* 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.
Step 3. 2-(5-bromopyridin-2-yl)propan-2-ol Methylmagnesium chloride 3.0M in THF (0.3 mL) was added dropwise to a mixture of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in tetrahydrofuran (10 mL) at 0° C. After stirring for 1 h at room temperature, the reaction was quenched with 1N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give crude 2-(5-bromopyridin-2-yl)propan-2-ol (0.1 g, 100percent). LCMS calculated for C8H11BrNO (M+H)+: m/z=215.9, 217.9. found: 215.8, 217.8.
86%
at 0 - 20℃; for 12 h;
To a stirred solution of 1-(5-bromopyridin-2-yl)ethan-1-one (1 , 6.2 g, 30.99 mmol) in tetrahydrofuran (100 mL), was added methyl magnesium chloride solution (18.6 mL, 55.78 mmol, 3.0 M in tetrahydrofuran) at 0 C and the reaction mixture was then stirred at room temperature for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude product was purified by silica gel column chromatography using 10percent ethyl acetate in hexane to afford the title compound 2-(5-bromopyridin-2-yl)propan-2-ol (2, 5.8 g, 86percent yield) as a yellow oil. Calculated (M+H): 216.0; Found (M+H): 216.1
To a solution of 1-(5-bromopyridine-2-yl)ethanone (2.9 g, 14.5 mmol) inanhydrous THF (87 mL) at -78 °C was added methylmagnesium bromide (38.66 mL,116.0 mmol) (3M in diethyl ether) dropwise. The resulted mixture was stirred at room temperature for overnight. Saturated ammonium chloride solution was added and the mixture stirred for 30 mm, then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (60-120 silicagel, 2-3percent EtOAc/hexane) to gave the product of Step 2 (1.66 g, 53percent yield) as a pale yellow liquid. LCMS retention time: 1.40 mm (Method 8).
42%
at -15 - 25℃; for 5 h; Inert atmosphere
2-(5-Bromopyridin-2-yl)propan-2-ol (B25.1) (0431) To a mixture of 1-(5-bromopyridin-2-yl)ethanone (400 mg, 2 mmol) in 8 mL THF was added 6 mL CH3MgBr (1 mol/L) at −15° C. under N2 atmosphere. The mixture was stirred for 5 h at 25° C., quenched with sat. NH4CI (30 mL) and stirred for 1 h, extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with 50 mL water and 50 mL brine, dried over Na2SO4, concentrated. The residue was purified on silica gel (PE/EA=10:1) to give title compound (180 mg, 42percent) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 6H), 7.31 (dd, 1H), 7.82 (dd, 1H), 8.58 (d, 1H).
42%
at -15 - 25℃; for 5 h; Inert atmosphere
To a mixture of 1 -(5- bromopyridin-2-yl)ethanone (400 mg, 2 mmol) in 8 mL THF was added 6 mL CH3MgBr (1 mol/L) at -15 °C under N2 atmosphere. The mixture was stirred for 5 h at 25 °C, quenched with sat. NH4CI (30 mL) and stirred for 1 h, extracted with ethyl actetate (50 mL x 2). The combined organic layers were washed with 50 mL water and 50 mL brine,dried over Na2SO4, concentrated. The residue was purified on silica gel (PE/EA1O:1)to give title compound (180 mg, 42percent) as a colorless oil. 1H-NMR (400 MHz, CDCI3) O ppm 1.54 (5, 6H), 7.31 (dd, 1H), 7.82 (dd, 1H), 8.58 (d, 1H).
With n-butyllithium In hexane; toluene at -40 - 20℃; for 2 h; Inert atmosphere
2,5-dibromo-pyridine (I-1-1) 8g the (33.7mmol) and toluene 337mL was stirred at -40 under a nitrogen atmosphere. After stirring for 40 minutes was added n- butyl lithium 1.6M in hexane 21.4mL a (1.02eq) in which, in addition N, N-dimethylacetamide (DMAc) 9.38mL (3.0eq), stirred It was slowly heated to 20 while. Thereafter, saturated aqueous ammonium chloride solution was added to quench the reaction, and extraction and liquid separation. The extract was purified by silica gel column chromatography,2-acetyl-5-bromopyridine to give (compound the I-1-2) of a white solid 6.74 g (100percent yield).
65%
Stage #1: With n-butyllithium In hexane; toluene at -50℃; for 0.75 h; Stage #2: at -50 - 20℃; for 1 h;
To a solution of 2,5-dibromopyridine (5 g, 22.026 mmol) in anhydrous toluene (200 mL) at -50 °C was added n-butyllithium (13.75 mL, 22.026 mmol) (1.6M in hexane) dropwise. The resulted mixture was stirred at -50 °C temperature for 45 mi N,Ndimethylacetamide (3.61 mL, 37.44 mmol) was added dropwise at the same temperatureand then allowed to reach room temperature slowly. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride solution, then extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (60-120 silica gel, 1percent EtOAc/hexane) to provide the product of Step 1 (2.9 g, 65percent yield) as a white solid. LCMS retention time: 1.46 mm(Method 7).
Reference：
[1] Patent: JP2016/56276, 2016, A, . Location in patent: Paragraph 0111; 0112
[2] Tetrahedron, 2008, vol. 64, # 17, p. 3794 - 3801
[3] Dalton Transactions, 2011, vol. 40, # 29, p. 7534 - 7540
[4] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12643 - 12647
[5] Patent: WO2015/27021, 2015, A1, . Location in patent: Page/Page column 78
[6] Patent: WO2012/21467, 2012, A1, . Location in patent: Page/Page column 32
4
[ 75-16-1 ]
[ 97483-77-7 ]
[ 214701-49-2 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: at -20 - -10℃; for 3 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at -40 - -35℃; for 0.166667 h;
Intermediate 10: 1-(5-Bromopyridin-2-yl)ethanone; see W098/46605; 5-Bromo-2-cyanopyridine (Markevitch, David Y.; Rapta, Miroslav; Hecker, Scott J. ; Renau, Thomas E. ; Synth. Commun.; 33; 19; 2003; 3285 - 3290) (8 g, 43.7 mmol) was dissolved in dry THF (200 mL) and cooled to - 20°C. Methylmagnesium bromide (43.7 mL, 3M) was added drop wise and the temperature was held between -20°C and -10°C for 3 hours. The reaction mixture was cooled to -40°C and conc. HCI (4.5 mL) in water (15 mL) was added dropwise. It was stirred for 10 minutes at -35°C and then poured into a beaker with potassium phosphate buffer (300 mL, 1M, pH 7), under stirring. Ethyl acetate (300 mL) was added and the organic phase was dried over sodium sulfate. Upon concentration at room temperature under reduced pressure to - 50 mL the product crystallized, 2.4 g, mp 112°C. The mother liquor was further concentrated and chromatographed on silica gel with dichloromethane/ ethylacetate (100:1) to give another 3.25 g product (65percent combined yield). 1H-NMR (DMSO-d6) No.: 2.60 (s, 3H) ; 7.88 (dd, 1H); 8.25 (dd, 1H); 8.86 (d, 1H).
65%
Stage #1: at -20 - -10℃; for 3 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at -40 - -35℃; for 0.166667 h; Stage #3: potassium phosphate buffer
Intermediate 10: 1-(5-Bromopyridin-2-yl)ethanone; See W098/46605; 5-Bromo-2-cyanopyridine (Markevitch, David Y. ; Rapta, Miroslav; Hecker, Scott J. ; Renau, Thomas E. ; Synth. Commun.; 33; 19; 2003; 3285 - 3290) (8 g, 43.7 mmol) was dissolved in dry THF (200 mL) and cooled to - 20°C. Methylmagnesium bromide (43.7 mL, 3M) was added drop wise and the temperature was held between -20°C and -10°C for 3 hours. The reaction mixture was cooled to -40°C and concentrated HCl (4.5 mL) in water (15 mL) was added dropwise. It was stirred for 10 minutes at -35°C and then poured into a beaker with potassium phosphate buffer (300 mL, 1M, pH 7), under stirring. Ethyl acetate (300 mL) was added and the organic phase was dried over sodium sulfate. Upon concentration at room temperature under reduced pressure to - 50 mL the product crystallized, 2.4 g, mp 112°C. The mother liquor was further concentrated and chromatographed on silica gel with dichloromethane/ ethylacetate (100:1) to give another 3.25 g product (65percent combined yield). (at)H-NMR (DMSO-d(at)) No.: 2.60 (s, 3H) ; 7.88 (dd, 1H) ; 8.25 (dd, 1H) ; 8.86 (d, 1H).
30%
Stage #1: at -20℃; for 3 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether at -40℃;
5-Bromopicolinonitrile (5.4 g, 29.7 mmol) was dissolved in anhydrous THF (120 mL) and cooled to -200C. MeMgBr (35 mL, IM in Et2O) was added dropwise, and the reaction mixture was stirred at -200C for 3 h. The reaction mixture was cooled to -40 0C, and neutralized with cone. HCl. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic phase was dried (Na2SO4) and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc - hexanes) to give l-(5-bromopyridin-2-yl)ethanone (1.9 g, 30percent yield).
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4868 - 4881
[2] Patent: WO2005/116022, 2005, A1, . Location in patent: Page/Page column 44
[3] Patent: WO2005/116023, 2005, A1, . Location in patent: Page/Page column 44-45
[4] Organic and Biomolecular Chemistry, 2015, vol. 13, # 36, p. 9418 - 9426
[5] Patent: WO2008/108988, 2008, A1, . Location in patent: Page/Page column 67
[6] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 22, p. 5909 - 5915
5
[ 1211592-38-9 ]
[ 676-58-4 ]
[ 214701-49-2 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0 - 20℃; for 1 h;
Step 2. 1-(5-bromopyridin-2-yl)ethanone Methylmagnesium chloride 3.0M in THF (0.5 mL) was added dropwise to a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8 mmol) in tetrahydrofuran (10 mL) at 0° C. After stirring for 1 hr at room temperature, the reaction was quenched with 1N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give the crude product 1-(5-bromopyridin-2-yl)ethanone (0.15 g, 90percent). LCMS calculated for C7H7BrNO (M+H)+: m/z=199.9, 201.9. found: 199.9, 201.9.
With aniline;toluene-4-sulfonic acid; for 3h;Heating;
[0533] Experimental Details: A solution of compound 2 (2 g, 0.01 mol) and ethylene glycol (3 g, 0.048 mol) in anline (100 mL) was heated in the presence of a trace of TsOH for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with an aqueous of 5% Na2CO3. The organic layer was separated and dried over Na2SO4. The solvent was concentrated to give compound 3.
With aniline;toluene-4-sulfonic acid; for 3h;Heating;
Experimental Details: A solution of compound 2 (2 g, 0.01 mol) and ethylene glycol (3 g, 0.048 mol) in anline (100 mL) was heated in the presence of a trace of TsOH for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with an aqueous of 5% Na2CO3. The organic layer was separated and dried over Na2SO4. The solvent was concentrated to give compound 3.
2-bromo-1-(5-bromopyridin-2-yl)ethanone hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With hydrogen bromide; bromine; In methanol; acetic acid; at 0 - 70℃; for 1.5h;
Intermediate 9: 2-Bromo-l-(5-bromopyridin-2-yl)ethanone; 1-(5-Bromopyridin-2-yl)ethanone (Intermediate 10, WO 98/46605) (5.65 g, 28.2 mmol) was dissolved in methanol/ acetic acid (50 mL + 70 mL), cooled to 0C and 30% HBr in acetic acid (8 mL) was added. Bromine (1.45 mL, 28.3 mmol) in acetic acid (10 mL) was added dropwise and the reaction mixture was allowed to reach room temperature and then was heated to 70C for 1 hour. It was cooled to - 50C and more bromine (0.4 mL) in acetic acid (5 mL) and methanol (15 mL) was added and it was heated to 70C for another 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure and the residue was crystallized from isopropanol to give 3.45 g (34%) of the crude hydrobromide salt of the product as a pale yellow solid. MS (ESP): 277.95/ 279.95/ 281.94 (MH+) for C7H5Br2NO ¹H-NMR (DMSO-d6) No.: 4.96 (s, 2H); 7.93 (m, 1H); 8.29 (m, 1H); 8.87 (m, 1H); 9.19 (brs, 1H).
34%
With hydrogen bromide; bromine; In methanol; acetic acid; at 70℃; for 2h;
Intermediate 9: 2-Bromo-l-(5-bromopyridin-2-vl)ethanone; 1-(5-Bromopyridin-2-yl)ethanone (Intermediate 10) (WO 9846605) (5.65 g, 28.2 mmol) was dissolved in methanol/ acetic acid (70 mL + 70 mL) and 30% HBr in acetic acid (8 mL) was added. Bromine (1.45 mL, 28.3 mmol) in acetic acid (15 mL) was added dropwise and the reaction mixture was heated to 70C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was crystallized from isopropanol to give 3.45 g (34%) of the crude hydrobromide salt of the product as a pale yellow solid. MS (ESP): 277.95/ 279.95/ 281.94 (MH+) for C7H5Br2NO 'H-NMR (DMSO-d6) No.: 4.96 (s, 2H) ; 7.93 (m, 1H) ; 8.29 (m, 1H) ; 8.87 (m, 1H) ; 9.19 (brs, 1H).
With hydrogen bromide; bromine; acetic acid; In methanol; at 0 - 70℃; for 1h;
1 -(5-bromopyridin-2-yl)ethanone (7.05 g, 35.2 mmol) was dissolved in a mixture of methanol (60 ml) and acetic acid (90 ml) and hydrobromic acid (33 wt% in acetic acid, 10 ml, 60.8 mmol) were added. The suspension was cooled at 0 C and to this was added dropwise a solution of bromine (1 .816 ml, 35.2 mmol) in acetic acid (12.5 ml). The suspension was heated at 70 C for 1 h. After 1 hour, a yellow solution was obtained. The reaction mixture was concentrated under reduced pressure. The green solid residue was crystallised from 2- propanol (-250 ml) to give 5.36 g of 2-bromo-1 -(5-bromo-2-pyridyl)ethanone hydrobromide as a pale green solid (85% pure). Used without further purification in the next step.
(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one[ No CAS ]
[ 214701-49-2 ]
(5R)-3-[4-(6-acetylpyridin-3-yl)-3-fluorophenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Reference Example 1: (5R)-3-[4-(6-AcetvlDvridin-3-Vl)-3-fluoroDhenvll-5-(lH-1,2,3- triazol-1-ylmethyl) -1,3-oxazoRdin-2-one; 1- (5-Bromopyridin-2-yl)ethanone (Intermediate 10,2.47 g, 12.4 mmol), ), (5R)-3-[3-fluoro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- [(1H-1,2,3-triazol-1- yl) methyl]oxazolidin-2-one (Intermediate 7, 4.0 g, 10.3 mmol) and sodium carbonate (3.98 g, 37.5 mmol) were dissolved/ suspended in DMF/ water (50 mL, 10: 1). It was degassed, flushed with nitrogen and tetrakis (triphenylphospine) palladium (0) (1.2 g, 1.03 mmol) was added. It was heated at 75 C for 3 hours, cooled to room temperature, and the solvent was evaporated. Chromatography on silica gel with hexanes/ acetone (1:1) to acetone and precipitation of the product from methanol/ dichloromethane (4:1, 50 mL) by removing most of the dichloromethane under reduced pressure gave 1.98 g product (50%), as an off-white solid, mp >210C (dec.). MS (ESP): 382.13 (MH+) for C19H16FN5O3 ¹H-NMR (DMSO-d6) No.: 2.66 (s, 3H); 3.96 (dd, 1H); 4.30 (dd, 1H); 4.86 (d, 2H); 5.19 (m, 1H); 7.43 (dd, 1H); 7.60 (dd, 1H); 7.72 (dd, 1H); 7.76 (s, IH); 8.03 (d, IH); 8.17 (m, 1H); 8.18 (s, 1H) ; 8.90 (s, 1 H).
l-(5-bromo-rhoyridin-2-yl)-ethanone (0.9g, 4.5mmol) was treated with DMF-DMA (1.19ml) and heated at 75C for 8 hours. The reaction mixture was reduced in vacuo and then re-evaporated with toluene. The residue was dissolved in EtOH (2ml) and then treated with hydrazine hydrate (0.28ml, 5.85mmol). The reaction mixture was stirred at ambient temperature for 48 hours, reduced in vacuo, and then triturated with methanol to give the product (0.34g). The residue was chromatographed using Biotage to give product (0.52g) which was combined with the previous solid to give total 5-bromo-2-(lH-pyrazol-3-yl)-pyridine (0.849g),(LC/MS acidic: Rt 2.36, [MH-H]+ no ion).
With bromine; In tetrachloromethane; at 70℃;Sealed tube;
Br2 (1.2 g, 7.6 mmol) was added to a solution of l-(5-bromopyridin-2- yl)ethanone (1.5 g, 7.6 mmol) in 6OmL of CCl4. The reaction mixture was sealed and stirred at 700C overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with water. The aqueous was extracted with EtOAc for several times. The combined organic phases were dried (Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (EtOAc - hexanes) to give compound 2-bromo-l-(5-bromopyridin-2-yl)ethanone (1.2 g, 57% yield).
To a solution of <strong>[214701-49-2]1-(5-bromo-2-pyridinyl)ethanone</strong> (300 mg) in dry DCM ( 5 mL) at O0C under nitrogen was added 2,6-lutidine (0.21 mL) and trimethylsilytriflate (0.27 mL). The reaction was stirred at O0C under nitrogen for 30 mins. lambda/-Bromosuccinimide (270 mg) was added and the mixture was stirred at room temperature under nitrogen for 30 mins. Water (15 mL) and 2M HCI (5 drops) were added and the organics were extracted into DCM (2 x 13 mL). The organics were separated, dried using a hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 0-100% EtOAc in cyclohexane to give the title compound.MS calcd for (C7H5Br2NO + H)+: 279/280/282MS found (electrospray): (M+H)+ = 279/280/282
With hydrogen bromide; bromine; acetic acid; at 70℃; for 3h;
a) 2-Bromo-l-(5-bromo-2-pyridyl)ethanone 2-Acetyl-5-bromopyridine (10.0 g, CAS: 214701-49-2) in HBr/HOAc solution (35 % ~39 %, 80 mL) was stirred at 70 C for 5 min. Br2 (9.6 g) was added dropwise. The reaction was continued at 70 C for 3 h, TLC analysis showed complete consumption of the starting material. The mixture was cooled to room temperature and filtered through filtration paper. Volatiles were removed under reduced pressure, and the residue was dried further under high vacuum to give crude 2-bromo-l-(5-bromo-2-pyridyl)ethanone (16.8 g, yield: 93.3 %) as a brown oil. The crude product was used in the next step without purification. MS (ESI): 281.9 ([{81Br}M+H]+), 277.9 ([{79Br}M+H]+).
With n-butyllithium; In hexane; toluene; at -40 - 20℃; for 2h;Inert atmosphere;
2,5-dibromo-pyridine (I-1-1) 8g the (33.7mmol) and toluene 337mL was stirred at -40 under a nitrogen atmosphere. After stirring for 40 minutes was added n- butyl lithium 1.6M in hexane 21.4mL a (1.02eq) in which, in addition N, N-dimethylacetamide (DMAc) 9.38mL (3.0eq), stirred It was slowly heated to 20 while. Thereafter, saturated aqueous ammonium chloride solution was added to quench the reaction, and extraction and liquid separation. The extract was purified by silica gel column chromatography,2-acetyl-5-bromopyridine to give (compound the I-1-2) of a white solid 6.74 g (100% yield).
80%
General procedure: The compounds ware prepared following a literature procedure.45,46 To a solution of halogenated pyridine substrate (1.0 equiv.) inanhydrous toluene (0.05 M) was added n-BuLi (1.1 equiv., 2.5M inhexane) dropwise at -78 C, and the resulting mixture was stirred for30 min. N, N-dimethylacetamide or DMF (1.5 equiv.) was added dropwiseand the mixture was stirred for another 30 min. After completion,the reaction was quenched with sat. NH4Cl (aq.) and extracted withethyl acetate (3×15 mL). The organic layer was dried over MgSO4 andconcentrated in vacuo. 7.1. 1-(5-Bromopyridin-2-yl)ethan-1-one (27a)This compound was prepared according to general procedure C bytreating 2,5-dibromopyridine (237 mg, 1 mmol) with N, N-dimethylacetamide(44 muL, 1.5 mmol). The crude product was purified by flashchromatography (hexane/ethyl acetate 10:1) to give the product 27a asa white solid (160 mg, 80%); Rf (hexane/ethyl acetate 8:1): 0.45; 1HNMR (300 MHz, CDCl3): delta 8.70 (1H, s), 7.95-7.88 (2H, m), 2.66 (3H, s);13C NMR (75 MHz, CDCl3): delta 199.2, 151.9, 150.2, 139.6, 125.4, 123.0,25.8. The spectroscopic data matched that reported in the literature.
80%
To a solution of 2,5-dibromopyridine 16 (20.0g, 84.4 mmol) in dry toluene (400mL), cooled to -40 C in a dry ice-CH3CN bath, under nitrogen, was added n-BuLi (1.6M in THF, 52.76mL, 84.42 mmol) over 30 minutes. The resulting deep reddish solution was allowed to stir for 40 minutes, then N,N-dimethylacetamide (14.28mL, 153.6 mmol) was added in over 10 minutes. The mixture was allowed to warm to room temperature over 3 hours, then the reaction was quenched by the addition of saturated aq. NH4Cl (50mL). The mixture was cast into EtOAc (250mL) and water (500mL) and the organic phase was separated. The aqueous phase was extracted with EtOAc (250mL) and the combined organic phases were washed with brine (500mL) and dried (Na2SO4). Filtration and concentration in vacuo gave 17 (13.54 g, 80%) as a tan solid. 1H NMR (400 MHz, CDCl3): d = 8.74 (d, J = 1.9 Hz, 1), 7.90-8.00 (2), 2.70 (s, 3); MS (ESI+) m/z 201.0 (M + H).
65%
To a solution of 2,5-dibromopyridine (5 g, 22.026 mmol) in anhydrous toluene (200 mL) at -50 C was added n-butyllithium (13.75 mL, 22.026 mmol) (1.6M in hexane) dropwise. The resulted mixture was stirred at -50 C temperature for 45 mi N,Ndimethylacetamide (3.61 mL, 37.44 mmol) was added dropwise at the same temperatureand then allowed to reach room temperature slowly. The reaction mixture was stirred at room temperature for 1 h and quenched with saturated ammonium chloride solution, then extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (60-120 silica gel, 1% EtOAc/hexane) to provide the product of Step 1 (2.9 g, 65% yield) as a white solid. LCMS retention time: 1.46 mm(Method 7).
In a 3-neck 1000 ml round bottom flask, 2,5-dibromopyridine (10.0 g, 42.2 mmol) was dissolved in toluene (400ml) and cooled to -40 C (CH3CN/dry ice). 1.6 M of n- butyllithium in tetrahydrofuran (26.38 mL, 42.21 mmol) was slowly added to the cooled solution to form a deep reddish solution, which was stirred at -40 C for 40 minutes. N,N- Dimethylacetamide (7.14 mL, 76.8 mmol) was added with no discernable change. The mixture was allowed to slowly warm to room temperature. Then, the mixture was quenched by adding 25ml sat'd ammonium chloride. Added 100ml H20 and extracted with EtOAc (250ml). The organic phase was washed with water (200 ml). The combined aqueous phases were extracted with EtOAc (100ml). The combined organic extracts were washed with brine, dried (Na2S04), filtered and evaporated in vacuo to generate 6.31 g of a tan solid. -NMR(CDC13): 5 8.74(d, J=1.9Hz, lH), 7.96(m, 2H), 2.70(s, 3H). HPLC: RT=3.237min., 60area% (at) 210nm; RT=3.238min., 87area% (at)254nm. LCMS: MS (ESI-) for C8H7BrO m/z 201.0 (M+H)+.
[0531] Experimental Details: A solution of 1 (2 g, 0.011 mol) in anhydrous THF (100 mL) was treated with MeMgCl (15 mL. 0.038 mol), at -20 C and stirred for 2 h at this temperature. This reaction mixture was quenched by adding the saturated aqueous OfNH4Cl. The resulting mixture was extracted with ethyl acetate (100 mL chi 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to give compound 2.
Example 26 Experimental Details: A solution of 1 (2 g, 0.011 mmol) in anhydrous THF (100 mL) was treated with MeMgCl (15 mL. 0.038 mol), at -20 C. and stirred for 2 h at this temperature. This reaction mixture was quenched by adding the saturated aqueous of NH4Cl. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to give compound 2.
Palladium tetrakis(triphenylphosphine) (289 mg, 0.25 mmol) was added to a degassed, ambient temperature solution of 2-bromopyridine (660 mg, 3.75 mmol), 1-(5-bromo-pyridin-2-yl)-ethanone (500 mg, 2.5 mmol) and hexamethylditin (1.2 g, 3.75 mmol) in degassed 1,4-dioxane (8 mL). After stirring at 110 C. overnight, the reaction mixture was cooled and KF/celite (1:1) was added. After stirring vigorously for 1 hr, reaction mixture was filtered and concentrated. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded the title compound.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 6h;Inert atmosphere;
Step 1: l-( -(4-methoxyphenyl)pyridin-2-yl)ethanone To a stirred solution of l-(5-bromopyridin-2-yl)ethanone (1.0 g, 5.0 mmol) in toluene (30 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.52 g, 10 mmol), 2M Na2C03 (14 mL), Pd(PPh3)4 (0.057 g, 0.05 mmol), the reaction was purged with argon and heated at 80C for about 6 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2 x 300 niL). The combined organic extracts were washed with brine solution (20 mL), organic layer was dried over Na2S04 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60- 120?) using 10% ethyl acetate in hexane eluent to afford l-(5-(4-methoxyphenyl)- pyridin-2-yl)ethanone as off white solid (1 g, 88% yield). XH NMR (400 MHz, DMSO-d6): ? 8.99 (s, IH), 8.20 (d, IH), 7.96 (d, IH), 7.76 (d, 2H), 7.027 (d, 2H), 3.80 (s, 3H), 2.63 (s, 3H). LC-MS m/z calcd for [M+H]+ 228.09, found 228.2.
88%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 70℃; for 5h;Inert atmosphere;
Step 1: l-(5-(4-Methoxyphenyl)pyridin-2-yl)ethanone To a stirred solution of toluene and ethanol (9 mL, 2: 1) of l-(5-bromopyridin- 2-yl) ethanone (200 mg, 1 mmol) was added (4-methoxyphenyl) boronic acid (304 mg, 2 mmol), 2M Na2C03 (2.84 mL), and Pd(PPh3)4 (11 mg, 0.01 mmol) under argon atmosphere and heating was continued for 5 hours at 70C. The reaction mixture was concentrated under vacuum and diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined extracts were washed with brine solution (20 mL), and organic layer was dried over Na2S04 and concentrated under vacuum to obtain crude product. This, on purification by flash chromatography (silica gel, 60- 120mu) using 10% ethyl acetate in hexane eluent, afforded l-(5-(4-methoxyphenyl) pyridin-2-yl) ethanone as off-white solid (200 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): delta 8.99 (d, 1H), 8.20 (dd, 1H), 7.97 (d, 1H), 7.76 (d, 2H), 7.07 (d, 2H), 3.81 (s, 3H), 2.63 (s, 3H); LC-MS m/z calculated for [M+H]+ 228.27, found 228.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 6h;Inert atmosphere;
Step 1: l-(5-(4-nitrophenyl)pyridin-2-yl)ethanone 80C / 6 h To a stirred solution of l-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in toluene (4 mL) and ethanol (2 mL) was added (4-nitrophenyl)boronic acid (160 mg, 1 mmol), 2M Na2C03 (1.4 mL), and Pd(PPh3)4 (6 mg, 0.005 mmol), the reaction was purged with argon, and then heated at 80C for about 6 h. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2S04 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60- 120?) using 10% ethyl acetate in hexane eluent to afford l-(5-(4-nitrophenyl)pyridin- 2-yl)ethanone as off white solid (105 mg, 86% yield). XH NMR (400 MHz, DMSO- d6): ? 9.14 (s, IH), 8.40-8.34 (m, 3H), 8.08 (dd, 3H), 2.67 (s, 3H), LC-MS m/z calcd for [M+H]+ 243.07, found 243.2.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; for 4h;Inert atmosphere; Reflux;
To a solution of <strong>[214701-49-2]1-(5-bromopyridin-2-yl)ethanone</strong> (2.0 g, 9.98 mmol) in dioxane (50 mL) was added bis(pinacolato)diboron (2.8 g, 11.0 mmol), potassium acetate (2.94 g, 30.0 mmol) and [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (244 mg, 0.30 mmol) under a nitrogen atmosphere. The mixture was heated at reflux for 4 hours. The mixture was then cooled to room temperature then filtered over Celite (washing with EtOAc) and concentrated at reduced pressure. The residue was purified directly via Biotage Isolera chromatography (eluting with a gradient of eluents; 0 - 50 % EtOAc in heptane) giving the desired product (2.22 g, 90% yield) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) delta [ppm] 8.89 (s, 1 H), 8.20 (dd, J = 7.7, 1.6 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 2.65 (s, 3H), 1.33 (s, 12H). LCMS (Analytical Method A): Rt=0.74 mins, mass ion not observed.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 2.5h;
The a mixture of l-(5-bromo-pyridin-2-yl)-ethanone (199 mg, 1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l ,3,2-dioxaborolane) (254 mg, 1 mmol), potassium acetate (AcOK) (196 mg, 2 mmol), Pd(dppf)Cl2 (73mg, 0.1 mmol) in 1 ,4-dioxane (2 ml) was stirred at 100 C for 2.5 h. The mixture was used in the next step without purification.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
To l-(5-bromopyridin-2-yl)ethanone (2g, lO.lmmol) in Dioxane (80 ml) was added bis(pinacolato)diboron (3.3g, 13.1mmol), PdCl2(d pf)2.CH2Cl2 (0.8 g, lmmol) and KOAc (3 g, 30.2 mmol). It was then degassed with Argon for five minute before heating at 100 C for 16 hours, at which time LC MS analysis confirmed full consumption of starting material. On cooling, the solvent was rotoevaporated, and the crude was redissolved in DCM (500ml), washed with water (1 x 125ml), brine (1 x 125ml), and dried over MgS04. Solvent was removed in vacuo and the crude compound l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridin-2-yl)ethanone was used for the next step without any further purification.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
To l -(5-bromopyridin-2-yl)ethanone (2g, 10.1 mmol) in Dioxane (80 ml) was added bis(pinacolato)diboron (3.3g, 13.1mmol), PdCl2(dppf)2.CH2Cl2 (0.8 g, lmmol) and KOAc (3 g, 30.2 mmol). It was then degassed with Argon for five minute before heating at 100 C for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, the solvent was rotoevaporated, and the crude was redissolved in DCM (500ml), washed with water (1 x 125ml), brine (1 x 125ml), and dried over MgS04. Solvent was removed in vacuo and the crude compound l-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyridin-2-yl)ethanone was used for the next step without any further purification.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 50℃; for 1h;Inert atmosphere;
A mixture of 17 (12.6 g, 63 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.20 g, 1.52 mmol) in dioxane (240mL) was degassed by sparging with nitrogen for 20 minutes. To this mixture was added a solution of diethyl zinc (50mL, 15% w/w) over 30 minutes. The mixture was then warmed to 50 C and the orange mixture gave way to a dark orange solution and yellow solids as it stirred at 50C for 60 minutes. The mixture was cooled to room temperature and was cast into EtOAc (400mL) and water (400mL). The organic phase was separated, the aqueous phase was extracted with EtOAc (2x250mL). The combined organic phases were washed with brine (1000mL), dried (Na2SO4), filtered and concentrated in vacuo to furnish crude 18 as a brown oil. Crude 18 was purified by distillation (BP = 54-55 C, 0.32mm Hg) to give 18 (8.27g, 88%) as a very pale yellow oil.1H NMR (400 MHz, CDCl3): delta = 8.50 (d, J = 1.9 Hz, 1), 7.96 (d, J = 7.9 Hz, 1), 7.63 (dd, J = 7.9, 1.9 Hz, 1), 2.71 (q, J = 7.6 Hz, 2), 2.69 (s, 3), 1.27 (t, J = 7.6 Hz, 3); MS (ESI+) m/z 150.1 (M + H).
palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In 1,4-dioxane; hexane; at 50℃;Inert atmosphere;
A mixture of 1 -(5-bromopyridin-2-yl)ethanone (6.30 g, 31.5 mmol; Supplier = Kalexsyn; Lot = 90) and [ l, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (560 mg, 0.76 mmol) in dioxane (120ml) was degassed by sparging with N2 for 10 minutes.Added a solution (15 w/w) of diethyl zinc in hexane (50ml) slowly, dropwise and heated to 50 C. The orange mixture turned dark, ultimately generating a dark orange with yellow solids as it stirred at 50 C for 30 minutes. Allowed to cool to room temperature. The reaction mixture was partitioned between EtOAc (200ml) and water (200ml), and the aqueous phase was extracted 2x with EtOAc. The combined organic phases were washed with brine (500ml), dried (Na2S04), filtered and evaporated in vacuo to give 4.14 g brown oil. Distilled under high vac using short-path distillation apparatus. BP = 55 C (at) 0.32 torr to give 2.249 g of slightly tinted oil. -NMR (CDC13): delta 8.50(d, J=1.9Hz, IH), 7.96(d, J=7.9Hz, IH), 7.63(dd, J=8.0, 2.2Hz, IH), 2.7 l(m, 2H), 2.69(s, 3H), 1.27(t, J=7.6Hz, 3H). HPLC: 2.01 lmin., 57 area% (at) 210nm; 2.012min., 75 area% (at) 254 nm. LCMS: MS (ESI-) for Ci0Hi2O m z 150.1 (M+H)+.
tert-butyl anti-3-(3-(6-acetylpyridin-3-yl)-7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
tert-butyl anti-3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yI)-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Step 2. 1-(5-bromopyridin-2-yl)ethanone Methylmagnesium chloride 3.0M in THF (0.5 mL) was added dropwise to a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8 mmol) in tetrahydrofuran (10 mL) at 0 C. After stirring for 1 hr at room temperature, the reaction was quenched with 1N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give the crude product 1-(5-bromopyridin-2-yl)ethanone (0.15 g, 90%). LCMS calculated for C7H7BrNO (M+H)+: m/z=199.9, 201.9. found: 199.9, 201.9.
With sodium hydroxide; In methanol; at 0℃; for 5h;
sodium hydroxide 4.73g a (3.0eq) methanol 394mLIt was cooled stirring in warming dissolved to 0 to. This, in addition to the 2-acetyl-5-bromo-pyridine (Compound I-1-2) 7.88g and (39.4mmol) 2- furaldehyde 3.26mL (1.0eq), 5 hours with stirring at 0 did. The solvent in the reaction solution was concentrated under reduced pressure, and extracted · min was concentrated the residue with dichloromethane. The extract was purified by silica gel column chromatography to give compound the I-1-3 as a yellow solid 8.24g (75% yield). The structures of the compounds the I-1-3 was confirmed by 1H-NMR spectra.
4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]benzonitrile bis(2,2,2-trifluoroacetate)[ No CAS ]
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