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Structure of 97483-77-7 * Storage: {[proInfo.prStorage]}
* 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.
Preparation 245-Bromopyridine-2-carboxylic acidAdd 5-bromopicolinonitrile (1 g, 5.46 mmol) to concentrated HC1 (13.4 mL, 139.66 mmol) in a round bottomed flask. Heat the mixture to reflux with stirring overnight. Cool the mixture to room temperature. Filter the resulting white solid, washing with water. Dry the solid under reduced pressure to give 5-bromopyridine-2- carboxylic acid (0.707 g, 64percent) as a white solid. LC-ES/MS m/z 202 [M+H]+.
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
4
[ 626-55-1 ]
[ 7677-24-9 ]
[ 55758-02-6 ]
[ 13958-98-0 ]
[ 97483-77-7 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
5
[ 2402-97-3 ]
[ 7677-24-9 ]
[ 55758-02-6 ]
[ 97483-77-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 2, p. 565 - 571
[2] Patent: WO2010/30811, 2010, A2, . Location in patent: Page/Page column 77
[3] Patent: WO2009/55696, 2009, A1, . Location in patent: Page/Page column 90-91
6
[ 626-55-1 ]
[ 7677-24-9 ]
[ 55758-02-6 ]
[ 13958-98-0 ]
[ 97483-77-7 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14733 - 14737
7
[ 97483-77-7 ]
[ 31181-90-5 ]
Yield
Reaction Conditions
Operation in experiment
60%
With diisobutylaluminium hydride In tetrahydrofuran at -78℃; for 4 h;
To a stirred solution of 5-bromopicolinonitrile (0.5 g, 2.732 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at -78 °C DIBAL (4 mL, 4.98 mmol, 1.5 eq) was added and reaction mixture was stirred for 4 h at -78 °C. The reaction mixture was monitored by TLC, and quenched with 2N HCI (2 mL) and extracted with dichloromethane (10 mL), dried over sodium sulphate and evaporated to provide fairly pure 5-bromopicolinaldehyde (0.3 g, ~ 60 percent) which was used to the next stage without further purification.
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
Stage #1: With sodium azide; ammonium chloride In dimethyl sulfoxide at 95℃; for 4 h; Stage #2: at 50℃; for 24 h; Stage #3: for 3 h;
The 5 - bromo -2 - cyano pyridine (800g, 4.4 µM), dimethyl sulfoxide (4L) adding 20L in the bottle, addition of sodium azide (425.7g, 6 . 55 µM), ammonium chloride (350.3g, 6 . 55 µM), stirring, heated to 95 degrees, stirring 4 hours, cooling to room temperature.By adding sodium hydroxide (470g, 11.8 µM), dropping the dimethyl sulfate (665g, 5.3 µM), heating up to 50 degrees, stirring 24 hours, the reaction is finished, the addition of water (11L), centrifugal drying to obtain the crude product.The crude product by adding dilute hydrochloric acid, stirring 3 hours, filtration, the aqueous phase is 40percent of NaOH to adjust the PH=9 - 10, separating out 2 - methyl -5 - (5 - bromo pyridine -2 - yl) tetrazole, (792g, 3.3 µM), yield: 75percent.
Reference：
[1] Patent: CN106699730, 2017, A, . Location in patent: Paragraph 0016; 0017; 0018; 0019; 0020; 0021
12
[ 97483-77-7 ]
[ 380380-64-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 22, p. 5909 - 5915
[2] Patent: CN106432182, 2017, A,
[3] Patent: CN106432182, 2017, A,
[4] Patent: CN106432182, 2017, A,
[5] Patent: CN106432182, 2017, A,
[6] Patent: CN106432182, 2017, A,
[7] Patent: WO2008/108988, 2008, A1,
[8] Patent: WO2005/116023, 2005, A1, . Location in patent: Page/Page column 67
13
[ 97483-77-7 ]
[ 380380-64-3 ]
[ 380380-63-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039
[2] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1305 - 1313
[3] Patent: CN106146559, 2016, A,
[4] Patent: WO2005/116022, 2005, A1,
14
[ 97483-77-7 ]
[ 137178-88-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 2074 - 2079
15
[ 97483-77-7 ]
[ 73183-34-3 ]
[ 741709-63-7 ]
Yield
Reaction Conditions
Operation in experiment
46%
With potassium acetate In dimethyl sulfoxide at 20 - 80℃; for 96 h;
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile Into a 250 mL RBF was added 3.0 g 5-Bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol), Bis(pinacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74 mmol), and DMSO (100 mL). After degassing for 20 minutes, PdCl2dppf-CH2Cl2 (1.39 g, 1.64 mmol) was added and the solution was stirred for 24 hours at 80° C., and then room temperature for 3 days. 50 mL water was added and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The dark-colored residue was purified by FCC eluding with 20percent acetone/hexanes to give a red solid. The solid was triturated with hexane to give 1.72 g (46percent) Int-26 as a light-pink solid. Into a 250 mL round-bottomed flask was added 3.0 g of 5-bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol), bis(piniacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74 mmol), and DMSO (100 mL). After degassing for 20 minutes, PdCl2dppf-CH2Cl2 (1.39 g, 1.64 mmol) was added and the solution was stirred for 24 hours at 80° C., and then at room temperature for 3 days. 50 mL water was added and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The dark-colored residue was purified by flash column chromatography eluting with 20percent acetone/hexanes to give a red solid. The solid was triturated with hexane to give 1.72 g (46percent) of I-238 as a light-pink solid.
24%
With potassium acetate; palladium diacetate; triphenylphosphine In N,N-dimethyl-formamide at 80℃; Inert atmosphere
[0450] To a solution of5-bromopicolinonitrile (1.00 g, 5.46mmol) in DMF (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.77 g, 10.9 mmol),Pd(OAc)2 (61.0mg, 0.273 mmol), PPh3 (285 mg, 1.09 mmol)and KOAc (1.61 g, 16.4 mol) under a nitrogen atmosphere.The resulting mixture was stirred at 80° C. overnight. Thereaction mixture was cooled tort and the solids were removedby filtration. The filtrate was concentrated under reducedpressure to obtain a residue, which was purified by flashcolunm chromatography on silica gel with EtOAc/petroleumether (1 :50 v/v) to obtain compound 1f as a white solid (300mg, 24percent yield). Mass Spectrum (LCMS, ESI pos.): Calcd.for C12H15BN20 2 : 231.1 (M+H). found: 231.1.
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5473 - 5494
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 5, p. 1277 - 1281
[3] Patent: US2009/136473, 2009, A1, . Location in patent: Page/Page column 36; 61
[4] Patent: US2014/364414, 2014, A1, . Location in patent: Paragraph 0438; 0449-0450
[5] Patent: WO2009/74812, 2009, A1, . Location in patent: Page/Page column 70
16
[ 97483-77-7 ]
[ 856866-72-3 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1305 - 1313
[2] Patent: WO2008/108988, 2008, A1,
21
[ 24424-99-5 ]
[ 97483-77-7 ]
[ 1188477-11-3 ]
Yield
Reaction Conditions
Operation in experiment
47%
With sodium tetrahydroborate; nickel(II) chloride hexahydrate In methanol at 0 - 15℃; for 3 h;
To a mixture of 5- bromopicolinonitrile (3.0 g, 16.4 mmol) in MeOH (60 mL) was added di-tert-butyl dicarbonate (7.2 g, 32.8 mmol) and nickel chloride hexahydrate (0.33 g, 1.64 mmol). The mixture was cooled to 0°C, followed by portion wise addition of NaBH4 (4.3 g, 0.115 mol) over 2 hr. The mixture was stirred at 15°C for 1 hr then poured into ice- water (200 g) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (2.2 g, 47percent yield) as a yellow solid. LC-MS: m/z 287,289 (M+H)+.
650 mg
With sodium tetrahydroborate; nickel(II) chloride hexahydrate In methanol at 0 - 20℃; for 14 h;
Step 1 Preparation of (5-Bromo-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester To a solution of 5-Bromo-pyridine-2-carbonitrile (1.0 g, 5.46 mmol) in methanol (10 mL) at 0° C. is added NiCl2.6H2O (0.12 g, 0.54 mmol), Di-tert-butyl dicarbonate (2.38 g, 0.010 mmol) and NaBH4 (0.413 g, 0.010 mmol) at 0° C. then stirred at room temperature for 14 hours. The reaction solvent is removed under reduced pressure and crude is diluted with water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated in vacuum. The crude is purified by column chromatography eluting with 30percent ethyl acetate in hexane to afford the title compound (650 mg). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 4.37 (d, J=5.44 Hz, 2H), 5.41 (bs, 1H), 7.18 (d, J=8.28 Hz, 1H), 7.75-7.78 (dd, J1=8.32 Hz, J2=2.28 Hz, 1H), 8.57 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=289.0.
1 g
at 0 - 20℃; for 18 h;
To a solution of 5-bromo-2-cyanopyridine (5.0 g, 27.32 mmol) in methanol (50 mL) at 0 °C were added nickel (II) chloride hexahydrate (649 mg, 27.32 mmol), di-tert-butyl dicarbonate (11.9 g, 54.64 mmol) and sodium borohydride (2.06 g, 54.64 mmol). The reaction mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to afford 1.0 g of the titled product. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 4.39 (d, = 5.4 Hz, 2H), 5.47 (br s, 1H), 7.21 (d, = 8.1 Hz, 1H), 7.79 (d, = 8.1 Hz, 1H), 8.59 (s, 1H); APCI-MS (m/z) 289 (M+H)+.
Reference：
[1] Chemical Research in Toxicology, 2014, vol. 27, # 12, p. 2052 - 2061
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4403 - 4407
With triethylamine; In acetonitrile; for 4h;Reflux;Product distribution / selectivity;
Step 2: The mixture of 3-bromopyridine-l-oxide 2 (3.48 g, 20mmol), TMSCN (5.94 g, 60 mmol), Et3N (5.05 mL, 40 mmol) and CH3CN (30 mL) was heated to reflux for 4h until TLC indicated no 3-bromopyridine-l-oxide 2 existed. The reaction mixture was concentrated and the residue was purified by column chromatography (PE:EA = 10:1). 0.3 g 5-bromopicolinonitrile / 3.0 g 3-bromopicolinonitrile 3 were obtained as a white solid, yield 82.0%
With triethylamine; In acetonitrile; for 4h;Heating / reflux;
Step 2 The mixture of 3-bromopy?dine-1-oxide 2 (3 48 g, 20mmol), TMSCN (5 94 g, 60 mmol), Et3N (5 05 mL, 40 mmol) and CH3CN (30 mL) was heated to reflux for 4h until TLC indicated no 3-bromopyridine-1-oxide 2 existed The reaction mixture was concentrated and the residue was purified by column chromatography (P E EA=101) 0 3 g 5-bromopicolmomt?le / 3 0 g 3-bromopicolmomt?le 3 were obtained as a white solid, yield 82 0%
With sodium hydroxide; hydroxylamine hydrochloride; In ethanol; water; at 60 - 65℃; for 16h;
To a solution of 5-bromo-2-cyanopyridine (1.0 g, 5.50 mmol) in EtOH (100.0 mL) was added a solution of NaOH (0.22 g, 5.50 mmol dissolved in 2.0 ml H2O) followed by addition of NH2OH. HCI (0.38 g, 5.50 mmol). The resulting solution was heated to 60- 650C for 16 h. After the completion of reaction (TLC monitoring), the solvent was evaporated and the residue was acidified with 3% HCI solution (20.0 mL) and heated to 1000C till a clear solution was obtained. The reaction mixture was then cooled to room temperature and extracted with DCM (2 x 50 mL) that was later on discarded. The aqueous layer was basified with aqueous NH3 till pH 8 and extracted with EtOAc <n="67"/>(3 x 50 ml_). The combined organics was dried (Na2SO4), filtered and concentrated to obtain the desired product (0.75 g, 64%). MS: 216.01 (M+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 - 20C. Methylmagnesium bromide (43.7 mL, 3M) was added drop wise and the temperature was held between -20C and -10C for 3 hours. The reaction mixture was cooled to -40C and conc. HCI (4.5 mL) in water (15 mL) was added dropwise. It was stirred for 10 minutes at -35C 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 112C. The mother liquor was further concentrated and chromatographed on silica gel with dichloromethane/ ethylacetate (100:1) to give another 3.25 g product (65% combined yield). ¹H-NMR (DMSO-d6) No.: 2.60 (s, 3H) ; 7.88 (dd, 1H); 8.25 (dd, 1H); 8.86 (d, 1H).
65%
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 - 20C. Methylmagnesium bromide (43.7 mL, 3M) was added drop wise and the temperature was held between -20C and -10C for 3 hours. The reaction mixture was cooled to -40C and concentrated HCl (4.5 mL) in water (15 mL) was added dropwise. It was stirred for 10 minutes at -35C 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 112C. The mother liquor was further concentrated and chromatographed on silica gel with dichloromethane/ ethylacetate (100:1) to give another 3.25 g product (65% 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%
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, 30% yield).
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 20 - 110℃; for 3h;
lOg of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100ml of dimethylformamide, 5.33g of sodiumazide, and 4.4g of ammoniumchloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110C for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10. 5g of the title compound. Yield 85%.
85%
With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; at 110℃; for 3h;Inert atmosphere;
To a solution of 2-cyano-5-bromopyridine 7 (10 g, 54.6 mmol) in DMF (100 mL) was added sodium azide (5.33 g, 82.0 mmol) and ammonium chloride (4.38 g, 82.0 mmol). The reaction mixture was stirred for 3 h at 110 C. After being cooled to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the title compound (10.5 g, 85%). 1H NMR (DMSO-d6): delta 8.75 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H).
85%
With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; at 110℃; for 3h;
Will be 10 grams2-cyano-5-bromopyridine was dissolved in 100 ml of dimethylformamide,5.33 g of sodium azide and at room temperature were added4.4 g of ammonium chloride was added to the solution,The solution was stirred at a temperature of 110 C for 3 hours to carry out the reaction. Water was added to the reaction mixture and then extracted with ethyl acetate. The resulting organic layer was separated by brine, dehydrated, filtered and concentrated in vacuo to give 10.5 g of the title compound in 85% yield.
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 130℃; for 4h;
A solution of 5-bromo-2-cyanopyridine (1 g), ammonium chloride (4.3 g), and sodium azide (5.32 g) in DMF (50 mL) was stirred at 130 C. for 4 hours, cooled to ambient temperature, diluted with dichloromethane, washed with water and brine, and dried (Na2SO4), filtered and concentrated
With sodium azide; triethylamine hydrochloride; In toluene; at 100 - 110℃;Product distribution / selectivity;
To a solution of 5-bromopyridine-2-carbonitrile (1.5 g) in toluene was added sodium azide (1.33 g) and triethylamine hydrochloride (2.89 g). The reaction mixture was stirred overnight at 100-1100C, filtered and washed with methanol. The solvent was removed under vacuum to yield the title compound (1.8 g).
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;Product distribution / selectivity;
The intermediates for this Reference Example were prepared as follows:; 5-Bromo-2-tetrazol-5-ylpyridine; A mixture of 3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g , 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in NN-dimethylformamide (20 mL) was heated for 1 h at 120 C. The reaction mixture was diluted with ethyl acetate ((at)100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 20 - 80℃; for 96h;Product distribution / selectivity;
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile Into a 250 mL RBF was added 3.0 g 5-Bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol), Bis(pinacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74 mmol), and DMSO (100 mL). After degassing for 20 minutes, PdCl2dppf-CH2Cl2 (1.39 g, 1.64 mmol) was added and the solution was stirred for 24 hours at 80 C., and then room temperature for 3 days. 50 mL water was added and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The dark-colored residue was purified by FCC eluding with 20% acetone/hexanes to give a red solid. The solid was triturated with hexane to give 1.72 g (46%) Int-26 as a light-pink solid. Into a 250 mL round-bottomed flask was added 3.0 g of 5-bromo-pyridine-2-carbonitrile (3.0 g, 16.39 mmol), bis(piniacolato)diboron (4.58 g, 18.03 mmol), KOAc (5.47 g, 55.74 mmol), and DMSO (100 mL). After degassing for 20 minutes, PdCl2dppf-CH2Cl2 (1.39 g, 1.64 mmol) was added and the solution was stirred for 24 hours at 80 C., and then at room temperature for 3 days. 50 mL water was added and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated. The dark-colored residue was purified by flash column chromatography eluting with 20% acetone/hexanes to give a red solid. The solid was triturated with hexane to give 1.72 g (46%) of I-238 as a light-pink solid.
24%
With potassium acetate; palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
[0450] To a solution of5-bromopicolinonitrile (1.00 g, 5.46mmol) in DMF (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.77 g, 10.9 mmol),Pd(OAc)2 (61.0mg, 0.273 mmol), PPh3 (285 mg, 1.09 mmol)and KOAc (1.61 g, 16.4 mol) under a nitrogen atmosphere.The resulting mixture was stirred at 80 C. overnight. Thereaction mixture was cooled tort and the solids were removedby filtration. The filtrate was concentrated under reducedpressure to obtain a residue, which was purified by flashcolunm chromatography on silica gel with EtOAc/petroleumether (1 :50 v/v) to obtain compound 1f as a white solid (300mg, 24% yield). Mass Spectrum (LCMS, ESI pos.): Calcd.for C12H15BN20 2 : 231.1 (M+H). found: 231.1.
A solution of 5-bromo-2-cyanopyridine (0.50 g, 2.73 mmol), bispinacolatodiboron (0.76 g, 3.0 mmol) and KOAc (0.34 g, 4.10 mmol) in 1 ,4-dioxane (10.0 mL) was degassed by flushing with nitrogen for 15 min. Tricyclohexylphosphine (0.091 g, 0.33 mmol) and tris(dibenzyledineacetone) dipalladium (0) (0.14 g, 0.14 mmol) was then added to the reaction mixture, which was again degassed by nitrogen for 15 min. The resulting reaction mixture was heated to 1000C for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was filtered through celite bed and the filtrate was concentrated to get the crude residue that was carried forward to the next step without further purification. MS: 231.10 (M+H)+.
Part A: Compound 414 (1.0 g, 5.46 mmol) was suspended in diethylether (30 mL) and cooled to -78 0C. Titanium (IV) isopropoxide (1.7 mL, 6.01 mmol) was added dropwise and stirred for 5 minutes. Ethyl magnesium bromide (3M in diethylether, 4.0 mL) was added dropwise and stirred for 30 minutes at the same temperature and 1 hour at room temperature. Boron trifluoride dietherate (1.55 g, 10.92 mmol) was added dropwise and the reaction was stirred for 2 hours. The reaction was quenched with 1 M hydrochloric acid and the aqueous layer was washed with diethyl ether. The aqueous layer was made basic (pH = 10) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Column chromatography (1 :1 hexanes/ethyl acetate) provided the desired product (350 mg, 30%). 1H NMR (400 MHz, CDCI3) delta 8.5 (d, 1 H), 7.7 (m, 1H)1 7.3 (d, 1 H), 1.25 (m, 2H), 1.15 (m, 2H).
21%
With titanium(IV) isopropylate; In tetrahydrofuran; at 0 - 20℃; for 5h;Inert atmosphere;
Step A Preparation of mt 3-1 To a stirred solution of 5-bromo-2-cyanopyridine (30.0 g, 0.165 mol) and Ti(O/-iPr)4 (51.5 g, 0.18 1 mol) in 900 mL THF was added EtMgBr (330 mL, 0.045 mmol) under nitrogen at 0 C. The reaction mixture was allowed to stir at room temperature for 5 hours. The reaction was quenched by water and extracted by EtOAc, filtrated and the organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel eluted with petroleum ether : EtAOc = 30:1 toprovide product (7.2 g, 21%). MS-ESI (m/z): 213, 215 (M+H)
21%
With titanium(IV)isopropoxide; In tetrahydrofuran; at 0 - 20℃; for 5h;Inert atmosphere;
To a stirred solution of 5-bromo-2-cyanopyridine (30.0 g, 0.165 mol) and Ti(OiPr)4 (51.5 g, 0.181 mol) in 900 mL THF was added EtMgBr (330 mL, 0.045 mmol) under61wo 2014/004416 PCT/US2013/047451nitrogen at 0 C. The reaction mixture was allowed to stir at room temperature for 5 hours. Thereaction was quenched by water and extracted by EtOAc, filtrated and the organic layers weredried over Na2S04, filtrated and concentrated in vacuo. The resulting residue was purified usingflash column chromatography on silica gel eluted with petroleum ether : EtAOc = 30:1 to5 provide product (7.2 g, 21 %). MS-ESI (m/z): 213, 215 (M+Ht
21%
With titanium(IV) isopropylate; In tetrahydrofuran; at 0 - 20℃; for 5h;Inert atmosphere;
Step A Preparation of mt 3-1 10272] To a stirred solution of 5-bromo-2-cyanopyridine (30.0 g, 0.165 mol) and Ti(O-iPr)4 (51.5 g, 0.181 mol) in 900 mE THF was added EtMgBr (330 mE, 0.045 mmol) under nitrogen at 0 C. The reaction mixture was allowed to stir at room temperature for 5 hours. The reaction was quenched by water and extracted by EtOAc, filtrated and the organic layers were dried over Na2504, filtrated and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel eluted with petroleum ether:EtAOc=30:1 to provide product (7.2 g, 21%). MS-ESI (mlz):213, 215 (M+H)
21%
With titanium(IV) isopropylate; In tetrahydrofuran; at 0 - 20℃; for 5h;Inert atmosphere;
To a stirred solution of 5-bromo-2-cyanopyridine (30.0 g, 0.165 mol) and Ti(O-iPr)4 (51.5 g, 0.181 mol) in 900 mL THF was added EtMgBr (330 mL, 0.045 mmol) under nitrogen at 0 C. The reaction mixture was allowed to stir at room temperature for 5 hours. The reaction was quenched by water and extracted by EtOAc, filtrated and the organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel eluted with petroleum ether:EtAOc=30:1 to provide product (7.2 g, 21%). MS-ESI (m/z): 213, 215 (M+H)+
Description 10: 1-(5-bromopyridi -2-yl)cyclopropanamine (D10)5-bromopicolinonitrile (D9) (43.6 g, 0.238 mol) was suspended in diethyl ether (1 .3L) and the resulting mixture was cooled to -78C. Titanium (IV) isopropoxide (74.4 g, 0.262 mol) was added dropwise and the reaction mixture was stirred for 5 min. Ethylmagnesium bromide 1 M in diethyl ether (525ml, 0.525 mol) was added dropwise and the resulting reaction mixture was stirred for 30 mins at -78C. The reaction mixture was allowed to warm to room temperature for 1 hour then boron trifluoride etherate (107ml) was added dropwise. After stirred at room temperature for 2 hours, the reaction was quenched with 1 M HCI (1 .5L). The aqueous layer was washed with diethyl ether (1 L) and then basified (pH= 9) with 2N NaOH (1 .25L). The resulting mixture was extracted with ethyl acetate. The organic layer was dried over Na2S04 and evaporated in vacuo. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate 1 :1 . Collected fractions after solvent evaporation afforded the title compound (D10) (15.7 g) as a grey solid.
5-bromopicolinonitrile (D9) (43.6 g, 0.238 mol) was suspended in diethyl ether (1.3 L) and the resulting mixture was cooled to -78 C. Titanium (IV) isopropoxide (74.4 g, 0.262 mol) was added dropwise and the reaction mixture was stirred for 5 min. Ethylmagnesium bromide 1M in diethyl ether (525 ml, 0.525 mol) was added dropwise and the resulting reaction mixture was stirred for 30 mins at -78 C. The reaction mixture was allowed to warm to room temperature for 1 hour then boron trifluoride etherate (107 ml) was added dropwise. After stirred at room temperature for 2 hours, the reaction was quenched with 1M HCl (1.5 L). The aqueous layer was washed with diethyl ether (1 L) and then basified (pH=9) with 2N NaOH (1.25 L). The resulting mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography eluting with a mixture petroleum ether/ethyl acetate 1:1. Collected fractions after solvent evaporation afforded the title compound (D10) (15.7 g) as a grey solid.
Example A17 A solution of 3-amino-4-fluoro-phenol (5.6 g, 44 mmol) in dimethylacetamide (60 mL) was degassed in vacuo and was treated with potassium tert-butoxide (5.3 g, 47 mmol). The resulting solution was stirred for 30 min. 5-Bromo-pyridine-2-carbonitrile (6.6 g, 36 mmol) was added in one-portion and the mixture was heated at 80 C. overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to provide 5-(3-amino-4-fluorophenoxy)picolinonitrile (3.5 g, 44% yield). 1H-NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=3.0 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.06 (t, J=9.2 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.28 (m, 1H), 5.44 (br s, 2H); MS (ESI) m/z: 230.0 (M+H+).
44%
A solution of 3-amino-4-fluoro-phenol (5.6 g, 44 mmol) in dimethylacetamide (60 mL) was degassed in vacuo and was treated with potassium tert- butoxide (5.3 g, 47 mmol). The resulting solution was stirred for 30 min. 5-Bromo- pyridine-2-carbonitrile (6.6 g, 36 mmol) was added in one -portion and the mixture was heated at 80 C overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to provide 5-(3-amino-4- fluorophenoxy)colinonpiitrile (3.5 g, 44 % yield). 1H-NMR (300 MHz, DMSO-i/6) δ 8.47 (d, J= 3.0 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.44 (dd, J = 8.8, 2.7 Hz, 1 H), 7.06 (t, J = 9.2 Hz, 1 H), 6.52 (d, J = 7.6 Hz, 1 H), 6.28 (m, 1 H), 5.44 (br s , 2 H); MS (ESI) m/z: 230.0 (M+H+).
With potassium fluoride; In 1-methyl-pyrrolidin-2-one; at 175℃; for 18h;
The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175 C for 18 h, cooled to RT,diluted with H2O, extracted with EtOAc, the combined organicportions were washed with H20, brine, dried with Na2S04,filtered, condensed, the crude compound was purified byflash column chromatography (5 to 20% of EtOAc in hexanes).The titled compound was obtained as an off-white solid.
With potassium fluoride; In 1-methyl-pyrrolidin-2-one; at 175℃; for 18h;
The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73 mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175 C. for 18 h, cooled to RT, diluted with H2O, extracted with EtOAc, the combined organic portions were washed with H2O, brine, dried with Na2SO4, filtered, condensed, the crude compound was purified by flash column chromatography (5 to 20% of EtOAc in hexanes). [1978] The titled compound was obtained as an off-white solid.
With pyridine; sodium azide; zinc(II) chloride; at 40 - 120℃; for 2h;
Pyridine (40.0 mL, 4.0 v/w) was placed in a reactor, and zinc chloride (11.2 g, 81.9 mmol) was added dropwise at 40C or less. Thereafter, sodium azide (8.90 g, 137 mmol) and 5-bromo-2-cyanopyridine (10.0 g, 54.6 mmol) were added into the reactor, and the reaction mixture was stirred to reflux at 120C for 2 hr. After the termination of the reaction, the reaction product was cooled to room temperature, added with purified water (200 mL, 20.0 v/w), stirred at room temperature for 1 hr, filtered, and washed with purified water (200 mL, 20.0 v/w). The filtered solid was added with a 6 N hydrochloric acid aqueous solution (200 mL, 20.0 v/w) and then stirred at room tem[43jperature for 2 hr. The reaction product was filtered, washed with purified water (200mL, 20.0 v/w), and concentrated under reduced pressure, thus yielding a desired whitecompound. Yield (11.34 g, 91.8%), Purity 99.4%5-bromo-2-(2H-tetrazol-5-yl)pyridine:1H NMRoe (DMSO-d6, ppm) 8.95 (d,1H), 8.35 (dd,1H), 8.17 (d,1H)
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;
5-Bromo-2-tetrazol-5-ylpyridine. A mixture OF 3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in N,N-dimethylformamide (20 mL) was heated for 1 h at 120 C. The reaction mixture was diluted with ethyl acetate (~ 100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;
5-BROMO-2-TETRAZOL-5-YLPYRIDINE A mixture of 3-BROMO-6-CYANO-PYRIDINE (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0. 59 g, 11 mmol) in N, N-DIMETHYLFORMAMIDE (20 mL) was heated for 1 h at 120 C. The reaction mixture was diluted with ethyl acetate (-100 ML) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;
5-Bromo-2-tetrazol-5-ylpyridine A mixture of 3-BROMO-6-CYANO-PYRIDINE (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in N, N-dimethylformamide (20 mL) was heated for 1 h at 120 C. The reaction mixture was diluted with ethyl acetate (-100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification
With sodium azide; ammonium chloride; In DMF (N,N-dimethyl-formamide); at 120℃; for 1h;
A mixture of 3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in N, N-DIMETHYLFORMAMIDE (20 mL) was heated for 1 h at 120 C. The reaction mixture was diluted with ethyl acetate (-100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
To the solution of 5-bromopicolinonitrile (2.33 g, 12.7 mmol) in DMF (26 mL) was added NH4Cl (2.18 g, 40.7 mmol) and NaN3 (1.24 g, 19.1 mmol) at r.t.and the mixture was heated to 120 0C for 4 h. The reaction mixture was poured into ice water (100 mL) and acidified to pH=2 with 6N HCl, stirred for 1 h, and the mixture was extracted with EtOAc. The organic phases were combined, dried (Na2SO4) and evaporated under vacuum to give crude 5-bromo-2-(2H-tetrazol-5-yl)pyridine in 3.15g, which was used for next step without further purification.
3.8 G of sodium and 300 mi of ter-amyl alcohol are heated up to 1 00C under a nitrogen atmosphere and stirred for 15 hours. The reaction mixture is allowed to cool to room temperature. 27.7 G OF 2-CYANO-5-BROMOPYRIDINE are added and heated up to 110C. As soon as the temperature has been reached, a solution of 16.2 G of <strong>[924-88-9]diisopropyl succinate</strong> and 100 mi of tert-amyl alcohol is added over 1 hour using a dropping funnel. When the addition has been completed, the reaction mixture is kept for 20 hours at 1 00C and cooled down to 65C. Then 300MOI of water are added and the resultant pigment suspension is filtered at room temperature, washed with methanol and water until washings run colorless and dried at 100C in vacuum, affording 6.6 G (9.8% of theory, based on dibutyl succinate) of 1,4-diketo- 3, 6-BIS-2- (5-BROMOPYRIDIN-YL)-PYRROLO- (3, 4-C)-PYRROLE
With potassium carbonate; In 1-methyl-pyrrolidin-2-one;
5-Bromo-pyridine-2-carbonitrile (2.63 g, 13. 7MMOL), sodium methanethiolate (1.44 g, 20.5 mmol), potassium carbonate (3.79 g, 27.4 mmol) in NMP (60 ML) were stirred in a sealed flask overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water several times, brine and dried over sodium sulphate. The solvent was removed in vacuo to afford the title compound as a yellow solid (2.0 g, 99%). 1H NMR (CD30D) : 8 8.54 (1H, d, J 2.3 Hz); 7.83-7. 71 (2H, m); 2.60 (3H, s).
99%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one;
5-Bromo-pyridine-2-carbonitrile (2.63 g, 13.7mmol), sodium methanethiolate (1.44 g, 20.5 mmol), potassium. carbonate (3.79 g, 27.4 mmol) in NMP (60 ml) were stirred in a sealed flask overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water several times, brine and dried over sodium sulphate. The solvent was removed in vacuo to afford the title compound as a yellow solid (2.0 g, 99%). 1H NMR (CD30D) : 8 8. 54 (1H, d, J 2.3 Hz); 7. 83-7. 71 (2H, m); 2.60 (3H, s).
With sodium t-butanolate; In water; acetonitrile; at 0 - 20℃; for 16h;
To a solution of AG-1 (82.0 g, 448 mmol) in ACN (1.0 L) is added sodium t-butoxide (64.5 g). The mixture is cooled to 0 C and sodium methanethiolate (172.5 g, 20% in H20) is added dropwise. The reaction mixture is then allowed to stir at rt for 16 h. Water (800 mL) is added and the mixture is extracted with DCM. The combined organic phases are washed with brine, dried (Na2S04) and concentrated. The residue is purified by Si02 flash chromatography to yield AO-2.
With sodium t-butanolate; In water; acetonitrile; at 0 - 20℃; for 16h;
To a solution of AI-1 (82.0 g, 448 mmol) in ACN (1.0 L) is added sodium t-butoxide (64.5 g). The mixture is cooled to 0 C and sodium methanethiolate (172.5 g, 20% in H20) is added dropwise. The reaction mixture is then allowed to stir at rt for 16 h. Water (800 mL) is added and the mixture is extracted with DCM. The combined organic phases are washed with brine, dried (Na2S04) and concentrated. The residue is purified by Si02 flash chromatography to yield AI-2.
With sodium t-butanolate; In acetonitrile; at 0 - 20℃; for 16h;
To AG-1 (82.0 g, 448 mmol)Sodium terp-butoxide (64.5 g) was added to the solution in ACN (1.0 L).The mixture was cooled to 0 C and sodium methanethiolate (172.5 g, 20% H 2 O solution) was added dropwise.The reaction mixture was then allowed to stir at rt for 16 h.Water (800 mL) was added and the mixture was extracted with DCM. The combined organics were washed with brine, dried (Na2EtOAc)The residue was purified by flash chromatography on SiO2 to yield AQ-1.
With sodium t-butanolate; In water; acetonitrile; at 20℃; for 16h;
To a solution of AG-1 (82.0 g, 448 mmol) in ACN (1.0 L) is added sodium t-butoxide (64.5 g). The mixture is cooled to 0 C and sodium methanethiolate (172.5 g, 20% in H20) is added dropwise. The reaction mixture is then allowed to stir at rt for 16 h. Water (800 mL) is added and the mixture is extracted with DCM. The combined organic phases are washed with brine, dried (Na2S04) and concentrated. The residue is purified by Si02 flash chromatography to yield AQ-1.
A solution of 5-bromopicolinonitrile (3.0 g, 16.4 mmol) in BH3 THF (99 mL, 99mmol, 1M) was heated at reflux temperature for 2h under N2. MeOH (12 mL) was added slowly followed by IN HC1 (24 mL). The mixture was then refluxed for an additional 7h. After cooling, the reaction mixture was poured into 10% of K2C03 (300 mL) and extracted with DCM (3x100 ml). The combined organic layers were concentrated to give crude product which was used in next step without further purification (2.1 g, Yield 70%).
With diborane; In tetrahydrofuran; at 0 - 25℃; for 1h;
Step 1: Preparation of (5-bromopyridin-2-yl)methanamine2 To a solution of borane (400 ml, 400 mmol, 1M in THF) was added 5-bromopicolinonitrile (15 g, 82 mmol, commercial from Shanghai EachChem Co. Ltd.) in portions at 0C. The resulting solution was stirred at 25 C for 1 h. The reaction was then quenched by the addition of water (200 ml). The resulting mixture was stirred at 60C for 30 min before the addition of hydrochloric acid (50 ml, 100 mmol, 2 M). The pH value of the mixture was adjusted to pH 8 with aqueous sodium hydroxide (2 M). The mixture was stirred at 25C for 10 min, after which it was extracted with DCM (3 x 100 ml). The combined organic fractions was dried over sodium sulfate, filtered and concentrated in vacuo to afford (5- bromopyridin-2-yl)methanamine which was used without further purification. MS (ESI) Calc'd for (C6H8BrN2) [M+H]+, 187, 189; found, 187, 189.
To a solution of 5-bromopicolinonitrile (5 g, 27.32 mmol) in THE, BH3.THF (IM solution) (163.92 mL, 163.92 mmol) was added at rt and the mixture was heated to reflux for 2 h. It was then cooled to 0C and MeOH (20 mL) and I N HCI solution were added. The mixturewas further refluxed for 7 h. It was quenched with 10% K2C03 solution (500 mL) and extracted with DCM (6 x 100 mL). The combined organic layer was dried over Na2SO4 and concentrated under vacuum affording the title product. It was taken for next step without any further purification (Yellow solid). LCMS: (Method A) 187.3 (M+H), Rt. 1.33 mm, 77.38% (Max).
To 5-bromo-pyridine-2-carbonitrile (209) (1.0 g, 5.46 mmol) in tetrahydrofuran (10 mL) at -78 C was added lithium aluminum hydride (1.0 M, 13.66 mL, 13.66 mmol). The reaction was stirred for 2 hours at -78 C. The mixture was quenched at-78 C with 10: 1 THF: water. The mixture was warmed to room temperature, diluted with ethyl acetate and stirred with 1.0 N sodium hydroxide for 10 minutes. The reaction mixture was filtered through celite and the layers were separated. The organic layer was washed with 1.0 N sodium hydroxide and brine, dried over sodium sulfate and concentrated to afford 210 as an oil (600 mg). material was used without further purification.
Example 311 Synthesis of (5-bromopyridin-2-yl)methanamine. To a solution of 5-bromopicolinonitrile (15 g, 81.96 mol) was added a borane THF complex solution (107 mL, 1 M). The mixture was stirred at ambient temperature overnight. The reaction was quenched with MeOH (50 mL), stirred at RT for lh, and then concentrated to give (5-bromopyridin-2-yl)methanamine (crude) as a brown oil which was used in the next step without purification. ESI-MS [M+H]+: 188.1.
A solution of 75 g of 5-bromo-pyridin-2-carbonitrile [97483-77-7] in 375 ml of tetrahydrofuran is treated dropwise with a solution of 172 ml methyl magnesium bromide (3M solution in diethyl ether) in 150 ml of tetrahydrofuran and stirred for Minutes at room temperature. The suspension is then treated with 750 ml of methanol and portionwise with 30 g of sodium borohydride. The reaction mixture is stirred 10 hours at room temperature, concentrated by evaporation and treated with ethyl acetate and 2m NaOH. The phases are separated and the aqueous phase is extracted with ethyl acetate (3x). The combined organic phases are washed with brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.54 (dichloromethane-methanol-25% ammonia conc. 80:10:1); Rt = 2.02 (gradient I).
A solution of 75 g of 5-bromo-pyridin-2-carbonitrile [97483-77-7] in 375 ml of tetrahydrofuran is treated dropwise with a solution of 172 ml methyl magnesium bromide (3M solution in diethyl ether) in 150 ml of tetrahydrofuran and stirred for Minutes at room temperature. The suspension is then treated with 750 ml of methanol and portionwise with 30 g of sodium borohydride. The reaction mixture is stirred 10 hours at room temperature, concentrated by evaporation and treated with ethyl acetate and 2m NaOH. The phases are separated and the aqueous phase is extracted with ethyl acetate (3x). The combined organic phases are washed with brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf = 0.54 (dichloromethane-methanol-25% ammonia conc. 80:10:1); Rt = 2.02 (gradient I).
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90℃;
Preparation 38; (E)-2-Aminomethyl-5-(2-cyclohexylvinyl)-pyridine; (E)-5-(2-Cyclohexylvinyl)-pyridine-2-carbonitrile; Combine a mixture of 5-bromo-2- cyano-pyridine (2 g, 10.93 mmol), 2-cyclohexylvinyl boronic acid (2.52 g, 16.39 mmol), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (446 mg, 0.546 mmol) and 2M aqueous Na2CO3 (18.2 mL, 36.07 mmol) in 1,4-dioxane (110 mL). Purge with nitrogen and heat at 90C overnight. Cool the reaction to room temperature and partition between EtOAc and water. Separate the aqueous phase and extract with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min and 19:1 over 5 min; 50 mL/min) to obtain the desired intermediate (1.76 g, 76%). MS (APCI+) m/z: 213 (M+H)+.
With modified hectorite-loaded ionic liquid; In dimethyl sulfoxide; at 100 - 110℃; for 8h;Inert atmosphere;
The organically modified hectorite-loaded ionic liquid material prepared by the first embodiment of the present invention (abbreviated as MHIL) is used as a catalyst for catalytic condensation to prepare an intermediate for the treatment of diabetes drugs 5-[(3R)-3-methylperazine Pyrazin-1-yl]pyridine-2-carbonitrile (CN 101400653A),The reaction is shown in Scheme3:5-bromo-2-cyanopyridine (10 mmol, 1.81 g) under nitrogen atmosphere,Catalyst MHIL (0.36g, 20wtpercent),(R)-(-)-2-methylpiperazine (1.3 g, 13 mmol) was placed in 20 ml of dimethyl sulfoxide at 100-110 ° C. After 8 h, the reaction liquid was HPLC-detected for substrate 5-bromine- 2-cyanopyridine was not detected. The catalyst was filtered to remove MHIL. The filtrate was added with 20 ml of a 3 Mpercent aqueous solution of methylamine, and then extracted twice with 20 ml of dichloromethane. The methyl chloride layer is concentrated under reduced pressure5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile 1.88 g, yield 93percent, HPLC purity 99.86percent, LC-MS: m/z = 203.1 [M +H].The organic modified hectorite-loaded ionic liquid material prepared by the invention (abbreviated as MHIL) is used as a catalyst for preparing an intermediate for the treatment of diabetes drugs 5-[(3R)-3-methylpiperazin-1-yl] Pyridine-2-carbonitrile does not require the addition of precious metal palladium as compared to CN 101400653A, and the yield is significantly improved.Although the embodiments of the present invention have been described in detail, it is understood that various changes, modifications and changes may be made in the embodiments of the present invention without departing from the spirit and scope of the invention.
39.1%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 0.583333h;Microwave irradiation;
Example 29V. 2-(3-(r(2J?')-4-(6-ri-amino-2.2.2-trifluoro-l-('trifluoromethvnethvnpyridin-3-vU- 2-meth ylpjperazin- 1 -yli sulfonyl ) phenyl*)- 1.1,1 -trifluoropropan-2-ol; Step A; A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2- cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalldium (0) (83.15 mg, 0.0908 mmol), rac-2,2'-bis(diphenylphosphino)-l,F-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at HO0C for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3lambda)-3- methylpiperazin-l-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1percent yield).
39.1%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 0.583333h;Microwave irradiation;
Example 142-(3-[(2R)-4-{6-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridin-3-yl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol; Step 1A: A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2-cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalldium (0) (83.15 mg, 0.0908 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (169.37 mg, 0.272 mmol) and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile as brown color oil (1.15 g, 39.1percent yield).
[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.
With potassium carbonate;copper(l) iodide; dimethylaminoacetic acid; In dimethyl sulfoxide; at 130℃; for 3h;
A mixture of 3-bromo-6-pyridinecarbonitrile (1.83g, lOmmolmmol), 3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole (1.9Og, lOmmol), copper (I) iodide (10mol%, 1 mmol, 191 mg), N,N-dimethylglycine (20mol%, 2mmol, 206mg), and potassium carbonate (21 mmol, 2.9Og) in dimethylsulfoxide (20ml) was stirred at 13O0C in an oil bath under argon for 3h. The reaction mixture was then filtered and the filtrate separated between dichloromethane and brine and the organic layer retained and dried over sodium sulphate. Sample was then purified on a 2Og pre-packed silica column using 20% ethyl acetate/petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a yellow solid (2.56g, 88%).LC/MS (ES): Found 293 (ES+), retention time 3.37mins. C14H11F3N4 requires 292.1 H-NMR (400MHz, CDCI3): 1.83-1.92 (4H, m), 2.69 (2H, m), 2.83 (2H, m), 7.83 (1 H, m), 8.10 (1 H, dd, J=8Hz, & 2Hz), 8.97 (1 H, d, J=2Hz).
6
To a degassed mixture of 5-bromo- 2-cyanopyridine (3.66 g, 0.02 mol) and 2,5-bis(trimethylstannyl) thiophene (4.90 g, 0.01 mol) in 60 ml_ anhydrous dioxane was added Pd(PPh3)4 (2 mol %) and the mixture was refluxed for 10-12 hr (TLC followed, 8:2 EtOAc:hexanes). Solvent was removed and the residue triturated with hexane, filtered, and then washed with hexane. The yellow cake with Pd was dissolved in approximately 400 ml_ hot DMF. Ethyl acetate (50 ml_) was added and the hot solution was filtered through a celite bed which was then washed with a mixture of hot DMF: EtOAc (3:1 , 100 ml_). The solvent was concentrated in vacuum, diluted with water and filtered, washed with water, and dried in vacuum. The solid was suspended in a methanol:CHCI3 (1 :3, 75 ml_) mixture, stirred, washed with hexane and dried in vacuum at 800C for 12 hr to provide the title dinitrile as a yellow solid (2.1 g, 73% yield); m.p. >290°C dec. 1H-NMR (DMSO-cfe): 9.20(d, 2H, J=2.1 Hz), 8.32(dd, 2H, J=2.1 Hz, J=8.4Hz), 8.11 (d, 2H, J=8.4Hz), 7.83(s, 2H). 13C-NMR (DMSO-c/6): 146.8, 145.8, 134.2, 133.2, 130.6, 129.8, 128.5, 117.3. MS: m/e 288(M+). Anal, calcd. for Ci6H8N4S: C, 66.65; H, 2.79; N, 19.43. Found: C, 66.61 ; H, 2.73; N, 19.33.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 83℃; for 18h;Inert atmosphere;
A mixture of 5-bromopicolinonitrile 1.83g (0.01mol), phenylboronic acid 1.83g (0.015mol), Tetrakis (triphenylphosphine)palladium 0.35g (0.65mmol), was added in tetrahydroufuran (THF) 24mL, and 2M potassium carbonate aqueous solution 10mL. The mixture was heated to 83C and stirred for 18h under nitrogen atmosphere. After cooling to room temperature, the mixture was extracted with dichloromethane and deionized water, the combined organic layer was dried with anhydrous magnesium sulfate overnight and filtered. The filtrate was evaporated to remove the solvent and the residual was purified on a silica column using PE/EtOAc (V: V=7: 1) as the eluent to give a white solid 1.35g (7.5mmol), yield 75%. 1H NMR (400MHz, CDCl3, TMS) delta: 8.97-8.91 (m, 1H), 8.01 (dd, J=8.1, 2.2Hz, 1H), 7.78 (d, J=8.1Hz, 1H), 7.60 (d, J=7.9Hz, 2H), 7.56-7.45 (m, 3H).
39%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 24h;
In an oven dried flask under a nitrogen atmosphere 2-cyano-5-bromopyridine I (1.0 g, 5.46 mmol, 1.0 eq), phenylboronic acid (0.80 g, 6.55 mmol, 1.2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.315 mg, 0.27 mmol, 0.05 eq) were combined. Degassed 1,2-dimethoxyethane (10 mL) and 2 M potassium carbonate in water (10 mL) were added. The reaction was heated to 90 C. for 24 hours. The DME was removed and the residue was taken up in ethyl acetate. The ethyl acetate was washed with brine and dried with sodium sulfate. The crude product was adsorbed onto silica gel and purified via column chromatography (hexanes/ethyl acetate gradient) to give 386 mg of a colorless oil (39% yield).
With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; at 85 - 94℃;
To a 22-L, three-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, thermocouple and heating mantle was charged 5-bromo-2- cyanopyridine (799 g, 4.37 mol, 1 weight), LambdazetajV-dimethylformamide (6.4 L, 8 volumes), ammonium chloride (350.3 g, 6.55 mol, 1.5 equivalents), and sodium azide (425.7 g, 6.55 mol, 1.5 equivalents) while stirring. The internal reactor temperature set-point was adjusted to 85C (Target temperature is 900C). The temperature set-point was reached after 45 minutes, and the reaction continued to self-heat to 94C over 40 minutes. The reaction was judged to be complete after 1 hour by HPLC analysis by complete consumption of the starting material with an assay of 76.7% (AUC) of the tetrazole ammonium salt. The mixture was cooled and filtered at room temperature. The reactor and wet cake were washed with 2-propanol (3.2 L, 4 volumes) and dried under high vacuum at ambient temperature to afford the tetrazole ammonium salt as an off-white solid (847.9 g, 80% yield, 89.9% AUC). A differential scanning calorimetry experiment was conducted on the tetrazole ammonium salt to understand its thermal stability. The salt melted at approximately 228C and had an energetic decomposition at approximately 2700C.
With diisobutylaluminium hydride; In tetrahydrofuran; at -78℃; for 4h;
To a stirred solution of 5-bromopicolinonitrile (0.5 g, 2.732 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at -78 C DIBAL (4 mL, 4.98 mmol, 1.5 eq) was added and reaction mixture was stirred for 4 h at -78 C. The reaction mixture was monitored by TLC, and quenched with 2N HCI (2 mL) and extracted with dichloromethane (10 mL), dried over sodium sulphate and evaporated to provide fairly pure 5-bromopicolinaldehyde (0.3 g, ~ 60 %) which was used to the next stage without further purification.
A solution of <strong>[97483-77-7]5-bromo-2-pyridinecarbonitrile</strong> (2.0 g, 10.9 mmol) in dichloromethane (75 mL) was cooled to -78 degrees C., then a solution of DIBAL in toluene (1.5 M, 7.3 mL, 10.9 mmol) was added dropwise, taking care to keep the temperature below -65 degrees C. The resulting orange solution was stirred at -78 degrees C. for 5 h, then was allowed to gradually warm to 0 degrees C. The reaction was cooled back to -78 degrees C., then was quenched by dropwise addition of 20% aq. HCl. After warming to room temperature, the organic layer was separated, concentrated in vacuo and purified by chromatography to provide the product. The aqueous layer was treated with solid sodium bicarbonate until neutral, then this emulsion was extracted with ethyl acetate (3×). These extracts were dried over sodium sulfate and concentrated in vacuo to provide additional product, 5-bromo-2-pyridinecarbaldehyde. 1H NMR (400 MHz, CDCl3) delta 7.85 (d, J=8.18 Hz, 1H), 8.02 (d, J=8.18 Hz, 1H), 8.85 (s, 1H), 10.03 (s, 1H).
With diisobutylaluminium hydride; In tetrahydrofuran; at -78℃; for 4h;
Step 1 To a stirred solution of 5-bromopicolinonitrile (0.5 g, 2.732 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at -78 C. DIBAL (4 mL, 4.98 mmol, 1.5 eq) was added and reaction mixture was stirred for 4 h at -78 C. The reaction mixture was monitored by TLC, and quenched with 2N HCl (2 mL) and extracted with dichloromethane (10 mL), dried over sodium sulfate and evaporated to provide fairly pure 5-bromopicolinaldehyde (0.3 g, 60%) which was used to the next stage without further purification.
Synthesis of 5-bromopicolinaldehyde To a stirred solution of 5-bromopicolinonitrile (5.00 g, 27.3 mmol, 1 eq) in THF (50 mL) was added 1 M DIBAL (41 mL, 40.98 mmol, 1 eq) slowly dropwise at -78C and the RM was stirred for 6 h at same temperature. The RM was quenched with 1 N HCI at -78C and neutralized with saturated NaHC03 solution, extracted with EtOAc, dried (Na2S04), and concentrated to get 5-bromopicolinaldehyde (3.00 g, 59%), which was used without further purification. TLC system: EtOAc/PE (2:3), Rf: 0.5
With potassium carbonate; In dimethyl sulfoxide; at 160℃; for 2h;
Step 1: 5-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)pyridine-2-carbonitrile A mixture of <strong>[17680-55-6]7-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (0.30 g, 1.4 mmol), 5-bromopyridine-2-carbonitrile (0.28 g, 1.5 mmol) and potassium carbonate (0.39 g, 2.8 mmol) in dimethyl sulfoxide (2.0 mL) was heated at 160 C. for 2 h. After cooled to r.t., the mixture was quenched with water (10 mL), and extracted with ethyl acetate (3*20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with 30% ethyl acetate in hexanes to afford the desired product (0.15 g, yield: 34%). Analytic LCMS (M+H)+: m/z=314.2/316.2.
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,2-dimethoxyethane; at 80℃; for 24h;Inert atmosphere;
A solution of Pd2(dba)3 (91.5mg, 0.10mmol), XPhos (191mg, 0.40mmol), K3PO4 (2.12g, 10mmol), and 5-bromo-2-cyanopyridine (732mg, 4.0mmol) in 1,2-dimethoxyethane (29mL) was stirred and degassed with nitrogen for 10min at room temperature. Piperidine (375mg, 4.4mmol) was added. The mixture was heated at 80C under nitrogen atmosphere and stirred for 24h. After cooling to room temperature, the product was isolated by column chromatography on silica gel using CH2Cl2/methanol (9/1) as an eluent (yellow oil, 674mg, 90%). 1H NMR (400Hz, CDCl3) delta=1.69 (s, 6H), 3.38 (s, 4H), 7.05 (dd, 1H, J=8.4, 3.2Hz), 7.47 (d, 1H, J=8.4Hz), 8.28 (d, 1H, J=2.4Hz); 13C{1H} NMR (100MHz, CDCl3) delta=24.0, 25.0, 47.8, 118.5, 118.9, 120.1, 129.0, 138.0, 148.1; MALDI-MS calcd for C11H14N3 [M+H]+ 188.1; Found 188.1. Anal. Calcd for C11H13N3: C 70.56, H 7.00, N 22.44; Found: C 70.32, H 7.26, N 22.09.
63%
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,2-dimethoxyethane; at 80℃;sealed tube; Inert atmosphere;
A solution of 500 mg (2.73 mmol) 5-bromopicolinonitrile, 63mg (0.07 mmol) Pd2dba3 and 130 mg (0.27 mmol) 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl in 20 ml DME was stirred and degassed with N2 for 10 min. 1.45 g (6.83 mmol) K3PO4 and 297 mul (3.0 mmol) piperidine were added. The mixture was heated at 80 0C under N2 over night. The mixture was cooled to r.t. and filtered through a plug of SiO2 with CH2Cl2MeOH 9:1. The filtrate was concentrated and purified by flash chromatography (SiO2, Pet. ether/EtOAc 4:1 ? 1 : 1) to afford 323 mg (63%, yellow oil). 1U NMR (CDCl3) delta 8.28 (d, IH), 7.47 (d, IH), 7.05 (m, IH), 3.37 (m, 4H), 1.69 (m, 6H).
63%
5-(piperidin-1-yl)picolinonitrile A solution of 500 mg (2.73 mmol) 5-bromopicolinonitrile, 63 mg (0.07 mmol) Pd2 dba3 and 130 mg (0.27 mmol) 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl in 20 ml DME was stirred and degassed with N2 for 10 min. 1.45 g (6.83 mmol) K3PO4 and 297 mul (3.0 mmol) piperidine were added. The mixture was heated at 80 C. under N2 over night. The mixture was cooled to r.t. and filtered through a plug of SiO2 with CH2Cl2/MeOH 9:1. The filtrate was concentrated and purified by flash chromatography (SiO2, Pet. ether/EtOAc 4:1?1:1) to afford 323 mg (63%, yellow oil). 1H NMR (CDCl3) delta 8.28 (d, 1H), 7.47 (d, 1H), 7.05 (m, 1H), 3.37 (m, 4H), 1.69 (m, 6H).
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 20h;
5-bromopicolinonitrile (2.0 g, 10.9 mmol), imidazole (818 mg, 12 mmol) potassium carbonate (1.66 g, 12 mmol) and dimethylformamide (40 mL) were combined and heated to 130 C. for 20 hours. The reaction solution was evaporated and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The phases were separated and the organic phase was washed with water (50 mL), dried over magnesium sulfate and evaporated to give a residue which was purified by flash chromatography eluting with 2-3% methanol in dichloromethane gradient to give 5-(1H-imidazol-1-yl)picolinonitrile (1.23 g, 66%).
66%
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 20h;
Acid Preparation 6: 5-(1H-imidazol-1-yl)picolinic acid 5-bromopicolinonitrile (2.0 g, 10.9 mmol), imidazole (818 mg, 12 mmol) potassium carbonate (1 .66 g, 12 mmol) and dimethylformamide (40 mL) were combined and heated to 130 C for 20 hours. The reaction solution was evaporated and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The phases were separated and the organic phase was washed with water (50 mL), dried over magnesium sulfate and evaporated to give a residue which was purified by flash chromatography eluting with 2-3% methanol in dichloromethane gradient to give 5-(1H-imidazol-1-yl)picolinonitrile (1.23 g, 66%).
At 0?, a solution of 3M methyl magnesium bromide in THF (2.09mL, 6.28mmol) was added into a solution of 5-bromo-2-cyanopyridine (1.0g, 5.46mmol) in anhydrous THF (10mL). The mixture was warmed to room temperature slowly, further stirred for 30mins, and followed by adding methanol (20mL), adding NaBH4 (410mg, 10.93mmol) in portions. The mixture was further stirred for 10hrs, followed by adding water (10mL) and 2M NaOH aq. solution (10mL) in turn, being extracted with EA (50mL*3). The organic phases were combined, washed in turn with water (20mL*3) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica preparative plate (PE:EA = 1:1) to give white solid 25-e (1.0g, yield 91%). LC-MS (ESI): m/z = 201 [M+H]+.
59%
PREPARATION 108[1-(5-Bromo-pyridin-2-yl)-ethyl]-carbamic acid tert-butyl esterTo a stirred solution of 5-bromo-pyridine-2-carbonitrile (1 g, 5.46 mmol) in dry THF (10 mL) was added dropwise MeMgBr (2.03 mL, 6.09 mmol,3M in THF) at -20 C under N2 atmosphere. After the addition, the reaction mixture was stirred at room temperature for 30 mins. The suspension was then treated with methanol (20 mL) and NaBH (0.4 g, 13.3 mmol). The reaction was stirred at room temperature for 10 hrs and then poured into H20 (10 mL) and aqueous NaOH (2M, 10 mL), extracted with EtOAc (50 mL chi 2). The combined organic layers were washed with brine (50 mL chi 3), dried over Na2S0 and concentrated in vacuum. The residue was purified by a silica gel columnchromatography (petroleum: EtOAc 3:1 ) to give 1-(5-bromo-pyridin-2-yl)-ethylamine (0.65 g, 59%) as a yellow liquid. To a solution of 1-(5-bromo-pyridin-2-yl)-ethylamine (500 mg, 2.48 mmol) and E_3N (300 mg, 2.98 mmol) in DCM (10 ml_) was added Boc20 (650 mg, 2.98 mmol) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 5 hrs. TLC (petroleum ether: EtOAc 5:1 ) indicated the reaction was completed. Then the mixture was poured into brine (10 ml_) and extracted with with DCM (50 ml_ 3), washed with brine (10 ml_ chi 3), dried over Na2SO4, concentrated in vacuum to give the residue, which was purified by Biotage (petroleum ether/EtOAc 3:1 , Rf~ 0.6) to give the title compound (450 mg, 60%) as a yellow solid.
To a stirred solution of 5-bromopicolinonitrile (10 g) in dry THE (150 mL) was added methylmagnesium bromide (20 mL, 3 M in THE) at -20C. After addition, the mixturewas allowed to warm to RT with stirring for 30 minutes. The reaction mixture was then treated with MeOH (200 mL) and NaBH4 (4 g). The reaction was stirred at RT for 15 hours and then poured into a solution of NaOH in water (200 mL, 1 M). The organic solvent was removed under reduced pressure and the aqueous phase was extracted with EA (100 mL x 3). The combined organic phase was washed with brine (50 mL) and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with DCM/MeOH = 99:1 to provide the subtitle compound. MS ESI: mlz = 201 [M+H].
To a solution of 5-bromopicolinonitrile (5.00 g, 27.3 mmol) in dry THF (50 mL) was added dropwise MeMgBr (3 M in THF, 10.1 mL, 30.5 mmol) at -20 under N2atmosphere. After the addition, the mixture was warmed to ambient temperature and stirred for 1 h. The suspension was then treated with MeOH (100 mL) and NaBH4(2.00 g, 52.6 mmol) , and the resulting mixture was stirred for 1 h, then partitioned between saturated aqueous Na2CO3solution and EtOAc (50 mL × 2) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (DCM:MeOH 30:1) to give the title compound.1H NMR (400 MHz, DMSO-d6) delta 8.58 (d, J 2.0 Hz, 1H) , 7.98 (dd, J 2.3, 8.3 Hz, 1H) , 7.48 (d, J 8.0 Hz, 1H) , 4.03 -3.93 (m, 1H) , 1.26 (d, J 7.0 Hz, 3H) . MS : m/z 201/203 (M +H+) .
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 75℃; for 1h;
First step: To a stirred solution of piperidine-4-carboxylic acid ethyl ester (3.70 g, 23.5 mmol) and 5-bromo-pyridine-2-carbonitrile (3.66 g, 20 mmol) in toluene (50 mol) was added NaOtBu (2.31 g, 24.0 mol), BINAP (374 mg, 0.60 mmol) and tris(dibenilideneacetone) dipalladium(O) (366 mg, 0.40 mmol). The reaction mixture was heated at 75C for 1 hours, cooled down to RT, and diluted with AcOEt (500 mL) and H20 (50 mL). The organic layer was separated and washed with brine, dried over Na2S04 and concentrated under vacuo. Column chromatography (Si02, EtO Ac / heptane, 1:9 to 1: 1) yielded 1.61 g (31%) of 6'-cyano-3,4,5,6-tetrahydro-2H- [l,3']bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 260.3 (M+H+).
31%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 75℃; for 1h;
First Step:To a stirred solution of piperidine-4-carboxylic acid ethyl ester (3.70 g, 23.5 mmol) and 5-bromo-pyridine-2-carbonitrile (3.66 g, 20 mmol) in toluene (50 mol) was added NaOtBu (2.31 g, 24.0 mol), BINAP (374 mg, 0.60 mmol) and tris(dibenilideneacetone) dipalladium(0) (366 mg, 0.40 mmol). The reaction mixture was heated at 75 C. for 1 hours, cooled down to RT, and diluted with AcOEt (500 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 1.61 g (31%) of 6'-cyano-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 260.3 (M+H+)
Description 9: 5-bromopicolinonitril D9)Phosphorus oxychloride (1 1 1 g, 0.720 mol) was added to a mixture of 5- bromopicolinamide (D8) (58 g, 0.288 mol) in dry toluene (300ml) The mixture was heated to reflux for 2 hours. The mixture was poured into ice/water, and basified to pH=12 with 2N NaOH. The resulting mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 10:1 . Collected fractions, after solvent evaporation afforded the title compound (D9) (43.6 g) as a yellow solid.1 HNMR (400 MHz, CHLOROFORM-d) delta (ppm): 7.60 (d, J = 8.4 Hz, 1 H), 8.00 (dd, J = 6.0, 2.0 Hz, 1 H), 8.79 (d, J = 2.0 Hz, 1 H).
43.6 g
With trichlorophosphate; In toluene; for 2h;Reflux;
Phosphorus oxychloride (111 g, 0.720 mol) was added to a mixture of <strong>[90145-48-5]5-bromopicolinamide</strong> (D8) (58 g, 0.288 mol) in dry toluene (300 ml) The mixture was heated to reflux for 2 hours. The mixture was poured into ice/water, and basified to pH=12 with 2N NaOH. The resulting mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 10:1. Collected fractions, after solvent evaporation afforded the title compound (D9) (43.6 g) as a yellow solid.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 95℃;Inert atmosphere;
5-bromopicolinonitrile (500mg, 2.7 mmol) and 2-methylpyridin-4-ylboronic acid (561.2 mg, 4.1 mmol) were added in a flask, followed by Pd2(dba)3 (250mg, 0.27mmol), s-Phos (224.3mg, 0.54mmol) and K3PO4 (1.16g, 5.4mmol) under the N2 protection. 25mL n-butanol and 5mL water were added into the reaction and the reaction was stirred well at 95°C for overnight. After cooling down the reaction to the RT, lOOmL water was added into the flask and then extracted by EA for three times. The combined organic layer was washed with brine, dried over Na2S04 and concentrated under the vacuum. The crude product was further purified by flash chromatography using EA/Hexane (1:1) to get 5-(2-memylpyiidm-4-yl)pyridine-2-carbomtrile (368mg, yield -70percent). Re- dissolved the solid into 50mL ethanol, after de-gas, 40mg raney nickel and 3 drops of ammonia water were added and the reaction was stirred at RT under a 3/4 balloon for overnight. After filtering through the c elite, the solution was concentrated under the vacuum. The crude product was jEiirther purified by flash chromatography using 10percentMeOH in DCM to get the final compound (5-(2- methylpyridin-4-yl)pyridin-2-yl)methanamine (246mg, yield -65percent ). MS m/z 200.1 (M + 1).
Stage #1: (3-bromophenyl)pentafluoro-λ6-sulfane With TurboGrignard In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: With zinc(II) chloride In tetrahydrofuran Inert atmosphere;
Stage #3: 2-Cyano-5-bromopyridine With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II) dichloride In tetrahydrofuran for 5h; Inert atmosphere;
With copper(l) iodide; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere;
A mixture of 5-bromopyridine-2-carbonitrile (3 g, 1 6.39 mmol, 1 .00 equiv), PhSO;>Na-2H:>0 (3.96 g ) and copper(I) iodide (3 1 0 mg, 1 .63 mmol, 0. 1 0 equiv) in DMSO (30 niL) was stirred under nitrogen for 2 h at 1 00 C The reaction was quenched by the addition of 1 00 mL of water/ice. The crude product was collected by filtration and then dissolved in 50 mL of dichloromethane. The solid material was removed by fi ltration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column with ethyl acetate/petroleum ether ( 1 50) to give 2.5 g (62%) of 5- (benzenesulfonyl)pyridine-2-carbonitrile as a white sol id LC/MS (Method C, ESI): RT = 1 .37 min, z = 245.0 [M+H]
Step 7: Preparation of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate. [0644] To a solution of 5-bromopicolinonitrile (5.00 g, 27.3 mmol), C0CI2 6H2O (9.75 g, 40.9 mmol) in MeOH (65 mL) was added NaBTU (3.10 g, 81.9 mmol) at 0 C, and the mixture was stirred at 0 C for 1 h under N2 atmosphere. TLC showed the reaction was completed. To the mixture was added H2O (8 mL) and B0C2O (11.9 g, 54.6 mmol). The mixture was stirred at 70 C for 15 h. The dark red mixture turned to black, and produced a purple solid. TLC indicated the reaction was completed. The resulting mixture was concentrated. The residue was diluted with H2O (130 mL) and DCM (130 mL) then filtered. The aqueous layer was extracted with DCM (120 mL x2). The combined organic layer was dried over anhydrous Na2SCri and concentrated under reduced pressure. The residue was purified by Combi Flash (25% EtOAc in pentane) to give tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (4.11 g, yield: 52%) as ayellow solid. NMR (400 MHz, CDCb) d 1.45 (9H, s), 4.39 (2H, d, J= 5.6 Hz), 5.47 (1H, br s), 7.19 (1H, d, J= 8.0 Hz), 7.77 (1H, dd, J= 8.4, 2.4 Hz), 8.59 (1H, d, J= 2.0 Hz).
47%
With sodium tetrahydroborate; nickel(II) chloride hexahydrate; In methanol; at 0 - 15℃; for 3h;
To a mixture of 5- bromopicolinonitrile (3.0 g, 16.4 mmol) in MeOH (60 mL) was added di-tert-butyl dicarbonate (7.2 g, 32.8 mmol) and nickel chloride hexahydrate (0.33 g, 1.64 mmol). The mixture was cooled to 0C, followed by portion wise addition of NaBH4 (4.3 g, 0.115 mol) over 2 hr. The mixture was stirred at 15C for 1 hr then poured into ice- water (200 g) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the desired product (2.2 g, 47% yield) as a yellow solid. LC-MS: m/z 287,289 (M+H)+.
650 mg
With sodium tetrahydroborate; nickel(II) chloride hexahydrate; In methanol; at 0 - 20℃; for 14h;
Step 1 Preparation of (5-Bromo-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester To a solution of 5-Bromo-pyridine-2-carbonitrile (1.0 g, 5.46 mmol) in methanol (10 mL) at 0 C. is added NiCl2.6H2O (0.12 g, 0.54 mmol), Di-tert-butyl dicarbonate (2.38 g, 0.010 mmol) and NaBH4 (0.413 g, 0.010 mmol) at 0 C. then stirred at room temperature for 14 hours. The reaction solvent is removed under reduced pressure and crude is diluted with water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated in vacuum. The crude is purified by column chromatography eluting with 30% ethyl acetate in hexane to afford the title compound (650 mg). 1H-NMR (400 MHz, CDCl3) delta: 1.44 (s, 9H), 4.37 (d, J=5.44 Hz, 2H), 5.41 (bs, 1H), 7.18 (d, J=8.28 Hz, 1H), 7.75-7.78 (dd, J1=8.32 Hz, J2=2.28 Hz, 1H), 8.57 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=289.0.
1 g
With methanol; sodium tetrahydroborate; nickel(II) chloride hexahydrate; at 0 - 20℃; for 18h;
To a solution of 5-bromo-2-cyanopyridine (5.0 g, 27.32 mmol) in methanol (50 mL) at 0 C were added nickel (II) chloride hexahydrate (649 mg, 27.32 mmol), di-tert-butyl dicarbonate (11.9 g, 54.64 mmol) and sodium borohydride (2.06 g, 54.64 mmol). The reaction mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to afford 1.0 g of the titled product. 1H NMR (300 MHz, CDCl3) delta 1.45 (s, 9H), 4.39 (d, = 5.4 Hz, 2H), 5.47 (br s, 1H), 7.21 (d, = 8.1 Hz, 1H), 7.79 (d, = 8.1 Hz, 1H), 8.59 (s, 1H); APCI-MS (m/z) 289 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
A mixture of 5-bromopyridine-2-carbonitrile (2.1 g, 1 1 .48 mmol, 1 .02 equiv), 3- (trifluoromethyl)benzene-l -thiol (2 g, 1 1 .22 mmol, 1 .00 equiv), and potassium carbonate (3. 1 g, 22.43 mmol, 2.00 equiv) in DMF (40 mL) was stirred overnight at 120 HC. The reaction was quenched by the addition of 60 mL of ice-water. The resulting solution was extracted with 4x50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1 /50) to give 2.2 g (70%) of 5-[[3-(trifluoromethyl)phenyl]sulfanyl]pyridine-2-carbonitrile as yellow oil. 1HNMR (300 MHz, CDCl3 ) delta 8.48-8.49 (m, 1 H), 7,78 (s, 1 H), 7.55 (m, 2H), 7.49-7.53 (m, 3H).
With potassium carbonate; In dimethyl sulfoxide; at 120℃;
A mixture of 5-bromopyridine-2-carbonitrile (7.6 g, 40 70 mmol, 1.00 equiv, 98%), tert-butyl 4-sulfanylpiperidine- l -carboxylate (28 g, 83.74 mmol, 2.06 equiv), and potassium carbonate (1 1 .6 g, 82.38 mmol, 2.02 equiv, 98%) in DMSO ( 1 50 mL) was stirred overnight at 1 20 C. After cooling to rt, the reaction mixture was quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate. The combined organic layers were washed with 2x100 mL of water, dried over anhydrous sodium sulfate, and then concentrated under vacuum The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 /10) to give 3.41 g (26%) of tert-butyl 4-[(6-cyanopyridin-3-yl)sulfanyl]piperidine-1-carboxylate as a yellow solid LC/MS (Method C, ESI): RT = 1 .57 min, no MS signal.
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1.5h;Inert atmosphere;
A mixture of 5-bromopyridine-2-carbonitrile (6.3 g, 34.43 mmol, 1 .00 equiv), 3 ,5-difluorobenzene- 1 -thiol (5 g, 34.21 mmol, 0.99 equiv ), and cesium carbonate (22.3 g, 68.23 mmol, 1 .98 equiv) in 1 -methylpyrrolidin-2-one (70 mL) was stirred under nitrogen at 1 00 "C for 1 .5 h. The reaction was then quenched by the addition of 200 mL of water. The precipitated product (4 6 g) was collected by filtration. The filtrate was extracted with 3x200 mL of ethyl acetate. The combined organic layers was washed with 3x200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give in total 7.6 y (89%) of 5-[(3 ,5-difluorophenyl)sulfanyl]pyridine-2- carbonitrile as a brown solid. LC/MS (Method J, ESI): RT = 1 .62 min, m z = 249.0 [M+H]
A solution of 5- bromopyridine-2-carbonitrile (5 g, 27.32 mmol, 1 .00 equiv) and sodium benzenesulfinate dehydrate (8.2 g, 41 .00 mmol, 1.50 equiv) in DMSO (50 mL) was stirred for 4 h at 1 20"C. The reaction mixture was cooled to rt and the product was precipitated by the addition of an ice/water ( 1000mL) mixture. The precipitate was collected by filtration and air-dried to give 6. 1 g (91 %) of 5- (benzenesulfonyl )pyridine-2-carbonitrile as a white solid LC/MS (Method O, ESI): RT = 1 .42 min, - 286.0 [M +CH-,CN+ H]
5-(2-(1,3-dithiol-2-ylidene)-1,3-dithiol-4-yl)pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: tetrathiafulvalene With lithium diisopropyl amide In tetrahydrofuran at -83℃; for 1h; Inert atmosphere;
Stage #2: With zinc(II) chloride In tetrahydrofuran at -83℃; for 1h; Inert atmosphere;
Stage #3: 2-Cyano-5-bromopyridine With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at -83 - 20℃; for 49h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; for 3.0h;Reflux; Inert atmosphere;
General procedure: N-(4-Bromobenzyl)-1H-indole-2-sulfonamide (1 g) was dissolved in a mixture of toluene (15 ml) and ethanol (15 ml). The required benzeneboronic acid (1 g) was added followed by (PPh3)4Pd (0.20 g). The mixture was stirred vigorously under N2 and 2 M Na2CO3 (15 ml) added. The mixture was refluxed with stirring for 3 hrs under an atmosphere of N2. The solvent was removed under vacuum, the residue dissolved in ethyl acetate washed with water and saturated NaCl solution. After drying (Na2SO4) the solvent was evaporated and the resultant oil purified by column chromatography to give a clear oil, which solidified on standing. Recrystallisation from diethyl ether / petroleum spirit gave white crystals.
5-Bromopyridine-2-carbonitrile (14.0 g, 76.5 mmol) was dissolved in dry tetrahydrofuran (280 mL) and cooled to -20 C. Ethylmagnesium bromide (31.9 mL of a 3M solution in diethyl ether, 95.6 mmol) was added dropwise at this temperature, with the reaction mixture allowed to warm to RT over 2 hours. After this time 1M aqueous hydrogen chloride solution was then added slowly at 0 C. and the mixture was allowed to re-warm to room temperature and was diluted with ethyl acetate. The organic layer was isolated, washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated in vacuo, after which time the golden oil crystallised to afford the title compound (15.51 g, 90% yield). No further purification was necessary. 1H NMR (250 MHz, Chloroform-d) delta [ppm] 8.74 (d, J=1.6 Hz, 1H), 8.02-7.89 (m, 2H), 3.22 (q, J=7.3 Hz, 2H), 1.23 (t, J=7.3 Hz, 3H). LCMS (Analytical Method A): Rt=1.13 min; MS (ESIPos) m/z=213.8/215.8 (M+H)+, Br isotope pattern.
85%
In tetrahydrofuran; diethyl ether; at -20 - 20℃; for 2h;
A solution of 5-bromopyridine-2-carbonitrile (5.0 g, 27.3 mmol) was dissolved in dry tetrahydrofuran (100 mL) and cooled to -20 C. ethylmagnesium bromide (11 .4 mL of a 3M solution in diethyl ether, 34.1 mmol) was added dropwise at this temperature, with the reaction mixture allowed to warm to RT over 2 hours. The reaction mixture was cooled to -20 C and 1M aqueous HCl solution slowly added and the mixture allowed to re-warm to room temperature. The reaction mixture was diluted with ethyl acetate, the organic layer collected and washed with brine, dried (MgS04), filtered and concentrated at reduced pressure. The golden coloured oil crystallised to give the title compound (5.25 g, 85% yield). 1H NMR (250 MHz, chloroform-d) delta [ppm] 8.74 (dd, J = 2.0, 0.9 Hz, 1 H), 8.04 - 7.89 (m, 2H), 3.22 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).
5-(ethylsulfanyl)pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 50℃;
Preparation 10 5-(Ethylsulfanyl)pyridine-2-carbonitrile Dissolve 5-bromopyridine-2-carbonitrile (49.42 g, 270.1 mmol) and potassium carbonate (113.5 g, 821.2 mmol) in 1-methyl-2-pyrrolidinone (280 mL) and add ethanethiol (26.4 mL, 356 mmol) in portions over 30 minutes such that temperature stays below 50 C. Cool the reaction to room temperature and stir overnight. Dilute with EtOAc (1200 mL) and water (2200 mL). Collect the organic layer and wash with brine (3*300 mL), dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (44.87 g, 100%) as an off white solid. 1H NMR (400.13 MHz, d6-DMSO) delta 8.63 (s, 1H), 7.93 (s, 2H), 3.17 (q, J=7.3, 2H), 1.29 (t, J=7.3, 3H).
100%
With 1-methyl-pyrrolidin-2-one; potassium carbonate; at 50℃; for 0.5h;
Dissolve 5-bromopyridine-2-carbonitrile (49.42 g, 270.1 mmol) and potassiumcarbonate (113.5 g, 821.2 mmol) in 1-methyl-2-pyrrolidinone (280 mL) and add ethanethiol (26.4 mL, 356 mmol) in portions over 30 minutes such that the temperature stays below 50 C. Cool the reaction to room temperature and stir overnight. Dilute withEtOAc (1200 mL) and water (2200 mL). Collect the organic layer and wash with brine (3 x300 mL), dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (44.87 g, 100%) as an off white solid. ?H NMR (400.13 MHz, d6-DMSO) 8.63 (s, 1H), 7.93 (s, 2H), 3.17 (q, J=7.3, 2H), 1.29 (t, J=7.3, 3H).
100%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 50℃;
Dissolve 5-bromopyridine-2-carbonitrile (49.42 g, 270.1 mmol) and potassium carbonate (113.5 g, 821.2 mmol) in 1-methyl-2-pyrrolidinone (280 mL) and add ethanethiol (26.4 mL, 356 mmol) in portions over 30 minutes such that the temperature stays below 50 C. Cool the reaction to room temperature and stir overnight. Dilute with EtOAc (1200 mL) and water (2200 mL). Collect the organic layer and wash with brine (3300 mL), dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (44.87 g, 100%) as an off white solid. 1H NMR (400.13 MHz, d6-DMSO) delta 8.63 (s, 1H), 7.93 (s, 2H), 3.17 (q, J=7.3, 2H), 1.29 (t, J=7.3, 3H).
100%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃;
5-Bromo-2-pyridinecarbonitrile in a 50 mL single-mouth bottle(940mg, 5.14mmol),Ethyl mercaptan (505 mg, 6.01 mmol),Potassium carbonate (981 mg, 7.11 mmol),NMP (10 mL).The reaction was stirred at room temperature overnight. Add water (20 mL),Extracted with ethyl acetate (3 x 30 mL).The organic layer was spin-dried to give the product 5-(ethylthio)pyridinecarbonitrile 900 mg.The yield is 100%.
100%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃;
<strong>[97483-77-7]5-bromo-2-pyridinecarbonitrile</strong> (940 mg, 5.14 mmol), ethanethiol (505 mg, 6.01 mmol), potassium carbonate (981 mg, 7.11 mmol), and NMP (10 mL) were added to a 50 mL single-mouth bottle. The obtained mixture reacted at room temperature while stirring overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL33). The organic layer was concentrated in vacuo to give the product of 5-(ethylthio) pyridinecarbonitrile (900 mg), with a yield of 100%. MS (ESI) m/z: 165.1 (MH+).
100%
With 1-methyl-pyrrolidin-2-one; potassium carbonate; at 20℃;
5-Bromo-2-picolinonitrile (940 mg, 5.14 mmol), ethyl mercaptan (505 mg, 6.01 mmol), potassium carbonate (981 mg, 7.11 mmol) and NMP (10 mL) were added in a 50 mL single-neck flask, and the mixture was stirred at room temperature overnight. Water (20 mL) was added, then the mixture was extracted with ethyl acetate (3?30 mL). The organic layers were concentrated in vacuo to afford a product 5-(ethylthio)picolinonitrile (900 mg), with a yield of 100%. MS (ESI) m/z: 165.1 (MH+).
[4-(9,9-dimethyl-9,10dihydroaciridin-10-yl)phenyl]boronic acid[ No CAS ]
[ 97483-77-7 ]
C26H20N4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; CyJohnPhos; In toluene; at 100℃; for 24h;Inert atmosphere;
A 50 mL two-necked flask was added with 2-CN-5-BrPy (0.22 g, 1.2 mmol), DMAC-P-B(OH)2 (0.33 g, 1 mmol), Pd(PPh3)4 (120 mg, 0.1 mmol), [1,1?-biphenyl]-2-yldicyclohexylphosphine) (0.035 g, 0.1 mmol), equipped with a magnetic stirring bar and a condensing tube, and charged with argon after evacuation. Then, toluene (20 mL) and K2CO3(aq) (1.6 mL, 2 M) were injected with a syringe, stirred, and heated to reflux, and cooled to RT after the reaction was stirred for 24 hours. The salts were filtered out with diatomite, and extraction was performed with water and ethyl acetate followed by dichlormethane. Finally, extraction was performed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the solid was purified by column chromatography (SiO2, CH2Cl2/Hexane=2/1), giving a yellow solid (0.36 g, 0.93 mmol, 93%). 1H NMR (400 MHz, CD2Cl2) delta (ppm) 9.16 (s, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.94 (quin), J=3.2 Hz, 4H), 6.29 (d, J=8.0 Hz, 2H), 1.66 (s, 6H). 13C NMR (100 MHz, CD2Cl2) delta (ppm) 156.54, 144.24, 144.02, 141.19, 136.29, 133.23, 133.08, 131.05, 130.46, 126.92, 125.96, 121.53, 116.50, 114.61, 66.58, 36.55, 31.54, 31.16. HRMS (FAB+, m/z) calcd for C26H20N44, 388.1688; found 388.1685. Anal. calcd (%) for C26H20N44: C, 80.39; H, 5.19; N, 14.42; found: C, 80.40; H, 5.15; N, 14.31. The preparation process is shown below.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 83℃; for 18h;Inert atmosphere;
General procedure: A mixture of 5-bromopicolinonitrile 1.83g (0.01mol), phenylboronic acid 1.83g (0.015mol), Tetrakis (triphenylphosphine)palladium 0.35g (0.65mmol), was added in tetrahydroufuran (THF) 24mL, and 2M potassium carbonate aqueous solution 10mL. The mixture was heated to 83C and stirred for 18h under nitrogen atmosphere. After cooling to room temperature, the mixture was extracted with dichloromethane and deionized water, the combined organic layer was dried with anhydrous magnesium sulfate overnight and filtered. The filtrate was evaporated to remove the solvent and the residual was purified on a silica column using PE/EtOAc (V: V=7: 1) as the eluent to give a white solid 1.35g (7.5mmol), yield 75%.
(R)-5-(2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)picolinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; ethanol; water; at 90 - 95℃; for 3h;Inert atmosphere;
General procedure: A mixture of the desired aryl boronic ester/ or acid (1 mmol) and the desired aryl bromide (1 mmol), Pd(dppf)2Cl2 (0.05 mmol) and K2CO3 (4 mmol) in dioxane (3 mL), EtOH (1 mL) and H2O ( 1 mL) was added to a nitrogen purged 25 mL flask. The mixture was heated to 90-95 C and stirred for 3 hrs. Then cooled to room temperature, filtrated and evaporated to dryness. Then the crude was dissolved in DMF (1 mL), and then it was purified by reversed phase column chromatography on prep- HPLC using gradient of (water/acetonitrile/ 0.1 %TFA). Those fractions containing pure product were pooled and lyophilized to give the pure products.
5-(ethylsulfonyl)pyridine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
In dimethylsulfoxide-d6; at 100℃; for 16h;Inert atmosphere;
To a stirred solution of 5-bromopicolinonitrile (3.60 g, 19.68 mmol) in DMSO (25 mL) were added <strong>[20035-08-9]sodium ethanesulfinate</strong> (3.20 g, 27.6 mmol), and the reaction mixture was stirred at 100C under Ar atmosphere for 16 hrs. The filtrate was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give white solids. The residue was crystallized from EtOAc-hexane to give the title compound (2.69 g, 13.71 mmol, 70%) as white solids. (4920) 1H NMR (300 MHz, CDC13):5 1.35 (3H, t, J = 7.6 Hz), 3.21 (2H, q, J = 7.3 Hz), 7.92 (1H, dd, J = 8.1, 0.9 Hz), 8.37 (1H, dd, J = 7.9, 2.3 Hz), 9.20 (1H, dd, J = 2.3, 0.8 Hz).
5-(cyclohex-1-en-1-yl)-2-picolinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In 1,4-dioxane; water; at 115℃; for 18h;Inert atmosphere;
In a dry flask under argon was added 5-bromo-2-cyanopyridine (1.83 g, 10 mmol), SPhos (410 mg, 1.0 mmol), cyclohexene-l -yl boronic acid (1.76 g, 14 mmol) and potassium phosphate tribasic (6.37 g, 30 mmol). The flask flushed with argon. Dioxane (30 mL) and water (4 mL) were added and the mixture was degassed with vacuum and backflushed with argon. Pd(OAc)2 (112 mg, 0.5 mmol) was added and the reaction was degassed again. The reaction mixture was stirred at 115 °C for 18 h. The crude reaction mixture was cooled, poured onto water and extracted with EtOAc (3X). The organic layers were washed with water and then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography (0-20percent EtOAc in hexanes) followed by re-purification by chromatography (5-8percent EtOAc/ hexanes) provided 5-(cyclohex-l-en-l-yl)picolinonitrile (1.22 g, 65percent yield). NMR (300 MHz, Chloroform-c delta 8.75 (d, J= 2.2 Hz, 1H), 7.76 (dd, J= 8.2, 2.2 Hz, 1H), 7.64 (d, J= 8.2 Hz, 1H), 6.43 - 6.30 (m, 1H), 2.48 - 2.35 (m, 2H), 2.35 - 2.23 (m, 2H), 1.92 - 1.78 (m, 2H), 1.77 - 1.66 (m, 2H).
Multi-step reaction with 4 steps
1.1: tetrahydrofuran / 1.5 h / 0 - 20 °C
1.2: 16 h / 20 °C
2.1: hydrogen / {(1,5-cyclooctadiene)Rh(1,2-bis((2S,5S)-2,5-dimethylphospholano)benzene)}triflate / methanol / 18 h / 20 °C / 6205.94 - 7757.43 Torr
3.1: dmap / tetrahydrofuran / 20 h / 50 °C
3.2: 20 h / 20 °C
4.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 20 °C
5-((5-bromopyrimidin-2-yl)amino)picolinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 101℃;Inert atmosphere;
General procedure: A mixture of appropriate aryl bromides (0.50 mmol), appropriate arylamine (0.50 mmol), Pd2(dba)3 (0.0050 mmol), Xantphos (0.012 mmol), Cs2CO3(1.0 mmol) in dry dioxane (10 mL) was heated 101 C for 5 h under nitrogen. The cooled reaction mixture was absorbed onto silica gel, and solvent was removed by evaporation. The residue obtained was purified by column chromatography (eluent gradient 4-5% EtOH in CH2Cl2), gave intermediate (79%-87%). CF3COOH (2.2 mmol) mL) was added in a mixture of intermediate (0.36 mmol) in CH2Cl2 (2.2 mL). The reaction mixture was stirred at room temperature for 2 h. Then the solvent was removed by evaporation, the residue obtained was purified by column chromatography (eluent CH2Cl2: MeOH: TEA = 10:1:1), gave 6-15.
5-(4-(4-nitrophenyl)piperazin-1-yl)picolinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With palladium diacetate; caesium carbonate; ruphos; In 1,4-dioxane; at 90℃; for 4h;Sealed tube;
l-(4-Nitrophenyl)piperazine (622 mg, 3.0 mmol), 5-bromopicolinonitrile (500 mg, 2.73 mmol), CS2CO3 (1.78 g, 5.46 mmol) and RuPhos (255 mg, 0.55 mmol) were suspended in an hydrous dioxane (15 ml) and degassed for 5 min with nitrogen. [Pd(OAc)2] (61 mg, 0.27 mmol) was then added, the mixture further degassed (3 min) and the reaction vessel was sealed and heated at 90 C for 4 h. After cooling to rt H20 was added and the resulting pre cipitate collected by filtration. The precipitate was washed with H20 (3 x) and diethyl ether (3 x) and dried to give the title compound (800 mg, 94%) as a yellow solid. NMR (400 MHz, DMSO): d 8.49 (d, J=3.0 Hz, 1H), 8.15 (d, J=9.3 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.43 (dd, J=3.0, 9.1 Hz, 1H), 7.10 (d, J=9.3 Hz, 2H), 3.73 (dd, J=5.8, 13.4 Hz, 8H). LC-MS: Rt = 1.52 min, m/z = 310 [M+H]+.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 5℃; for 0.416667h;
Step C: at 0 ~ 5 , benzyl alcohol (7.68g, 71.0mmol) was added dropwise 60% sodium hydride (2.84g, 71.0mmol) in DMF (60mL) suspension.After the addition was completed, stirring was continued for 10 minutes, and then 5-bromo-2-cyanopyridine (10.0 g, 54.6 mmol) was added portionwise.The resulting mixture was stirred at this temperature for a further 15 minutes.Add water (180 mL), filter, and filter cake with water (100 mL)5-Benzyloxy-2-cyanopyridine (25) (9.2 g) was obtained. The yield was 80.2%.
5-(4-(2-methoxyethoxy)phenyl)picolinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide at 90℃;
1 General Procedure E: Biaryl coupling using Suzuki conditions
General procedure: To a stirred solution of the aryl halide component (1 equivalent) in 5:1 (v/v) dioxane/water (-0.15 M) or 5:1 (v/v) N,N-dimethylformamide (-0.15 M), was added the arylboronate or arylboronic acid component (1-1.5 equivalents), sodium carbonate (2-3 equivalents) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 equivalents). The mixture was heated (90 °C) overnight and then filtered through a plug of Celite. The Celite was rinsed with ethyl acetate and the combined filtrate was washed with brine, dried (NaiSCE) and concentrated. The residue was purified by flash chromatography over silica.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In toluene for 12h; Inert atmosphere; Reflux;
2.2.1 Synthesis of Compound 1b2.2.1 Synthesis of Compound 1b
General procedure: 5-Bromopicolinonitrile (0.653g, 3.51mmol), compound 1a (1.8g, 3.93mmol), Pd(PPh3)4 (230mg, 0.20mmol) and stir bar were added into a 50mL two-neck bottle. Under N2 atmosphere, toluene (10mL) and the solution of K2CO3 (7mL, 2.5M) were added. The system was refluxed for 12h. After cooling to room temperature, the reaction mixture was flash through celite and extracted with ethyl acetate and brine. The organic layer was dried by MgSO4 and concentrated via rotary evaporator. The crude product was purified by column chromatography (silica gel) with eluent (CH2Cl2/petroleum ether=1/2), and the product was obtained as a light green solid (1.3g, 84%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; for 12h;Inert atmosphere; Reflux;
5-Bromopicolinonitrile (0.653g, 3.51mmol), compound 1a (1.8g, 3.93mmol), Pd(PPh3)4 (230mg, 0.20mmol) and stir bar were added into a 50mL two-neck bottle. Under N2 atmosphere, toluene (10mL) and the solution of K2CO3 (7mL, 2.5M) were added. The system was refluxed for 12h. After cooling to room temperature, the reaction mixture was flash through celite and extracted with ethyl acetate and brine. The organic layer was dried by MgSO4 and concentrated via rotary evaporator. The crude product was purified by column chromatography (silica gel) with eluent (CH2Cl2/petroleum ether=1/2), and the product was obtained as a light green solid (1.3g, 84%). 1H NMR (400MHz, DMSO-d6) δ 9.07 (s, 1H), 8.31 (d, J=10.5Hz, 1H), 8.08 (d, J=8.1Hz, 1H), 7.67 (d, J=8.4Hz, 2H), 7.23-7.09 (m, 11H), 7.07-6.95 (m, 6H). 13C NMR (101MHz, CDCl3) δ 149.43, 145.34, 143.38, 143.35, 143.30, 142.19, 139.77, 139.37, 134.53, 133.45, 132.47, 131.92, 131.37, 131.35, 131.30, 128.42, 127.94, 127.90, 127.76, 126.85, 126.78, 126.76, 126.52, 117.46.
tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-cyanopyridin-3-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
310 mg
Stage #1: tert-butyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate With iodine; zinc powder In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;
Stage #2: 2-Cyano-5-bromopyridine With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl(2’,4’,6’-triisopropyl-[ 1,1’-bi-phenyl]-2-yl)phosphane In N,N-dimethyl-formamide at 20℃;
(4) Synthesis of Fmoc-protected amino acid 5
To a solution of zinc powder (400 mg, 6.12 mmol) in 3 mL of DMF, iodine (66 mg, 0.26 mmol) was added and the mixture was stirred at room temperature under nitrogen atmosphere for 5 minutes. To the reaction mixture was added tert-butyl (R)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino (R)-3-iodopropanoate (1.0 g, 2.03 mmol) in 5 mL of DMF, then iodine (25 mg, 0.099 mmol) was added under room temperature, and the mixture was stirred for 2 hours. 5-Bromopyridine-2-carbonitrile (440 mg, 2.40 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (97 mg, 0.203 mmol), and Electronic Supporting Information for Bulletin of the Chemical Society of Japan 2021 The Chemical Society of Japan tris(dibenzylideneacetone)dipalladium (92 mg, 0.100 mmol) were added to the reaction mixture at room temperature. After filtration of the insoluble material, ethyl acetate was added to the filtrate, and the mixture was washed with sodium thiosulfate solution. The organic layer was dried over magnesium sulfate and then the solvent was removed under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane: ethyl acetate = 100:0 to 85/15), and tert-butyl (S)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-cyanopyridin-3-yl)propanoate (310 mg) was obtained as a yellow oil. MS (ESI m/z): 470.3 (M+H). RT (min): 1.83. tert-Butyl-(S)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-cyanopyridin-3-yl)propanoate (310 mg) was dissolved in 1 mL of TFA and stirred at room temperature for 30 min, then the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (MeOH:n-hexane:ethyl acetate = 0:40:60 to 20: 0:80) to give Fmoc-protected amino acid 5 (210 mg). MS (ESI m/z): 414.4 (M+H). RT (min): 1.39. 1H-NMR (CDCl3) δ: 8.69 (1H, s), 8.51 (1H, s), 7.87-7.79 (2H, m), 7.68 (1H, s), 7.63-7.58(2H, m), 7.45-7.30 (4H, m), 5.48 (1H, d, J = 3 Hz), 4.72-4.63 (2H, m), 4.50-4.20 (1H, m), 4.24 (1H, t, J = 6.9 Hz), 3.32-3.12 (2H, m)
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