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Product Details of [ 1613192-96-3 ]

CAS No. :	1613192-96-3	MDL No. :	MFCD28805788
Formula :	C₅H₃BrCl₂FN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	246.89	Pubchem ID :	-
Synonyms :

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Application In Synthesis of [ 1613192-96-3 ]

* 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 [ 1613192-96-3 ]
Downstream synthetic route of [ 1613192-96-3 ]

[ 1613192-96-3 ] Synthesis Path-Upstream 1~1

1
[ 1613192-96-3 ]
[ 1211540-92-9 ]

Yield	Reaction Conditions	Operation in experiment
41 g	With sodium hydroxide In dichloromethane for 1 h; Cooling with ice	[ 0505] 3 -bromo-4-chloro-5-fluoro-pyridine hydrochloride18 ( 62 g, 251.1 mmol) was suspended in DCM ( 600 mL) andstirred. The mixture was cooled in an ice bath and sodiumhydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly.The resulting mixture was stirred for 1 hour. The mixture wasphase-separated. More DCM/water was added to aid phaseseparation. Some tarry particulates remained in the aqueousphase. The organic phase was washed with brine, dried(MgS04 ), filtered and concentrated. The residue was trituratedwith heptane. The heptane solution was filtered througha florsil pad, eluting with heptane. The filtrate was concentratedto an oil which solidified. This gave 41 g offree base.

Reference： [1] Patent: US2015/158872, 2015, A1, . Location in patent: Paragraph 0503; 0505

[ 1613192-96-3 ] Synthesis Path-Downstream 1~6

1
[ 892493-65-1 ]
[ 1613192-96-3 ]
[ 1613193-36-4 ]

Yield	Reaction Conditions	Operation in experiment
65%		3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (62 g, 251.1 mmol) was suspended in DCM (600 mL) and stirred. The mixture was cooled in an ice bath and sodium hydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly. The resulting mixture was stirred for 1 hour. The mixture was phase-separated. More DCM/water was added to aid phase separation. Some tarry particulates remained in the aqueous phase. The organic phase was washed with brine, dried (MgS04), filtered and concentrated. The residue was triturated with heptane. The heptane solution was filtered through a florsil pad, eluting with heptane. The filtrate was concentrated to an oil which solidified. This gave 41g of free base. [00384] A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine free base (55 g, 0.26 mol), potassium fluoride (31 g, 0.53 mol) and Me4NCl (5.8 g, 53 mmol) in DMSO (400 mL) was heated to 130°C for 2 hours. The reaction mixture was cooled to room temperature and <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> 22 (66 g, 0.30 mol) and DIPEA (65 g, 0.50 mol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was portioned between DCM/water. The organic layer was washed with water (3x), dried over Na2S04, and filtered over silica gel using DCM as eluent. The filtrated was evaporated to give tert-butyl l-(3-bromo-5- fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61g, 65percent) as a light yellow solid; 1H NMR (500 MHz, DMSO-i/6) delta 8.47 (s, 1H), 8.41 (d, 1H), 3.39 - 3.36 (m, 2H), 3.12 (tt, 2H), 2.49 - 2.43 (m, 1H), 1.91 - 1.87 (m, 2H), 1.71 - 1.64 (m, 2H) and 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) delta -135.2; MS (ES+) 361.0.

Reference： [1]Patent: WO2014/89379,2014,A1 .Location in patent: Paragraph 00383; 00384

2
[ 407-20-5 ]
[ 1613192-96-3 ]

Yield	Reaction Conditions	Operation in experiment
69%		A solution of diisopropylamine (101.2 g, 140.2 mL, 1.000 mol) in tetrahydrofuran (1.148 L) was cooled to between -25C and -20C. Butyllithium (2.5M in hexanes) (400 mL of 2.5 M, 1.000 mol) was added at such a rate as to maintain the reaction temperature below - 20C (addition 20 minutes). The mixture was then allowed to warm to 4C over 1 hour, then re-cooled to -78C. <strong>[407-20-5]3-bromo-5-fluoro-pyridine</strong> (153.0 g, 869.6 mmol) in tetrahydrofuran (382.5 mL) was added over 40 minutes. The mixture was stirred for 90 minutes, then a solution of 1, 1,1,2,2,2-hexachloroethane (205.9 g, 869.6 mmol) in tetrahydrofuran (350.0 mL) was added dropwise over 40 minutes. Once the addition was complete the mixture was allowed to warm to ambient overnight. The mixture was cooled to 0C then transferred into cold water (2 L), stirred for 20 mins then MTBE (2.5 L) added and stirred vigorously for 30 mins then transferred to separating funnel and organic layer separated. Aqueous was transferred back to reaction vessel and further extracted with MTBE (2.5 L), stirred for 10 mins vigorously then transferred to separating funnel and organic layer separated. Organics were combined, dried (MgS04), filtered and concentrated to a brown oil. The oil was dissolved in pentane (500 ml) and ether (300ml). HC1 (2M in ether) (434.8 mL of 2 M, 869.6 mmol) was added slowly with stirring. On complete addition the mixture was stirred for 20 mins then solid collected by filtration, washed with ether and dried under vacuum for lh to leave product 18 as a beige solid (148.9g, 69%); XH NMR (500 MHz, DMSO-d6) delta 8.77 (2H, s); 19F NMR (500 MHz, DMSO-d6) delta -124.8; MS 210.8.
69%		[0504] A solution of diisopropylamine (101.2 g, 140.2 mL,1.000 mol) in tetrahydrofuran (1.148 L) was cooled tobetween -25 C. and -20 C. Butyllithium (2.5M in hexanes)( 400 mL of 2.5 M, 1.000 mol) was added at such a rate as tomaintain the reaction temperature below -20 C. (addition20minutes). The mixture was then allowed to warm to 4 o C. over1 hour, then re-cooled to -78 C. <strong>[407-20-5]3-bromo-5-fluoro-pyridine</strong>(153.0 g, 869.6 mmol) in tetrahydrofuran (382.5 mL) wasadded over 40 minutes. The mixture was stirred for 90 minutes,then a solution of 1,1,1,2,2,2-hexachloroethane (205.9g, 869.6 mmol) in tetrahydrofuran (350.0 mL) was addeddropwise over 40 minutes. Once the addition was completethe mixture was allowed to warm to ambient overnight. Themixture was cooled to oo C. then transferred into cold water (2L), stirred for 20 mins then MTBE (2.5 L) added and stirredvigorously for 30 mins then transferred to separating funneland organic layer separated. Aqueous was transferred back toreaction vessel and further extracted with MTBE (2.5 L),stirred for 10 mins vigorously then transferred to separatingfunnel and organic layer separated. Organics were combined,dried (MgS04), filtered and concentrated to a brown oil. Theoil was dissolved in pentane (500 ml) and ether (300 ml). HCl(2M in ether) (434.8 mL of 2M, 869.6 mmol) was addedslowly with stirring. On complete addition the mixture wasstirred for 20 mins then solid collected by filtration, washedwith ether and dried under vacuum for 1 hr. to leave product18 as a beige solid (148.9 g, 69%); 1H NMR (500 MHz,DMSO-d6) o8.77 (2H, s); 19F NMR (500 MHz, DMSO-d6)o -124.8; MS 210.8.
60%	With hydrogenchloride; In diethyl ether; pentane; for 0.0833333h;	Preparation 10: (l-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-l- yl)methanone (hydrochloride) 17b Scheme 5 Step 1: 3-bromo-4-chloro-5-fluoropyridine hydrochloride 18 [00261] To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20C then cooled back down to -78C. A solution of <strong>[407-20-5]3-bromo-5-fluoro-pyridine</strong> (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70C (approx 30 mins). The reaction mixture was stirred at - 78C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70C (over approximately 30 mins). The mixture was stirred at -78C for 20 minutes, allowed to warm to room temperature, cooled back to 0C and quenched with water (100 rnL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for 10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown oil that turned to a crystalline solid on standing, 1 1.85 g, 89%). lH NMR (DMSO-d6) delta 8.78 (s, 1H), 8.76 (s, 1H). [00262] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). XH NMR (DMSO-d6) delta 8.77 (s, 1H), 8.75 (s, 1H).

Reference： [1]Patent: WO2014/89379,2014,A1 .Location in patent: Paragraph 00382
[2]Patent: US2015/158872,2015,A1 .Location in patent: Paragraph 0503; 0504
[3]Patent: WO2014/143240,2014,A1 .Location in patent: Paragraph 00260; 00262
[4]Patent: WO2014/89379,2014,A1

3
[ 1211540-92-9 ]
[ 1613192-96-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With hydrogenchloride; In diethyl ether; pentane; for 0.0833333h;	To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20C then cooled back down to -78C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70C (approx 30 mins). The reaction mixture was stirred at - 78C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 niL) was then added dropwise, keeping temperature below -70C (over approx 30 mins). The mixture was stirred at -78C for 20 minutes, allowed to warm to room temperature, cooled back to 0C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown011 that turned to a crystalline solid on standing, 11.85 g, 89%). XH NMR (DMSO-d6) delta 8.78 (s, 1H), 8.76 (s, 1H). [00372] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). XH NMR (DMSO-d6) delta 8.77 (s, 1H), 8.75 (s, 1H).
60%	With hydrogenchloride; In diethyl ether; pentane; for 0.0833333h;	Preparation 9: (l-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-l- yl)methanone (hydrochloride) 17 Scheme 4 Step 1: <strong>[1211540-92-9]3-bromo-4-chloro-5-fluoropyridine</strong> hydrochloride 18 [00264] To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20C then cooled back down to -78C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70C (approx 30 mins). The reaction mixture was stirred at - 78C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70C (over approx 30 mins). The mixture was stirred at -78C for 20 minutes, allowed to warm to room temperature, cooled back to 0C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for 10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown 011 that turned to a crystalline solid on standing, 11.85 g, 89%). 1H NMR (DMSO-d6) delta 8.78 (s, 1H), 8.76 (s, 1H). [00265] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). 1H NMR (DMSO-d6) delta 8.77 (s, 1H), 8.75 (s, 1H).
60%	With hydrogenchloride; In diethyl ether; pentane;	To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). ?H NMR (DMSO-d6) oe 8.77 (s, 1H), 8.75 (s, 1H).

Reference： [1]Patent: WO2014/89379,2014,A1 .Location in patent: Paragraph 00371; 00372
[2]Patent: WO2014/143242,2014,A1 .Location in patent: Paragraph 00263; 00265
[3]Patent: WO2015/84384,2015,A1 .Location in patent: Paragraph 00244

4
[ 1613192-96-3 ]
[ 1613191-99-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydroxide / dichloromethane / 1 h / Cooling with ice 1.2: 2 h / 130 °C 1.3: 20 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Benzophenone imine; caesium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 2.2: 0.5 h / 20 °C 3.1: pyridine / 95 °C / Inert atmosphere 4.1: hydrogenchloride / water; 1,4-dioxane / Inert atmosphere 5.1: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: sodium carbonate / cyclohexanol / 18 h / 120 °C / Inert atmosphere 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Benzophenone imine; caesium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 2.2: 0.5 h / 20 °C 3.1: pyridine / 95 °C / Inert atmosphere 4.1: hydrogenchloride / water; 1,4-dioxane / Inert atmosphere 5.1: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: sodium hydroxide / dichloromethane / 1 h / Cooling with ice 1.2: 2 h / 130 °C 1.3: 20 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Benzophenone imine; caesium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 2.2: 0.5 h / 20 °C 3.1: pyridine / 95 °C / Inert atmosphere 4.1: triethylsilane / dichloromethane / 20 - 40 °C 5.1: hydrogenchloride / 1-methyl-pyrrolidin-2-one; 1,4-dioxane / 0.33 h / 20 °C 6.1: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere

	Multi-step reaction with 6 steps 1.1: sodium carbonate / cyclohexanol / 18 h / 120 °C / Inert atmosphere 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Benzophenone imine; caesium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 2.2: 0.5 h / 20 °C 3.1: pyridine / 95 °C / Inert atmosphere 4.1: triethylsilane / dichloromethane / 20 - 40 °C 5.1: hydrogenchloride / 1-methyl-pyrrolidin-2-one; 1,4-dioxane / 0.33 h / 20 °C 6.1: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere
	Multi-step reaction with 5 steps 1: sodium carbonate / cyclohexanol / 40 - 120 °C / Inert atmosphere 2: Benzophenone imine; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 3: pyridine / 16 h / 90 - 100 °C 4: acetonitrile / 16 h / 75 - 80 °C 5: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere
	Multi-step reaction with 5 steps 1: sodium carbonate / cyclohexanol / 40 - 120 °C / Inert atmosphere 2: Benzophenone imine; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 3: pyridine / 95 °C / Inert atmosphere 4: acetonitrile / 16 h / 75 - 80 °C 5: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere
	Multi-step reaction with 7 steps 1: sodium hydroxide / dichloromethane / 1 h / Cooling with ice 2: potassium fluoride; tetramethlyammonium chloride / dimethyl sulfoxide / 2 h / Heating 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 20 °C 4: Benzophenone imine; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 5: pyridine / 16 h / 90 - 100 °C 6: acetonitrile / 16 h / 75 - 80 °C 7: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere
	Multi-step reaction with 7 steps 1: sodium hydroxide / dichloromethane / 1 h / Cooling with ice 2: potassium fluoride; tetramethlyammonium chloride / dimethyl sulfoxide / 2 h / Heating 3: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 20 °C 4: Benzophenone imine; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 5: pyridine / 95 °C / Inert atmosphere 6: acetonitrile / 16 h / 75 - 80 °C 7: N-[(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Inert atmosphere

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2014/89379, 2014, A1
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2014/89379, 2014, A1
[3]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2014/89379, 2014, A1
[4]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2014/89379, 2014, A1
[5]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/158872, 2015, A1
[6]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/158872, 2015, A1
[7]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/158872, 2015, A1
[8]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/158872, 2015, A1

5
[ 1613192-96-3 ]
[ 138007-24-6 ]
[ 1613193-36-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium carbonate; In cyclohexanol; at 120℃; for 18h;Inert atmosphere;	A 3L flange flask equipped with a thermometer, condensor, nitrogen line and overhead stirrer was heated at 40°C (external) then charged with cyclohexanol (750 mL), disodium carbonate (129.8 g, 1.225 mol), 3-bromo-4-chloro-5-fluoro-pyridine (Hydrochloric Acid 18) (137.5 g, 556.8 mmol) and <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (123.8 g, 668.2 mmol) rinsed in with cyclohexanol (350 mL). Mixture was heated to 120°C internal temperature overnight (18h). Reaction mixture was removed from hotplate and allowed to cool to room temperature. Water (687.5 mL) and EtOAc (687.5 mL) were added, stirred for 10 mins then transferred to separating funnel. Additional EtOAc (1.238 L) was added, mixed and aqueous phase was removed. Organic phase was further washed with water (687 mL), aqueous phase removed, organic layer collected. Aqueous phases were combined and back extracted with EtOAc (687.5 mL), aqueous layer removed and organic phase combined with other organics. Organics concentrated in vacuo (water bath temp = 60°C, vaccum down to 2 mBar) leaving a viscous brown oil. [00379] Oil was dissolved in 25percent EtO Ac/petrol then passed through a short silica pad, eluting with 25percent EtOAc/petrol until no more product came off. Filtrate was concentrated in vacuo to leave a brown oil, 127. lg. Product re-purified by ISCO companion (1.5Kg Silica, loaded in DCM, eluting 0 to 20percent EtO Ac/petrol), product fractions combined and concentrated in vacuo to leave desired product 26 as a pale yellow to cream solid, (98g, 49percent yield). 'H NMR (500 MHz, DMSO-d6) delta 8.47 (s, 1H), 8.41 (d, 1H), 3.39 - 3.36 (m, 2H), 3.12 (tt, 2H), 2.49 - 2.43 (m, 1H), 1.91 - 1.87 (m, 2H), 1.71 - 1.64 (m, 2H) and 1.43 (s, 9H). MS (ES+) 361.0.
49%	With sodium carbonate; In cyclohexanol; at 40 - 120℃;Inert atmosphere;	[0499] A 3 L flange flask equipped with a thermometer,condenser, nitrogen line and overhead stirrer was heated at40° C. (external) then charged with cyclohexanol (750 mL),disodium carbonate (129.8 g, 1.225 mol), 3-bromo-4-chloro-5-fluoro-pyridine (Hydrochloric Acid 18) (137.5 g, 556.8mmol) and <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (123.8 g,668.2 mmol) rinsed in with cyclohexanol (350 mL). Mixturewas heated to 120° C. internal temperature overnight (18 hr.).Reaction mixture was removed from hotplate and allowed tocool to room temperature. Water (687.5 mL) and EtOAc( 687.5 mL) were added, stirred for 10 mins then transferred toseparating funnel. Additional EtOAc (1.238 L) was added,mixed and aqueous phase was removed. Organic phase wasfurther washed with water ( 687 mL ), aqueous phase removed,organic layer collected. Aqueous phases were combined andback extracted with EtOAc (687.5 mL), aqueous layerremoved and organic phase combined with other organics.Organics concentrated in vacuo (water bath temp=60° C.,vacuum down to 2 mBar) leaving a viscous brown oil.[0500] Oil was dissolved in 25percent EtOAc/petrol then passedthrough a short silica pad, eluting with 25percent EtOAc/petroluntil no more product came off. Filtrate was concentrated invacuo to leave a brown oil, 127.1 g. Product re-purified byISCO companion (1.5 Kg Silica, loaded in DCM, eluting 0 to20percent EtOAc/petrol), product fractions combined and concentratedin vacuo to leave desired product 26 as a pale yellow tocream solid, (98 g, 49percent yield). 1 H NMR (500 MHz, DMSOd6)o 8.47 (s, lH), 8.41 (d, lH), 3.39-3.36 (m, 2H), 3.12 (tt,2H), 2.49-2.43 (m, lH), 1.91-1.87 (m, 2H), 1.71-1.64 (m, 2H)and 1.43 (s, 9H). MS (ES+) 361.0.

Reference： [1]Patent: WO2014/89379,2014,A1 .Location in patent: Paragraph 00378; 00379
[2]Patent: US2015/158872,2015,A1 .Location in patent: Paragraph 0498; 0499; 0500

6
[ 1613192-96-3 ]
[ 1211540-92-9 ]

Yield	Reaction Conditions	Operation in experiment
41 g	With sodium hydroxide; In dichloromethane; for 1h;Cooling with ice;	[ 0505] 3 -bromo-4-chloro-5-fluoro-pyridine hydrochloride18 ( 62 g, 251.1 mmol) was suspended in DCM ( 600 mL) andstirred. The mixture was cooled in an ice bath and sodiumhydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly.The resulting mixture was stirred for 1 hour. The mixture wasphase-separated. More DCM/water was added to aid phaseseparation. Some tarry particulates remained in the aqueousphase. The organic phase was washed with brine, dried(MgS04 ), filtered and concentrated. The residue was trituratedwith heptane. The heptane solution was filtered througha florsil pad, eluting with heptane. The filtrate was concentratedto an oil which solidified. This gave 41 g offree base.

Reference： [1]Patent: US2015/158872,2015,A1 .Location in patent: Paragraph 0503; 0505

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[ CAS No. 1613192-96-3 ] {[proInfo.proName]}

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[ 1613192-96-3 ] Synthesis Path-Upstream 1~1

[ 1613192-96-3 ] Synthesis Path-Downstream 1~6

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