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Chemical Structure| 1628047-84-6
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Product Details of [ 1628047-84-6 ]

CAS No. :1628047-84-6 MDL No. :MFCD28334265
Formula : C18H17BrN2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :QTUZSJSEZUZNAS-UHFFFAOYSA-N
M.W : 389.24 Pubchem ID :86269454
Synonyms :

Safety of [ 1628047-84-6 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
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Application In Synthesis of [ 1628047-84-6 ]

* 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 [ 1628047-84-6 ]

[ 1628047-84-6 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 98549-88-3 ]
  • [ 889858-12-2 ]
  • tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)-oxy)-4-bromobenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% In a 10-L reactor equipped with mechanical stirrer, thermometer and condenser, charged <strong>[98549-88-3]5-hydroxy-7-azaindole</strong> (compound 8, 97.5 g, 0.73 mol), tert-butyl 4-bromo-2-fluorobenzoate (compound 7b, 200 g, 0.73 mol), N,N-dimethylformamide (1.4 L) and acetonitrile (1.4 L). The mixture was stirred at 20-25C for 15 minutes (until complete dissolution). The solution was treated with K3PO4 (216 g, 1.02 mol, 1.4 equiv) at 20-25C. The reaction mixture (suspension was heated and stirred for 24 h at 90-95C then cooled to 10-15C, water (8.2 L) was added and the reaction mixture was stirred for 2 days at below 25C. The slurry was filtered and the wet-cake was washed with water (2x0.8 L), n-heptane (2x0.8 L) and dried overnight under vacuum at 60-65C to obtain tert-butyl 4-bromo-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoate (246 g, 87%).
194.8 g With sodium t-butanolate; In N,N-dimethyl-formamide; at 0 - 50℃; To a 3 L three-neck Morton flask were charged <strong>[98549-88-3]1H-pyrrolo[2,3-b]pyridin-5-ol</strong> (80.0 g, 1.00 eq.) tert-butyl 4-bromo-2-fluorobenzoate (193 g, 1.15 eq.), and anhydrous DMF (800 mL). The mixture was stirred at 20 C. for 15 min. The resulting solution was cooled to about zero to 5 C. A solution of sodium tert-butoxide (62.0 g) in DMF (420 mL) was added slowly over 30 min while maintaining the internal temperature at NMT 10 C and rinsed with DMF (30 mL). The reaction mixture was stirred at 10 C. for 1 hour (an off-white slurry) and adjusted the internal temperature to ?45 C. over 30 min. The reaction mixture was stirred at 45-50 C. for 7 hr and the reaction progress monitored by HPLC (IP samples: 92% conversion % by HPLC). The solution was cooled to ?20 C. The solution was stirred at 20 C. overnight. Water (1200 mL) was added slowly to the reaction mixture at <30 C. over 1 hour (slightly exothermic). The product slurry was adjusted to ?20 C., and mixed for NLT 2 hours. The crude product was collected by filtration, and washed with water (400 mL). The wet-cake was washed with heptane (400 mL) and dried under vacuum at 50 C. overnight to give the crude product (236.7 g). Re-crystallization or Re-slurry: 230.7 g of the crude product, (potency adjusted: 200.7 g) was charged back to a 3 L three-neck Morton flask. Ethyl acetate (700 mL) was added, and the slurry heated slowly to refluxing temperature over 1 hr (small amount of solids left). Heptane (1400 mL) was added slowly, and the mixture adjusted to refluxing temperature (78 C.). The slurry was mixed at refluxing temperature for 30 min., and cooled down slowly to down to ?-10 C. at a rate of approximate 10 C./hour), and mixed for 2 hr. The product was collected by filtration, and rinsed with heptane (200 ml). The solid was dried under vacuum at ?50 C. overnight to give 194.8 g, 86% isolated yield of the product as an off-white solid. MS-ESI 389.0 (M+1); mp: 190-191 C. (uncorrected). 1H NMR (DMSO-d6): delta 1.40 (s, 9H), 6.41 (dd, J=3.4, 1.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 7.40 (dd, J=8.3, 1.8 Hz, 1H), 7.51 (t, J=3.4 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 11.72 (s, 1H, NH).
  • 2
  • tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)-oxy)-4-bromobenzoate [ No CAS ]
  • [ 1235865-77-6 ]
  • 4
  • [ 1628047-84-6 ]
  • [ 1628047-87-9 ]
  • [ 1628047-90-4 ]
YieldReaction ConditionsOperation in experiment
88.9% Stage #1: 1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazine dihydrochloride With potassium phosphate In toluene for 0.5h; Stage #2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid tert-butyl ester With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; sodium t-butanolate In tetrahydrofuran; toluene at 55℃; for 16h; Inert atmosphere; 8 Synthesis of tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (Compound (K)) General Considerations: [0152] this chemistry is considered air and moisture sensitive. While the catalyst precursors in their solid, dry form can be handled and stored in air without special precautions, contact with even small amounts of solvent may render them susceptible to decomposition. As a result, traces of oxygen or other competent oxidants (e.g., solvent peroxides) must be removed prior to combination of the catalyst precursors with solvent and care must be used to prevent ingress of oxygen during the reaction. Also, care must be taken to use dry equipment, solvents, and reagents to prevent formation of undesirable byproducts. The sodium t-butoxide used in this reaction is hygroscopic and it should be properly handled and stored prior to or during use. [0153] To a 2.0 L three-neck RB flask equipped with a mechanical stirrer were charged the bis-hydrochloride salt (Compound (I), 42.5 g) and toluene (285 ml). 20% K3PO4 (285 ml) was added and the biphasic mixture was stirred for 30 min. The layers were separated and the organic layer was washed with 25% NaCl (145 ml). The organic layer concentrated to 120 g and used in the coupling reaction without further purification. [0154] NaOtBu (45.2 g) and Compound (I) in toluene solution (120 g solution -30 g potency adjusted) were combined in THF (180 ml) in a suitable reactor and sparged with nitrogen for NLT 45 min. Pd2dba3 (0.646 g), Compound (J) (0.399 g), and Compound (D) (40.3 g) were combined in a second suitable reactor and purged with nitrogen until oxygen level was NMT 40 ppm. Using nitrogen pressure, the solution containing Compound (I) and NaOtBu in toluene/THF was added through a 0.45 μm inline filter to the second reactor (catalyst, Compound (J) and Compound (D)) and rinsed with nitrogen sparged THF (30 ml). [0155] The resulting mixture was heated to 55° C. with stirring for NLT 16 h, then cooled to 22° C. The mixture was diluted with 12% NaCl (300 g) followed by THF (300 ml). The layers were separated. [0156] The organic layer was stirred with a freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 ml). After 1 h the layers were separated. [0157] The organic layer was stirred with a second freshly prepared solution of L-cysteine (15 g), NaHCO3 (23 g), and water (262 ml). After 1 h the layers were separated. The organic layer was washed with 12% NaCl (300 g), then filtered through a 0.45 μm inline filter. The filtered solution was concentrated in vacuo to 300 mL, and chased three times with heptane (600 mL each) to remove THF. [0158] The crude mixture was concentrated to 6 volumes and diluted with cyclohexane (720 ml). The mixture was heated to 75° C., held for 15 min, and then cooled to 65° C. over NLT 15 min. Seed material was charged and the mixture was held at 65° C. for 4 hours. The suspension was cooled to 25° C. over NLT 8 h, then held at 25° C. for 4 hours. The solids were filtered and washed with cyclohexane (90 ml) and dried at 50° C. under vacuum. [0159] Isolated 52.5 g (88.9% yield) as a white solid. Melting point (uncorrected) 154-155° C. 1H NMR (DMSO-d6): δ 0.93 (s, 6H), 1.27 (s, 9H), 1.38 (t, J=6.4 Hz, 2H), 1.94 (s, 2H), 2.08-2.28 (m, 6H), 2.74 (s, 2H), 3.02-3.19 (m, 4H), 6.33 (dd, J=3.4, 1.9 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.72 (dd, J=9.0, 2.4 Hz, 1H), 6.99-7.06 (m, 2H), 7.29 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 2H), 7.41-7.44 (m, 1H), 7.64 (t, J=6.7 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 11.53 (s, 1H).
  • 5
  • [ 105931-73-5 ]
  • [ 1628047-84-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -5 - 0 °C 1.2: 1 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide / 0 - 50 °C
Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -5 - 0 °C / Inert atmosphere; Large scale 1.2: 1 h / 0 - 5 °C / Inert atmosphere; Large scale 2.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 8 h / 0 - 55 °C / Inert atmosphere; Large scale
Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -10 - -5 °C 1.2: 1 h / -5 - 0 °C 2.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 10 h / 100 °C
  • 6
  • [ 24424-99-5 ]
  • [ 1628047-84-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -5 - 0 °C 1.2: 1 h 2.1: sodium t-butanolate / N,N-dimethyl-formamide / 0 - 50 °C
Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -5 - 0 °C / Inert atmosphere; Large scale 1.2: 1 h / 0 - 5 °C / Inert atmosphere; Large scale 2.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 8 h / 0 - 55 °C / Inert atmosphere; Large scale
Multi-step reaction with 2 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -10 - -5 °C 1.2: 1 h / -5 - 0 °C 2.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 10 h / 100 °C
  • 7
  • [ 1628047-84-6 ]
  • [ 2131743-82-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid tert-butyl ester In tetrahydrofuran at 20 - 25℃; for 0.0025h; Stage #2: With water; sodium t-butanolate In tetrahydrofuran at 60 - 65℃; 19.A.2 Step 2 - preparation of compound 5 In a 10-L reactor equipped with mechanical stirrer, thermometer and condenser, charged tert-butyl 4-bromo-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzoate (compound 6b, 235 g, 0.6 mol) and THF (5.6 L). The mixture was stirred at 20-25°C for ~15 minutes (until complete dissolution). The solution treated with NaOtBu (162.5 g, 1.7 mol, 2.8 equiv) and water (282 ml). The reaction mixture was heated and stirred overnight at 60-65°C then NaOtBu (162.5 g, 1.7 mol, 2.8 equiv) was added. The reaction mixture was stirred overnight at 60-65°C then NaOtBu (81.25 g, 0.85 mol, 1.4 equiv) was added. The reaction mixture was stirred for 5 h at 60-65°C then NaOtBu (81.25 g, 0.85 mol, 1.4 equiv) was added. The reaction mixture was stirred overnight at 60-65°C then water (4.7 L) was added. The reaction mixture cooled to below 25°C and acidified to pH 2-3 using aqueous sulfuric acid. After THF was removed in vacuum the reaction mixture was stirred overnight at below 25°C. The slurry was filtered and the wet-cake was washed with water (2x0.78 L), n-heptane (2x0.78 L) and dried under vacuum at 60-65°C for 26 h to obtain desired compound (206 g, 102%; THF: 5.2%).
  • 8
  • [ 1228780-72-0 ]
  • tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)-oxy)-4-bromobenzoate [ No CAS ]
  • tert-butyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)-oxy)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate [ No CAS ]
  • 9
  • [ 1628047-84-6 ]
  • [ 73183-34-3 ]
  • [ 2383068-37-7 ]
YieldReaction ConditionsOperation in experiment
78.6% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane; dichloromethane at 85℃; for 4h; Inert atmosphere; Intermediate 1-c: tert-butyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate To a mixture of tert-butyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-bromobenzoate (130 g, 334.2 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (127 g, 501.3 mmol) and KOAc (98.3 g, 1002.3 mmol) in 1, 4-dioxane (1.3 L) was added Pd (dppf) Cl 2 (24.5 g, 66.8 mmol), the mixture was stirred at 85 °C under N 2 for about 4 h. The reaction mixture was cooled to ambient temperature and concentrated, the residue was slurried in DCM (1 L), filtered, the mother liquid was concentrated, purified by chromatography column on silica (EA/DCM = 1/1) to give the crude product. The crude product was recrystallized from EA (100 mL) /PE (100 mL) and dried to give the product as a brown powder (114.5 g, 78.6%). MS (ESI, m/e) [M+1] + 437.2, 355.1
  • 10
  • [ 1628047-84-6 ]
  • [ 2387359-34-2 ]
  • [ 2387359-33-1 ]
YieldReaction ConditionsOperation in experiment
412 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; B38.1 Step 1: tert-butyl (S)-2-((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(1- (3- (2- (2-cyclopropylphenyl) pyrrolidin-1-yl) cyclobutyl) -1H-pyrazol-4-yl) benzoate The mixture of (S)-1-(3- (2- (2-cyclopropylphenyl) pyrrolidin-1-yl) cyclobutyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (520 mg, 1.2 mmol), tert-butyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-bromobenzoate (389 mg, 1.0 mmol), Pd (dppf) 2Cl 2 (146 mg, 0.2 mmol), Cs 2CO 3 (975 mg, 3 mmol) in a 1, 4-dioxane (40 mL) and water (5 mL) was heated to 100 °C and stirred for overnight. The reaction was concentrated in vacuo and purified by chromatography column on silica gel (eluent: EA/PE = 1/10 to 1/2) to give the target product (412 mg). MS (ESI, m/e) [M+1] + 615.9.
  • 11
  • [ 1628047-84-6 ]
  • [ 2387359-20-6 ]
  • [ 2387359-48-8 ]
YieldReaction ConditionsOperation in experiment
60 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; F125.1 Step 1: methyl tert-butyl (S)-2-((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(2- (2- (2-cyclopropylphenyl) pyrrolidin-1-yl) spiro [3.5] non-6-en-7-yl) benzoate To a mixture of (S)-2-(2-cyclopropylphenyl)-1-(7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) spiro [3.5] non-6-en-2-yl) pyrrolidine (200 mg, 0.461 mmol) and tert-butyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-bromobenzoate (160 mg, 0.461 mmol) in 1, 4-dioxane (20 ml) and H 2O (2 ml) was added Pd (dppf) Cl 2 (67.4 mg, 0.0922 mmol) and Cs 2CO 3 (450 mg, 1.383 mmol). The mixture was stirred at 100 °C for overnight under nitrogen protection. The mixture was cooled to room temperature and diluted with DCM (100 ml), then washed with brine, dried over Na 2SO 4, concentrated and purified by chromatography column on silica gel (eluent: PE: EA = 2/1 to 1/1) to give the product 60 mg. MS (ESI, m/e) [M+1] +616.0.
  • 12
  • [ CAS Unavailable ]
  • [ 1628047-84-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
89.5% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 90℃; for 2h; Inert atmosphere; 57.1 First step4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(tert-butoxycarbonyl)phenyl)-3,6-dihydropyridine-1 (2H)-tert-Butyl formate The 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-bromobenzoic acid tert-butyl ester 57a (according to Journal of Organic Chemistry, 84(8), 4814-4829; 2019 synthesis) (0.15 g, 0.39 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine -1(2H)-tert-butyl formate (0.14 g, 0.45 mmol), sodium carbonate (0.12 g, 1.11 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride ( 28 mg, 0.04mmol)Add to 1,4-dioxane/water mixture (5/1, 6 mL), replace the system with nitrogen 3 times,The temperature was raised to 90°C and reacted for 2 hours. After cooling to room temperature, the mixture was quenched with 25 mL of water and 25 mL of ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (25 mL × 2),The combined organic phase was washed with saturated brine (50 mL × 2). The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure. The residue was separated and purified by silica gel column (50% ethyl acetate/petroleum ether) to obtain 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxo)-4-(tert-butyl (Oxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 57b(0.17 g, white solid), yield: 89.5%.
  • 13
  • [ 1628047-84-6 ]
  • [ 2134637-19-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide / tetrahydrofuran; toluene / 24 h / 60 °C / Inert atmosphere 2: potassium hydroxide; water monomer / tetrahydrofuran; ethanol / 8 h / 80 °C
Multi-step reaction with 2 steps 1: sodium tertiary butoxide; (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; tris-(dibenzylideneacetone)dipalladium(0) / toluene; tetrahydrofuran / 60 °C / Inert atmosphere 2: potassium hydroxide / tetrahydrofuran; ethanol; water monomer / 8 h / 80 °C
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide / tetrahydrofuran; toluene / 24 h / 60 °C / Inert atmosphere 2: potassium hydroxide; water monomer / tetrahydrofuran; ethanol / 8 h / 80 °C
  • 14
  • [ 1628047-84-6 ]
  • [ 2134637-20-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide / tetrahydrofuran; toluene / 24 h / 60 °C / Inert atmosphere 2: potassium hydroxide; water monomer / tetrahydrofuran; ethanol / 8 h / 80 °C 3: dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 3 h / 20 °C
Multi-step reaction with 3 steps 1: sodium tertiary butoxide; (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; tris-(dibenzylideneacetone)dipalladium(0) / toluene; tetrahydrofuran / 60 °C / Inert atmosphere 2: potassium hydroxide / tetrahydrofuran; ethanol; water monomer / 8 h / 80 °C 3: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; dmap / dichloromethane / 3 h / 20 °C
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide / tetrahydrofuran; toluene / 24 h / 60 °C / Inert atmosphere 2: potassium hydroxide; water monomer / tetrahydrofuran; ethanol / 8 h / 80 °C 3: dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 3 h / 20 °C
  • 15
  • [ 1628047-84-6 ]
  • [ 2134637-21-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide / tetrahydrofuran; toluene / 24 h / 60 °C / Inert atmosphere 2: potassium hydroxide; water monomer / tetrahydrofuran; ethanol / 8 h / 80 °C 3: dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 3 h / 20 °C 4: hydrogenchloride / water monomer; isopropanol / 8 h / 65 °C
Multi-step reaction with 4 steps 1: sodium tertiary butoxide; (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; tris-(dibenzylideneacetone)dipalladium(0) / toluene; tetrahydrofuran / 60 °C / Inert atmosphere 2: potassium hydroxide / tetrahydrofuran; ethanol; water monomer / 8 h / 80 °C 3: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; dmap / dichloromethane / 3 h / 20 °C 4: hydrogenchloride / water monomer; isopropanol / 8 h / 65 °C
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide / tetrahydrofuran; toluene / 24 h / 60 °C / Inert atmosphere 2: potassium hydroxide; water monomer / tetrahydrofuran; ethanol / 8 h / 80 °C 3: dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 3 h / 20 °C 4: hydrogenchloride; isopropanol; water monomer / 8 h / 65 °C
  • 16
  • [ 1628047-84-6 ]
  • [ 57260-71-6 ]
  • [ 2376761-90-7 ]
YieldReaction ConditionsOperation in experiment
40 g With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide In tetrahydrofuran; toluene at 60℃; for 24h; Inert atmosphere; 1.3 3) Preparation of compound 1-e Tert-butyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d) (77.8 g), Boc-piperazine (55.8 g), tris(dibenzylideneacetone)dipalladium (9 g), [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (5.2 g), sodium tert-butoxide (96.1 g), toluene (800 mL) and tetrahydrofuran (300 mL) were mixed and the mixture was stirred, heated to 60 °C and reacted for 24 h under nitrogen atmosphere. The reaction solution was washed successively with a solution of L-cysteine (100 g) and NaHCO3 (150 g) in water (1.5 L) (750 mL × 2), and then washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated to give compound 1-e (40 g). ESI-MS: m/z = 495.4 [M+H]+.
With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide In tetrahydrofuran; toluene at 60℃; Inert atmosphere; 4.2.2. tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(tertbutoxycarbonyl)phenyl)piperazine-1-carboxylate (9) A mixture of the intermediate 8 (77.8 g, 200 mmol), tert-butylpiperazine-1-carboxylate (55.8 g, 300 mmol), Pd2(dba)3 (9 g, 10 mmol),NaOBu-t (96.1 g, 1000 mmol) and AMPhos (5.2 g, 20 mmol) was dissolved in toluene (800 mL) and THF (300 mL). The resulting reaction medium was evacuated and refilled with nitrogen three times. The temperature was increased to 60°C and stirred overnight, then treated with saturated NaHCO3 and L-cysteine, and extracted three times with ethyl acetate. The combined organic layers were dried by anhydrous Na2SO4, filtered and concentrated in vacuum to give the intermediate 9(40 g, crude), which was used in the next step without further purification.MS (ESI, m/z): 495.4 [M+H]+. 1H NMR (500 MHz, DMSO-d6), δ:12.21 (s, 1H), 11.58 (s, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.9 Hz,1H), 7.46 (t, J = 2.8 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.8,2.3 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.38-6.36 (m, 1H), 3.39-3.37 (m,4H), 3.32-3.20 (m, 4H), 1.42 (s, 9H), 1.39 (s, 9H).
40 g With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide In tetrahydrofuran; toluene at 60℃; for 24h; Inert atmosphere; 1.3 3) Preparation of compound 1-e Tert-butyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d) (77.8 g), Boc-piperazine (55.8 g), tris(dibenzylideneacetone)dipalladium (9 g), [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (5.2 g), sodium tert-butoxide (96.1 g), toluene (800 mL) and tetrahydrofuran (300 mL) were mixed, and the mixture was stirred, heated to 60 °C and reacted for 24 h under nitrogen atmosphere. The reaction solution was washed with a solution of L-cysteine (100 g) and NaHC03 (150 g) in water (1.5 L, 750 mL × 2), and then washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated to give compound 1-e (40 g). ESI-MS: m/z = 495.4 [M+H]+.
40 g With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine; sodium tertiary butoxide In tetrahydrofuran; toluene at 60℃; for 24h; Inert atmosphere; 1.3 3) Preparation of compound 1-e Tert-butyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d) (77.8 g), Boc-piperazine (55.8 g), tris(dibenzylideneacetone)dipalladium (9 g), [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (5.2 g), sodium tert-butoxide (96.1 g), toluene (800 mL) and tetrahydrofuran (300 mL) were mixed, and the mixture was stirred, heated to 60 °C and reacted for 24 h under nitrogen atmosphere. The reaction solution was washed with a solution of L-cysteine (100 g) and NaHC03 (150 g) in water (1.5 L, 750 mL × 2), and then washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated to give compound 1-e (40 g). ESI-MS: m/z = 495.4 [M+H]+.

  • 17
  • [ 1628047-84-6 ]
  • [ 18162-48-6 ]
  • [ 2376762-20-6 ]
YieldReaction ConditionsOperation in experiment
150 g Stage #1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid tert-butyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at -10℃; for 0.5h; 7.3 3) Preparation of compound 7-g NaH (21.1 g) was dissolved in THF (100 mL), and the solution was cooled to -20 °C and stirred for 10 min. Tert-butyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d, 128.3 g) was dissolved in THF (200 mL), and then was slowly added dropwise to the reaction solution, with the internal temperature maintained below 0 °C. After the addition, the mixture was stirred for 30 min. The reaction solution was added dropwise with a solution of TBSCl (64.7 g) in THF (200 mL), with the internal temperature maintained at about -10 °C, and reacted for 30 min after the addition. After the reaction was completed, the reaction solution was extracted with 500 mL of saturated sodium bicarbonate and ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to give compound 7-f (150 g). ESI-MS: m/z = 503.1 [M+H]+.
150 g Stage #1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid tert-butyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at -10℃; for 0.5h; 2.3 NaH (21.1 g) was dissolved in THF (100 mL), and the solution was cooled to -20 °C and stirred for 10 min. Tert-butyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d, 128.3 g) was dissolved in THF (200 mL), and the resulting solution was then slowly added dropwise to the reaction solution, with the internal temperature maintained below 0 °C. After the addition, the mixture was stirred for 30 min. To the reaction solution was added dropwise a solution of TBSCl (64.7 g) in THF (200 mL), with the internal temperature maintained at about -10 °C. After the addition, the resulting mixture was reacted for 30 min. After the reaction was completed, saturated sodium bicarbonate (500 mL) was added, and the resulting mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to give compound 2-f (150 g). ESI-MS: m/z = 503.1 [M+H]+.
150 g Stage #1: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid tert-butyl ester With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at -10℃; for 0.5h; 2.3 NaH (21.1 g) was dissolved in THF (100 mL), and the solution was cooled to -20 °C and stirred for 10 min. Tert-butyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d, 128.3 g) was dissolved in THF (200 mL), and the resulting solution was then slowly added dropwise to the reaction solution, with the internal temperature maintained below 0 °C. After the addition, the mixture was stirred for 30 min. To the reaction solution was added dropwise a solution of TBSCl (64.7 g) in THF (200 mL), with the internal temperature maintained at about -10 °C. After the addition, the resulting mixture was reacted for 30 min. After the reaction was completed, saturated sodium bicarbonate (500 mL) was added, and the resulting mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to give compound 2-f (150 g). ESI-MS: m/z = 503.1 [M+H]+.
  • 18
  • [ 25637-16-5 ]
  • [ 1628047-84-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
73% With [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine]nickel(II) dichloride; tris-(trimethylsilyl)silane; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; sodium carbonate In 1,2-dimethoxyethane at 20℃; Glovebox; Sealed tube; Irradiation;
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