5.5h;Inert atmosphere;	To an nitrogen purged suspension of <strong>[885588-14-7]methyl 2-bromo-5-fluoroisonicotinate</strong> (2.8 g, 12 mmol) in dioxane (55 ml) is added successively tert-butyl carbamate (1.68 g, 14.4 mmol),tris(dibenzylidene-acetone)dipalladium(0) (219 mg, 239 umol), 4,5-bis(diphenylphos-phino)-9,9- dimethylxanthene (277 mg, 479 ummol) and cesium carbonate (5.46 g, 16.8 mmol). The mixture is then stirred for 5.5 hrs at 100C under nitrogen atmosphere. After 5 min at 100C the redbrown suspension has turned green. The mixture is diluted with ethyl acetate, washed twice with water, once with brine, dried with magnesium sulfate and the solvent is removed in vacuo. The product is isolated by chromatography of the residue (3.85 g) on a 70 g Silicycle silica cartridge using a heptane / ethyl acetate 10 - 40% gradient affording methyl 2-(tert- butoxycarbonylamino)-5-fluoroisonicotinate (1.8 g, 55.7%) as a light yellow solid. MS: m/z= 271.2 (M+H+).
8.43 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 24.0h;Inert atmosphere; Sonication;	To a solution of methyl 2-bromo-5-fluoro-pyridine-4-carboxylate (10.3 g, 44.0 mmol) in 1,4- dioxane (150 mL) were added tert-butyl carbamate (6.18 g, 52.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.86 g, 0.88 mmol), 4,5 -bis(diphenylphosphino)-9,9- dimethylxanthene (1.02 g, 1.76 mmol) and cesium carbonate (20.08 g, 61.6 mmol). The reaction mixture was purged with argon, sonicated, caped and left to stir at 90C for 24h. The reaction mixture was cooled, filtrated through pad of celite and washed with ethyl acetate. Mother liquor was washed with water (2x 100 mL) and brine (100 mL) and evaporated under reduced pressure affording the cmde product, which was triturated from ethyl acetate affording methyl 2-(tert-butoxycarbonylamino)-5 - fluoro-pyridine-4-carboxylate (8.43g). LCMS: MW (calcd): 270.1; MS (ES, m/z): 215.41 (M+H-56).

Reference： [1]Patent: WO2018/118705,2018,A1 .Location in patent: Page/Page column 104
[2]Patent: WO2019/156929,2019,A1 .Location in patent: Page/Page column 126; 142
[3]Patent: US2012/142665,2012,A1 .Location in patent: Page/Page column 28
[4]Patent: WO2012/76430,2012,A1 .Location in patent: Page/Page column 77-78
[5]Patent: WO2019/12284,2019,A1 .Location in patent: Paragraph 0151

11
[ 885588-14-7 ]
tert-butyl (3-(1 H-pyrazol-1-yl)propyl)(6-(trimethylstannyl) pyridin-3-yl)carbamate [ No CAS ]
methyl 5'-((3-(1H-pyrazol-1-yl)propyl)(tert-butoxycarbonyl)amino)-5-fluoro-[2,2'-bipyridine]-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/207813,2017,A1 .Location in patent: Page/Page column 151

12
[ 885588-14-7 ]
tert-butyl (3-(1 H-pyrazol-1-yl)propyl)(6-(trimethylstannyl) pyridin-3-yl)carbamate [ No CAS ]
5'-((3-(1H-pyrazol-1-yl)propyl)(tert-butoxycarbonyl)amino)-5-fluoro-[2,2'-bipyridine]-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2017/207813,2017,A1

13
[ 885588-14-7 ]
methyl 2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-fluoropyridine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/118705,2018,A1
[2]Patent: WO2019/156929,2019,A1

14
[ 885588-14-7 ]
tert-butyl (4-(hydroxymethyl)-5-fluoropyridin-2-yl)(4-methoxybenzyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2018/118705,2018,A1
[2]Patent: WO2019/156929,2019,A1

15
[ 885588-14-7 ]
tert-butyl [4-(bromomethyl)-5-fluoropyridin-2-yl](4-methoxybenzyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2018/118705,2018,A1
[2]Patent: WO2019/156929,2019,A1

16
[ 885588-14-7 ]
(2S,3R)-3-((2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-5-fluoropyridin-4-yl)methyl)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/118705,2018,A1
[2]Patent: WO2019/156929,2019,A1

17
[ 885588-14-7 ]
1-butyl-5-(trimethylstannyl)-1H-pyrrolo[2,3-c]pyridine [ No CAS ]
methyl 2-(1-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,4-dioxane; at 110℃; for 16.0h;	In a pressure tube, to a stirred solution of reference example 15 (400 mg, 1.183 mmol) in 1, 4-dioxane (10 mL), <strong>[885588-14-7]methyl 2-bromo-5-fluoroisonicotinate</strong> (275 mg, 1.183 mmol), CsF (359 mg, 2.366 mmol) and Cul (112 mg, 0.591 mmol) were added. The resulting solution was degassed with N2, and Pd(PPh3)4 (136 mg, 0.118 mmol) was added. The resulting mixture was heated to 110C for 16h. The reaction mixture was diluted with 10%MeOH/DCM and filtered through celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 20% EtOAc in pet ether to afford the title compound (150 mg, 38%) as an off white solid; LC-MS (method 3): R, = 1.85 min; m/z, = 328.26 (M+H+)

Reference： [1]Patent: WO2018/149986,2018,A1 .Location in patent: Page/Page column 147

18
[ 885588-14-7 ]
tert-butyl N-[5-fluoro-4-[[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidyl]carbamoyl]-2-pyridyl]carbamate [ No CAS ]

Reference： [1]Patent: WO2019/12284,2019,A1

19
[ 885588-14-7 ]
2-amino-5-fluoro-N-[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidyl]pyridine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/12284,2019,A1

20
[ 885588-14-7 ]
2-(tert-butoxycarbonylamino)-5-fluoropyridine-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/12284,2019,A1

21
[ 1013-88-3 ]
[ 885588-14-7 ]
methyl 2-((diphenylmethylene)amino)-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.3 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16.0h;Inert atmosphere; Sonication;	To a degassed and purged with argon suspension of methyl 2-bromo-5-fluoro-pyridine-4- carboxylate (308 mg, 1.32 mmol) in 1,4-dioxane (6 mL) was added benzophenoneimine (0.266 mL, 1.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (24.1 mg, 0.026 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (30.5 mg, 0.053 mmol) and cesium carbonate (602.0 mg, 0.053 mmol). The reaction mixture was flushed with argon, sonicated, caped and left to stir at 100C for 1 6h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL), washed with water (15 mL), brine (15 mL), and evaporated under reduced pressure affording methyl 2-((diphenylmethylene)amino)-5-fluoroisonicotinate (230 mg). LCMS: MW (calcd): 334.1; MS (ES, m/z): 335.34 (M+H).

Reference： [1]Patent: WO2019/12284,2019,A1 .Location in patent: Paragraph 0152

22
[ 885588-14-7 ]
2-(4-cyanophenyl)-5-fluoroisonicotinic acid [ No CAS ]

Reference： [1]Patent: JP2019/131544,2019,A

23
[ 885588-14-7 ]
C₂₃H₁₉F₄N₅O₂ [ No CAS ]

Reference： [1]Patent: JP2019/131544,2019,A

24
[ 885588-14-7 ]
[ 171364-82-2 ]
methyl 2-(4-cyanophenyl)-5-fluoroisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
152 mg	With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium carbonate; In methanol; toluene; at 65℃; for 2.0h;Cooling with ice;	2-Bromo-5-fluoroisonicotinic acid methyl ester crude product obtained in the previous step (234 mg),4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile(229 mg),Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (14 mg) and potassium carbonate (415 mg) were mixed in toluene (3 mL) and methanol (2 mL).The reaction mixture was stirred at 65 C. for 2 hours.Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture,The pH was adjusted to 7. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated aqueous sodium chloride solution.The organic layer was dried with sodium sulfate.Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 5: 1). The eluate was concentrated, and hexane was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound (152 mg).

Reference： [1]Patent: JP2019/131544,2019,A .Location in patent: Paragraph 0450; 0454-0456

25
[ 885588-14-7 ]
[ 149507-26-6 ]
methyl 5-fluoro-2-(3-fluoro-4-methoxyphenyl)isonicotinate [ No CAS ]