* 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.
To a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at −78° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88percent).
88%
at -78 - 20℃;
[B] 1 -(5-Bromo-pyridin-3-yl)-ethanoneTo a solution of 5-bromo-N-methoxy-N-methyl-nicotinamide (2.08 g, 8.5 mmol) in THF (20 mL) was added MeMgBr (1.52 g, 12.75 mmol) at -78 °C. After the addition, the reaction mixture was stirred at room temperature for 2 hours before quenching with water. After extraction with EtOAC, the organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash column chromatography to afford the title compound (1.5 g, 88percent).
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
[2] Patent: WO2013/37779, 2013, A1,
[3] Patent: US2013/72679, 2013, A1,
7
[ 59-67-6 ]
[ 38940-62-4 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
8
[ 39620-02-5 ]
[ 38940-62-4 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
9
[ 20986-40-7 ]
[ 141-78-6 ]
[ 38940-62-4 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2381,2383
10
[ 38940-62-4 ]
[ 142337-95-9 ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium hydroxide; hydrazine In diethylene glycol at 140℃; for 6 h;
Sodium hydroxide (10g, 0.25 mol) and hydrazine monohydrate (10ML) were added to a solution of 3-acetyl-5-bromopyridine (5g, 25 mmol) dissolved in diethylene glycol (18mL). The reaction mixture was heated to 140 C for 6 hours and then partitioned between H2O and Ether. The organic layers were washed with brine, dried over MGS04 and concentrated. The residue was purified by flash silica gel chromatography (0percent to 40percent EtOAc in hexanes) to give the title compound (3 g, 65percent). 1H NMR (400 MHz, CDCI3) : 6 1.26 (t, J=7. 6 Hz, 3 H), 2.65 (q, J=7.6 Hz, 2 H), 7.67 (s, 1H), 8.37 (s, 1 H), 8.51 (s, 1 H).
58%
With sodium hydroxide; hydrazine In diethylene glycol at 140℃; for 6 h;
A mixture of NaOH (10 g, 0.25 mol), hydrazine monohydrate (10 mL) and 3-acetyl-5-bromopyridine (5g, 25 mmol) suspended in diethylene glycol (18 mL) was heated to 140 °C for 6 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0percent to 15percent EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58percent). 1H NMR (400 MHz, CDCI3): 5 1.26 (t, J=7.6 Hz, 3 H), 2.65 (d, J=7.6 Hz, 2 H), 7.67 (t, J=2.0 Hz, 1 H), 8.37 (d, J=1.8 Hz, 1 H), 8.51 (d, J=2.0 Hz, 1 H).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at 60℃; Sealed tube
Heat the mixture of l-(5-bromopyridin-3-yl)ethanone (500 mg, 2.5 mmol), bis-(2-methoxyethyl)aminosulfur trifluoride (BAST, 2.2 g, 10 mmol) in dichloromethane (8 mL) in a sealed tube at 60°C overnight. TLC (PE:EtOAc=l :l) shows the reaction is complete. Concentrate the mixture, purify the residue by flash chromatography (silica gel, PE:EtOAc=l :1) to afford the title compound (200 mg, 36percent). MS: (M+1): 222/224.
36%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at 60℃; Sealed tube
Heat the mixture of 1-(5-bromopyridin-3-yl)ethanone (500 mg, 2.5 mmol), bis-(2-methoxyethyl)aminosulfur trifluoride (BAST, 2.2 g, 10 mmol) in dichloromethane (8 mL) in a sealed tube at 60° C. overnight. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate the mixture, purify the residue by flash chromatography (silica gel, PE:EtOAc=1:1) to afford the title compound (200 mg, 36percent). MS: (M+1): 222/224.
With sodium hydroxide; hydrazine; In diethylene glycol; at 140℃; for 6h;
Sodium hydroxide (10g, 0.25 mol) and hydrazine monohydrate (10ML) were added to a solution of <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (5g, 25 mmol) dissolved in diethylene glycol (18mL). The reaction mixture was heated to 140 C for 6 hours and then partitioned between H2O and Ether. The organic layers were washed with brine, dried over MGS04 and concentrated. The residue was purified by flash silica gel chromatography (0% to 40% EtOAc in hexanes) to give the title compound (3 g, 65%). 1H NMR (400 MHz, CDCI3) : 6 1.26 (t, J=7. 6 Hz, 3 H), 2.65 (q, J=7.6 Hz, 2 H), 7.67 (s, 1H), 8.37 (s, 1 H), 8.51 (s, 1 H).
58%
With sodium hydroxide; hydrazine; In diethylene glycol; at 140℃; for 6h;
A mixture of NaOH (10 g, 0.25 mol), hydrazine monohydrate (10 mL) and <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (5g, 25 mmol) suspended in diethylene glycol (18 mL) was heated to 140 C for 6 hours. The mixture was cooled to room temperature and partitioned between H2O and ether. The ether extracts were dried over MgSO4 and concentrated to a clear oil. Flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as a clear oil (2.9 g, 58%). 1H NMR (400 MHz, CDCI3): 5 1.26 (t, J=7.6 Hz, 3 H), 2.65 (d, J=7.6 Hz, 2 H), 7.67 (t, J=2.0 Hz, 1 H), 8.37 (d, J=1.8 Hz, 1 H), 8.51 (d, J=2.0 Hz, 1 H).
Commercially available 3-acetyl-5- bromopyridine (6.53 g, 32.8 mmol), solid NaOH (13.1 g, 326 mmol), and hydrazine hydrate (13 mL) was heated in di ethylene glycol (25 mL) at 140 0C for 4 hours. The reaction mixture <n="170"/>was partitioned between ether and water. The organic layer was separated and concentrated to give a residue which was purified using flash chromatography to give an oil. This was dissolved in tetrahydrofuran (40 mL) and cooled to 0 0C. Isopropylmagnesiumchloride (20 mL, 2.0 M in THF) was syringed in and the reaction mixture was stirred for 2 hours at room temperature. N,N-dimethylformamide (7 mL) in tetrahydrofuran (15 mL) was added and stirring was continued for. an additional hour. The solution was quenched with 2 N HCl to pH of 3 then partitioned between ethyl acetate and water. The organic layer was separated and concentrated to give a residue which was purified using flash chromatography to give 3- ethyl-5-formylpyridine (0.78 g, 18%) as a solid. 1H NMR (DMSO-^6): delta 10.1 (s, IH), 8.91 (s, IH), 8.71 (s, IH), 8.00 (s, IH), 2.75 (q, 2H), 1.31 (t, 3H). MS m/z calculated for (M + H)+ 152, found 152.
methyl 4-(5-bromopyridin-3-yl)-2,4-dioxobutanoate, sodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium methylate; In methanol; at 20℃; for 2h;
3-Acetyl-5-bromopyridine (0.6 g) was added portionwise to a stirred solution of sodium methoxide (0.324 g) and dimethyl oxalate (0.708 g) in methanol (10 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The precipitate was isolated, washed in turn with methanol and diethyl ether and dried under vacuum. There was thus obtained methyl 4-(5-bromorhoyridin-3-yl)-2,4-dioxobutanoate, sodium salt, (0.730 g); Mass Spectrum: M+eta+ 286.
To a solution of ethyl 5-bromonicotinate (3.9 g, 16.9 mmol) in ether (50 ml) at 0 C. was added a 3M solution of methylmagnesium bromide (16.9 ml, 50.8 mmol). The resulting thick slurry was warmed slowly to room temperature and after 1.5 hours it was poured slowly into an excess of 1M aqueous monobasic sodium phosphate. The mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel, eluting with a 1:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-acetyl-5-bromopyridine compound. This preparation also afforded 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine described in Example 25.
Step 2 3-acetyl-5-bromopyridine 1.24 g of ground magnesium chloride was suspended in 13 ml of toluene and 6.2 ml of triethylamine and 2.93 g of diethyl malonate were added in turn. After stirring at room temperature for 1.5 hours, a suspension of 4.08 g of 5-bromonicotinoyl chloride obtained in the step 1 in 10 ml of toluene was added dropwise over 15 minutes, followed by stirring at room temperature for 2 hours. After neutralizing with 40 ml of 1N hydrochloric acid, the aqueous layer was separated. The aqueous layer was extracted with diethyl ether and the organic layers were combined, and then the solvent was distilled off under reduced pressure. To the resulting oily product, dimethyl sulfoxide-water (17 ml-0.7 ml) was added, followed by stirring with heating at 150 to 160C for 2 hours. The reaction solution was air-cooled and water was added, and then the deposited crystal was collected by filtration.
With magnesium; In tetrahydrofuran; tetrachloromethane; ethanol; sulfuric acid; water; acetic acid;
EXAMPLE A 5-Bromo-3-acetyl-pyridine 44.2 g (0.276 mol) of diethylmalonate, 19.9 g (0.432 mol) of absolute ethanol and 7 g (0.288 mol) of magnesium chips are refluxed for 18 hours with stirring in 254 ml of ether and 1.27 ml of carbon tetrachloride. To this solution, 55.3 g (0.25 mol) of 5-bromonicotinic acid chloride in 170 ml of absolute tetrahydrofuran are slowly added dropwise and refluxed for a further hour. The reaction mixture is cooled in an ice bath and carefully mixed with 508 ml of 2N sulphuric acid. The organic phase is separated off, dried over sodium sulphate and concentrated by evaporation. The residue is taken up in 83 ml of water, 127 ml of glacial acetic acid and 16.6 ml of concentrated sulphuric acid and refluxed for 18 hours. The reaction solution is evaporated down, the residue is diluted with 200 ml of water and adjusted to pH 8 with sodium hydroxide solution. It is then extracted with chloroform, dried over sodium sulphate and evaporated down. Yield: 15.2 g (30.4% of theory). Melting point: 78-80 C.
Step 3 1-(5-bromopyridin-3-yl)-3-(dimethylamino)-2-propen-1-one This compound was prepared by version of the method described in the document (Japanese Unexamined Patent Publication (Kokai) No. 6-87834). To 859 mg of <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> obtained in the step 2, 563 mg of N,N-dimethylformamide dimethyl acetal was added and the mixture was heated at reflux for one hour. After air cooling, the reaction solution was directly purified by silica gel column chromatography. The resulting crude crystal was washed with diethyl ether and then collected by filtration to obtain 860 mg of the objective compound as a yellow crystal. Melting point: 131-131.5C 1H-NMR(CDCl3)delta: 2.98(3H, s), 3.21(3H, s), 5.63(1H, d), 7.87(1H, d), 8.33(1H, t), 8.73(1H, d), 8.98(1H, d)
for 1h;Heating / reflux;
Step 3 1-(5-bromopyridin-3-yl)-3-(dimethylamino)-2-propen-1-one To 859 mg of <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> obtained in the step 2, 563 mg of N,N-dimethylformamide dimethyl acetal was added and the mixture was heated at reflux for 1 hour. After air cooling, the reaction solution was directly purified by silica gel column chromatography. The resulting crude crystals were washed with diethyl ether and then collected by filtration to obtain 860 mg of the objective compound as yellow crystals. Melting point: 131-131.5C
Step 1 3-Acetyl-5-Bromopyridine To a solution of ethyl 5-bromonicotinate (3.9 g, 16.9 mmol) in ether (50 ml) at 0 C. was added a 3M solution of methylmagnesium bromide (16.9 ml, 50.8 mmol). The resulting thick slurry was warmed slowly to room temperature and after 1.5 hours it was poured slowly into an excess of 1M aqueous monobasic sodium phosphate. The mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel, eluding with a 1:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-acetyl-5-bromopyridine compound. This preparation also afforded 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine described in Example 25.
With water; In dimethyl sulfoxide; at 150 - 160℃; for 2h;
1.24 g of ground magnesium chloride was suspended in 13 ml of toluene and 6.2 ml of triethylamine and 2.93 g of diethyl malonate were added in turn. After stirring at room temperature for 1.5 hours, a suspension of 4.08 g of 5-bromonicotinoyl chloride obtained in the step 1 in 10 ml of toluene was added dropwise over 15 minutes, followed by stirring at room temperature for 2 hours. After neutralizing with 40 ml of 1N hydrochloric acid, the aqueous layer was separated. The aqueous layer was further subjected to extraction with diethyl ether and the organic layers were combined, and then the solvent was distilled off under reduced pressure. To the resulting oily product, dimethyl sulfoxide-water (17 ml-0.7 ml) was added, followed by stirring with heating at 150 to 160C for 2 hours. The reaction solution was air-cooled, and then water was added. Then, the deposited crystals were collected by filtration. The deposited crystals were dissolved in ethyl acetate, washed in turn with water and an aqueous saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. 0.60 g of activated carbon (Kyoryoku Shirasagi MOIWY433) was added and, after standing for 10 minutes, activated carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.89 g of the objective compound as pale yellow crystals. Melting point: 87-89.5C
With hydrogen bromide; bromine; In chloroform; acetic acid;
EXAMPLE B 5-Bromo-3-bromoacetyl-pyridine hydrobromide 4 g (0.02 mol) of 5-bromo-3-acetyl-pyridine are dissolved in 50 ml of chloroform, 5 drops of glacial acetic acid/hydrobromic acid (35%) are added and the mixture is heated to boiling. To this boiling solution, 3.2 g (0.02 mol) of bromine in 30 ml of chloroform are added dropwise over a period of 5 hours with stirring. After cooling to ambient temperature the yellow solid product is suction filtered. Yield: 5 g (70% of theory). Melting point: 225 C. (decomp.).
2-oxo-4-phenyl-3-pyrrolidinecarboxylic acid[1-(5-bromo-pyridine-3-yl)-(E/Z)-ethylidene]-hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; acetic acid; for 10h;Heating / reflux;
2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid [1-(5-bromo- pyridine-3-yl)-( E/Z)-ethylidene]-hydrazide (7)[0151] 2-Oxo-4-phenyl-3-pyrrolidinecarboxylic acid hydrazide (21.9 mg,0.10 mmol) and 5-bromo-3-acetyl pyridine (40.0 mg, 0.20 mmol) was taken up inEtOH:AcOH (9:1 , 1 mL) and refluxed for 10 h. The solvent was evaporated in vacuo and the residue purified by column chromatography (silica, 0-3% MeOH inDCM). Yield: 26.6 mg.[0152] LC-MS (AP2): purity (UV/MS): 99/85, R1 1.95/2.27 min (two isomers)
Example 18; A solution of (S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (253 mg, 1 mmol) and trimethyl borate (0.135 mL, 1.2 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 hour after which time borane-methylsulfide complex (10 mL, 2M in tetrahydrofuran, 20 mmol) was added in one portion and the mixture cooled to O0C. A solution of <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (2 g, 10 mmol) in tetrahydrofuran (10 mL) was added dropwise over 2 hours at 00C and then the mixture was allowed to warm to room temperature and was stirred overnight. After this time dilute aqueous hydrochloric acid (2M, 90 mL) was added with initial cooling and the mixture was stirred at room temperature for 2 hours. Dimethyl sulfide and tetrahydrofuran were removed under reduced pressure and the resulting yellow solution was basified to pH 11 with aqueous ammonia, extracted with ethyl acetate (3 x 50 mL) and the extracts washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give (lR)-l-(5-bromopyridin-3-yl)ethanol (1.9 g) in acceptable purity.
With sodium carbonate;trans-{PdBr2(triphenylphosphine)2}; In ethanol; water; toluene; for 1h;Heating / reflux;
F. Synthesis of WBZ5[00124] Preparation of 5- (Phenyl)-3-acetylpyridine (step 5.1). A mixture of 5-Bromo-3- acetylpyridine (2g, 10 mmol), phenylboronic acid (1.5g, 12 mmol), trans- dibromobis(triphenylphosphine) palladium (II) (0.4g, 0.5 mmol), toluene (60 ml), ethanol (20 ml) and 2M aqueous sodium carbonate (40 ml) was refluxed for 1 hour under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel eluting with a gradient of 0-100% EtoAc in hexane to afford the: 5- (Phenyl)-3- acetylpyridine as a solid. 2g (10 mmol, 100%). TLC R/ 0.3 (1 :1 hexane/EtOAc); MS: 198.5(M+H); 1H NMR(DMSO) delta 9.12 (dd, J= 2.2 Hz, 2H), 8.50 (t, J= 2.1 Hz, IH), 7.83 (d, J= 8.1Hz, 2H), 7.54 (t, J= 7.7 Hz, 2H), 7.49 (t, J= 7.7 Hz, IH), 3.02 (s, 3H); 13C NMR delta 197.51,151.30, 148.12, 136.14, 135.51, 134.05, 133.34, 132.00, 129.91, 129.78, 129.19, 127.64, 27.14.
iron(III)-acetylacetonate; In tetrahydrofuran; at -78 - 20℃; for 2.16667h;
Step 2: l-(5-Bromo-pyridin-3-yl)-ethanone; 5-Bromo-nicotinoyl chloride (0.5 g, 2.268 mmol) is suspended in THF (24 ml) at room temperature under an atmosphere of Argon. Fe(acac)3 (0.04g, 0.113 mmol) is added and the reaction mixture is stirred for 10 minutes until a solution forms. The reaction mixture is cooled to -78 C and a solution of MeMgBr (3M in diethyl ether, 0.907 ml, 2.722 mmol) is added dropwise with stirring for 2 hours at -78 C. On warming to room temperature silica is added to the reaction mixture and the solvents are reduced in vacuo. Purification by flash chromatography eluting with 50:50 EtOAc/iso-hexanes affords the title compound as a yellow solid [MH+199.90 and 201.90].
Example 1.1.65: (R)-I -(5-(prop-l-en-2-yl)pyridin-3-yl)ethanamine; To a stirred solution of l-(5-bromopyridin-3-yl)ethanone (5.0 g, 25.0 mmol) in anhydrous MeOH (5OmL) at 00C, was added NaBH4 (1.32g, 35.0mmol) and the reaction was allowed to warm to room temperature. All solvent was removed. The residue was dissolved in cold water and extracted with EtOAc ( 2x 7OmL), The combined organic layers was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (40% EtOAc in hexanes) to provide 4.555 g of l-(5-bromopyridin-3- yl)ethanol.
With sodium tetrahydroborate; ethanol; at 20℃; for 0.5h;
Step 3: Suspended l-(5-bromopyridin-3-yl)ethanone (3.83 g, 19 mmol) in EtOH (56 ml, 957 mmol) and added sodium borohydride (0.80 g, 21 mmol). The reaction mixture was stirred at ambient temperature for 30 min and then treated mixture with water and aqueous sodium hydroxide. The resulting solution was extracted with 3x DCM. The combined organic layers were washed with brine and then dried over sodium sulfate. The solution was concentrated in vacuo to afford (l-(5-bromopyridin-3-yl)ethanol.
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0 - 20℃; for 0.75h;
To a stirred solution of l-(5-bromopyridin-3-yl)ethanone (4.8 g, 0.024 mol) in methanol (110.0 mL) and tetrahydrofuran (22.0 mL) cooled to 0 C, added sodium borhydride (1.7 g, 0.048 mol) and the resulting mixture was allowed to stir at room temperature for 0.75 h. The reaction mixture was concentrated and diluted with water (75 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organics were dried over sodium sulphate and concentrated under vacuum to obtain racemic mixture. The racemic mixture was separated by chiral HPLC (analytical conditions: column:CHIRALPAK IA( 250 mm X 4.6mm X 5mu?iota), mobile phase: n-heptane: 0.1%diethylamine in ethanol, flow rate: l.OmL/min) to get two isomers. MS (M+2): 204.1.
2.9 g
With methanol; sodium tetrahydroborate; for 16h;
1-(5-Bromo-pyridin-3-yl)-ethanone (3.0 g, 15 mmol) is dissolved in MeOH (20 mL) and sodium borohydride (1.1 g, 30 mmol) is added in 5 small portions every 15 min. The mixture is stirred for 16 hrs and the solvent is then removed in vacuo. Saturated aqueous NH4Cl solution (10 mL) is added along with 30 mL of water. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 2.9 g of 1-(5-bromo-pyridin-3-yl)-ethanol.
With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; isopropyl alcohol; for 5.16h;Heating / reflux;
Example 1.1.64: l-(5-isopropylpyridin-3-yl)ethanamine; A stirred solution of l-(5-bromopyridin-3-yl)ethanone (600 mg, 3.0 mmol), potassium isopopenyltrifluoroborate (148 mg, 3.0 mmol), and Et3N (1.25 mL, 9.0 mmol) in 'PrOH (2OmL) and H2O (1OmL) was degassed with argon for 10 min and then PdC12 (dppf) -CH2Cl2 (74 mg, 0.09 mmol) was added and the reaction mixture was heated to reflux for 5 h. The solution was cooled to room temperature and diluted with Ether and H2O. The layers were separated and the aqueous layer was extracted with Ether (2 x50 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc in hexanes) to provide 460 mg of l-(5-(prop-l-en-2-yl)pyridin-3-yl)ethanone.
A solution of 1 (40.0 g, 200 mmol) and R-l (1 19.0 g, 1000 mmol) in 500 mL of THF was stirred at 70 C overnight. TLC indicated the reaction was completed. The mixture was cooled to room temperature and removed the solvent at reduced pressure. The resulting solid was washed with hexane to afford 2 as a yellow solid (47.2 g, 93%).
93%
In tetrahydrofuran; at 70℃;
A solution of 1 (40.0 g, 200 mmol) and R-l (1 19.0 g, 1000 mmol) in 500 mL of THF was stirred at 70 C overnight. TLC indicated the reaction was completed. The mixture was cooled to room temperature and removed the solvent at reduced pressure. The resulting solid was washed with hexane to afford 2 as a yellow solid (47.2 g, 93%).
at 100℃; for 1h;
3-Acetyl-5-bromopyridine (1 eq, 0.2 g) and dimethoxymethyl-dimethyl-amine (2.5 eq, 133 mul) are heated at 100 0C for 1 hour. After cooling to RT, Et2O/iso-hexane (10 ml of a 1:1 mixture) is added which results in the formation of a yellow precipitate. The solid is filtered and washed with Et2theta/iso-hexane (20 ml of a 1:1 mixture). The resulting solid is dried in vacuo at RT for 3 hours to afford the title compound as a beige solid [M+H]+ = 255/257.
With titanium(IV) tetraethanolate; In tetrahydrofuran; for 7h;Reflux;
A solution of compound (38)(5.00 g), (R)-(+)-2-methyl-2-propanesulfinamide (3.33 g) and tetraethyl orthotitanate (17.11 g) in tetrahydrofuran (50 ml) was reacted under heating to reflux for 7 hours, and then, it was poured portionwise into saturated brine and the resulted insoluble materials were filtered off It was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silicagel column chromatograph to give compound (39)(6.37 g). 1H-NMR (CDCl3) delta: 1.34 (9H, s), 2.79 (3H, s), 8.26 (1H, t, J = 2.3 Hz), 8.76 (1H, d, J = 2.3 Hz), 8.96 (1H, d, J = 2.3 Hz).
A solution of <strong>[38940-62-4]1-(5-bromopyridin-3-yl)ethanone</strong> (2.04 g, 27.5 mmol) in methanol (55 mL) was added slowly to a cold solution of 2-oxoacetic acid (2.04 g, 27.5 mmol) and potassium carbonate (7.22 g, 52.24 mmol) in water (50 mL). The mixture was stirred at room temperature for 2h. The resultant solution was partially evaporated under reduced pressure at 30 C to remove most of the methanol and then extracted three times with ethyl acetate. The cooled aqueous solution was carefully treated with acetic acid (11 mL, 192 mmol) and washed with dichloromethane. Ethylhydrazine oxalate (3.61 g, 26.1 mmol) was added to the aqueous phase, and the mixture heated under reflux for 2 h. A further 3.61 g ethylhydrazine oxalate (26.12mmols) was added and the mixture heated under reflux for 2 d. The solution was neutralised with potassium carbonate to pH 7 and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure and the crude purified in a 40M column from Biotage on a SP1 automatic purification system using hexane and ethyl acetate as solvents (0-100% ethyl acetate) in 20 column volumes. The appropriate fractions were collected and evaporated to give 3.71 g (47% yield) of the title compound. HPLC/MS (9 min) retention time 5.32 min. LRMS: m/z 282 (M+1)
A mixture of 1~(5-bromo-pyridin-3-yl)-ethanone (200 mg. 1.000 mmol), ethanesuifonamide (136 mg, 1.250 mmol) and titanium(IV) isopropoxide (586 mul_, 2.0 mmol) in toluene (20 ml) was heated to reflux for 8 h. After concentration, the residue was dissolved in THF (5 ml). A solution of methylmagnesium bromide (1000 mul, 3.00 mmol) was added dropwise at - 50 0C. The resulting mixture was slowly warmed up to room temperature over a course of 2 h. The mixture was stirred at this temperature overnight and quenched with NH4CI solution. After filtration, wash with CH2CI? and concentration, the residue was purified by flash column (Ethyl acetate / heptane, v/v, 10percent to 50percent) and yielded a yellow oil (35 mg). ESI-MS mlz: 309.1 [M+1]f. Retention time "1.22 mialpha 'H NMR (400 MHz, CDCI3): delta 1.43 (t, J * 7.4 Hz, 3H), 1.84 (s. 6H), 2.98 (q, J s 7.4 Hz, 2H)1 5.07 (brs, 1H), 8.04 (s. 1H). 8.66 (s, 1H), 8.77 (s. 1H).
Example 1 : Synthesis of (Z)-3-(2-(5-bromopyridin-3-yl)-2-oxoethylidene)-4- chloroindolin-2-one[0133] This example demonstrates the synthesis of a compound of the technology wherein R2 is substituted pyridine, wherein the substituted pyridine group may further be reacted to provide other substituted pyridine compounds of the present technology. 4- chloroindoline-2,3-dione (1.0 g, 5.1 mmol) was suspended in 20 mL anhydrous ethanol and l -(5-bromopyridin-3-yl)ethanone (1.21 g, 6.06 mmol) was added, followed by diethylamine (0.63 mL, 6.06 mmol) which was slowly dropped into the solution while the solid dissolved and the solution turned dark red/brown. Within a few minutes, a large amount of solid precipitated, leaving a yellow solution behind. After 2 hours of additional stirring, the mixture was triturated with 50 mL of n-pentane and all precipitate was filtered off, washed with diethyl ether (2 X 15 mL) and dried under vacuum, furnishing 3- (2-(5-bromopyridin-3-yl)-2-oxoethyl)-4-chloro-3-hydroxyindolin-2-one (1 .660 g, 4.35 mmol, 79 % yield) as a light grey solid that was used without further purification.
With diethylamine; In ethanol; at 20℃;
General Procedure: An isatin (1 eq.) with the desired substitution pattern or N-alkylation (see general procedure above) was condensed with the desired aryl methyl ketone (1 eq.) using diethylamine (1 eq.) in anhydrous ethanol for 2-48 hours (most reactions were complete after 2-3 h). The condensation product could be precipitated in quantitative yield using pentane and isolated by filtration. Without further purification, it was subjected to a 4:1 mixture of glacial acetic acid with concentrated hydrochloric acid and carefully heated to boiling with a heatgun for 20-30 min. The acidic mixture was diluted tenfold with water and neutralized with sodium hydroxide and sodium bicarbonate, whereby the highly colored OVK products precipitated. After filtration and drying, the crude products were dissolved in a minimal amount of acetone and DCM. The solution was gradually triturated with pentane and any precipitating dark impurities filtered off. The final product either crystallized from this solution or could be obtained by removing the volatiles. In most cases, the product was sufficiently pure without any further effort. If necessary, a small quantity of product could be purified by preparative TLC on 1 mm glass-backed silica gel plates, typically using 3:2 ethyl acetate - pentane as developing solvent and 100% ethyl acetate as eluent.
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 1h;
Step A. 2-( 5-Bromopyridin-3-yl)- 1,1,1 -trifluoropropan-2-ol To a solution of <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (0.20 g, 1.0 mmol) in tetrahydrofuran (3.3 mL) were added a solution of trimethyl(trifluoromethyl)silane in tetrahydrofuran (0.5 M, 4.0 mL, 2.0 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 0.1 mL, 0.1 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then diluted with water and dichioromethane. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0 to 6%dichioromethane in acetone) provided the title compound: LCMS m/z 271.75 [M + H]+; 1H NMR (500 MHz, CDC13) delta 8.71 (s, 1 H), 8.68 (s, 1 H), 8.1 l(s, 1 H), 3.12 (br s, 1 H), 1.82 (s, 3H).
To a flask containing <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (2.27 g, 11.4 mmol) was added a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) at 0 C. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 11.4 mL, 11.4 mmol) was then added, and the reaction stirred at room temperature until the reaction was complete. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (10 - 50% ethyl acetate in hexanes) to provide the racemic title compound: LCMS m/z 269.85 [M + 2 + H]+; 1H NMR (500 MHz, CD3OD) delta 8.70 (s, 1 H), 8.65 (1 H), 8.13 (s, 1 H), 1.81 (s, 3 H). The racemic title compound was resolved by supercritical fluid chromatography on a chiral AD column, eluting with 10% ethanol:C02. Data for enantiomer A: LCMS m/z 271.85 [M + H]+; NMR (500 MHz, CDC13) 8.71 (s, 1 H), 8.68 (d, J = 2.0 Hz, 1 H), 8.10 (s, 1 H), 1.82 (s, 3 H). Data for enantiomer B: LCMS m/z 271.83 [M + H]+; 1H NMR (500 MHz, CDC13) 8.71 (s, 1 H), 8.68 (s, 1 H), 8.10 (s, 1 H), 1.81 (s, 3 H).
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 0 - 20℃;
To a flask containing <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (2.27 g, 11.4 mmol) was added a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) at 0 C. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 11.4 mL, 11.4 mmol) was then added, and the reaction stirred at room temperature until the reaction was complete. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (10 - 50% ethyl acetate in hexanes) to provide the racemic title compound: LCMS m/z 269.85 [M + 2 + H]+; 1H NMR (500 MHz, CD3OD) delta 8.70 (s, 1 H), 8.65 (1 H), 8.13 (s, 1 H), 1.81 (s, 3 H). The racemic title compound was resolved by supercritical fluid chromatography on a chiral AD column, eluting with 10% ethanol:C02. Data for enantiomer A: LCMS m/z 271.85 [M +H]+; 1H NMR (500 MHz, CDC13) 8.71 (s, 1 H), 8.68 (d, J = 2.0 Hz, 1 H), 8.10 (s, 1 H), 1.82 (s, 3 H). Data for enantiomer B: LCMS m/z 271.83 [M + H]+; 1H NMR (500 MHz, CDC13) 8.71 (s, 1 H), 8.68 (s, 1 H), 8.10 (s, 1 H), 1.81 (s, 3 H).
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 0.5h;
Preparative Example 2.3 - 2-(5-Bromopyridin-3 -yl)- 1, 1, 1 -trifluoropropan-2-ol PrepEx 2.3 [00221] Tetrabutylammonium fluoride (1.0 M in THF, 33 mu, 0.033 mmol) was added to a solution of l-(5-bromopyridin-3-yl)ethanone (65 mg, 0.33 mmol) and trimethyl(trifluoromethyl)silane (92 mg, 0.65 mmol) in THF (1.1 mL) at ambient temperature. After 30 minutes, the reaction mixture was diluted with water and extreacted with DCM, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 30 % ethyl acetate/hexanes, linear gradient) to afford 2-(5- bromopyridin-3-yl)-l, l, l-trifluoropropan-2-ol. MS ESI calc'd. for C8H8BrF3NO [M + H]+ 270 and 272, found 270 and 272. H NMR (500 MHz, CDC13) delta 8.72 (s, 1H), 8.69 (d, J= 2.5 Hz, 1H), 8.10 - 8.08 (m, 1H), 2.58 (s, 1H), 1.82 (s, 3H).
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 0 - 20℃;
To a flask containing <strong>[38940-62-4]3-acetyl-5-bromopyridine</strong> (2.27 g, 11.4 mmol) was added a solution of (trifluoromethyl)trimethylsilane in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) at 0 C. A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 11.4 mL, 11.4 mmol) was then added, and the reaction stirred at room temperature until the reaction was complete. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (10% to 50% ethyl acetate/ hexanes linear gradient) to provide the racemic title compound: LCMS m/z 269.85 [M + 2 + H]+; 1H NMR (500 MHz, CD3OD) delta 8.70 (s, 1 H), 8.65 (1 H), 8.13 (s, 1 H), 1.81 (s, 3 H). The racemic title compound was resolved by supercritical fluid chromatography on a chiral AD column, eluting with 10% ethanohCC^. Data for enantiomer A: LCMS m/z 271.85 [M + H]+; 1H NMR (500 MHz, CDC13) 8.71 (s, 1 H), 8.68 (d, J = 2.0 Hz, 1 H), 8.10(s, 1 H), 1.82 (s, 3 H). Data for enantiomer B: LCMS m/z 271.83 [M + H]+; 1H NMR (500 MHz, CDC13 8.71 (s, 1 H), 8.68 (s, 1 H), 8.10 (s, 1 H), 1.81 (s, 3 H).
1.12 g
To a solution of <strong>[38940-62-4]1-(5-bromo-pyridin-3-yl)-ethanone</strong> (1.0 g, 5.0 mmol) in THF (dry, 25 ml) at room temperature is added tetrabutyl-ammonium fluoride (0.35 ml, 1M in THF, 0.35 mmol). Then trimethyl-trifluoromethyl-silane (3.25 ml, 2.0M in THF, 6.5 mmol) is added to the reaction mixture dropwise. The reaction mixture is stirred for 3 h. Then HCl (4N, 6.6 ml, 26.5 mmol) is added to the mixture. The reaction mixture is stirred for 4 h at room temperature and then is neutralized by adding Na2CO3 powder slowly. The resulting mixture is partitioned between water and EtOAc, and the aqueous phase is extracted with EtOAc. The combined organic phases are concentrated in vacuo. The crude mixture is separated by flash silica gel column (EtOAc/ Heptane 0 to 30% gradient, then 30%) to obtain 1.12 g 2-(5-bromo-3-pyridyl)-1,1,1-trifluoro-propan-2-ol.
To a cooled (-78 C ) solution of 3-acetyl-5-bromo pyridine (1.98 g, 9.90 mmol) in tetrahydrofuran (33 mL) was added dropwise a solution of methyl magnesium bromide in diethyl ether (3.0 M, 6.60 mL, 19.8 mmol). The reaction was warmed to room temperature, and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0 - 60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 217.83 [M + Hf; NMR (500 MHz, CDC13) delta 8.61 (s, 1 H), 8.53 (s, 1 H), 8.01 (d, J= 1.9 Hz, 1 H), 2.38 (br s, 1 H), 1.61 (6 H).
In tetrahydrofuran; at 0℃; for 1.5h;
Methyl magnesium bromide (5.3 mL, 0.075 mol) was added to a stirred solution of l-(5-bromopyridin-3-yl)ethanone (1.0 g, 0.05 mol) in tetrahydrofuran (20.0 mL), cooled to 0 C and the resulting mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with IN hydrochloric acid (20 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain 2-(5-bromopyridin-3-yl)propan- 2-ol. MS (M+l): 217.1.
In tetrahydrofuran; diethyl ether; at -78 - 20℃;
To a cooled (-78 C ) solution of 3-acetyl-5-bromo pyridine (1.98 g, 9.90 mmol) in tetrahydrofuran (33 mL) was added dropwise a solution of methyl magnesium bromide in diethyl ether (3.0 M, 6.60 mL, 19.8 mmol). The reaction was warmed to room temperature, and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0 - 60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 217.83 [M + H]+; 1H NMR (500 MHz, CDC13) delta 8.61 (s, 1 H), 8.53 (s, 1 H), 8.01 (d, J= 1.9 Hz, 1 H), 2.38 (br s, 1 H), 1.61 (6 H).
With tert.-butylhydroperoxide; trifluoroacetic acid; In dichloromethane; water; for 17h;
General procedure: Difluoromethylation of Heterocycles Standard Procedures: Procedure B: To a solution of heterocycle (0.25 mmol, 1.0 equiv) and zinc difluoromethanesulfinate (DFMS) (173 mg, 0.50 mmol, 2.0 equiv ?calculated as anhydrous?) in dichloromethane (1.0 mL) and water (0.4 rnL) at room temperature was added trifluoroacetic acid (20 muL, 0.25 rnmol, 1.0 equiv) followed by slow addition of tert-butyl hydroperoxide (70% solution in water, 0.1 mL, 0.75 mmol, 3.0 equiv) with vigorous stirring. The reaction was monitored by thin layer chromatography until completion. For substrates which do not go to completion in 24 hours, a second addition of DFMS (2.0 equiv) and tert-butyl hydroperoxide (3.0 equiv) may be added to drive the reaction further. Upon consumption of starting material, the reaction was partitioned between dichioromethane (2.0 mL) and saturated sodium bicarbonate (2.0 mL) . The organic layer was separated, and the aqueous layer was extracted with dichioromethane (3 X 2.0 mL) . The organic layers were dried with sodium sulfate, concentrated and purified by column chromatography on silica gel. If substrates are less reactive, alpha,alpha,-trifluorotoluene can be substituted for DCM, as it causes improved reactivity for some cases. For water-soluble starting materials, a purely aqueous reaction (1.0 mL of water) can be run and in some cases, it was also found to display improved reactivity. In lieu of a workup, these reactions can be concentrated and the product purified directly. If the addition of tert-butyl hydroperoxide is performed too rapidly, the resulting exotherm can result in reduced yield and selectivity. This is especially important on larger scales (see gram scale procedure: substrate 2), where a syringe pump can be used to meter in tert-butyl hydroperoxide.It is noted that trifluoroacetic acid (TFA) is not required in either of the above procedures. It was also found that TFA showed improved rate and conversion for selected nitrogen heteroarene substrates, but was not essential to achieve the desired reactivity for most cases. When present, TFA is typically used at about 0.25 to about 2 equivalents per equivalent of nitrogen heteroarene, and more preferably at about 0.5 to about 1.5 equivalents relative to the nitrogen heteroarene.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 20h;Inert atmosphere;
In a typical experiment, the bromopyridine (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc (4 mL) under an argon atmosphere. The reaction mixture was stirred at 100 C or 150 C (see schemes) for 20 h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 20h;Inert atmosphere;
In a typical experiment, the bromopyridine (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc (4 mL) under an argon atmosphere. The reaction mixture was stirred at 100 C or 150 C (see schemes) for 20 h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 20h;Inert atmosphere;
In a typical experiment, the bromopyridine (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc (4 mL) under an argon atmosphere. The reaction mixture was stirred at 100 C or 150 C (see schemes) for 20 h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 20h;Inert atmosphere;
In a typical experiment, the bromopyridine (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc (4 mL) under an argon atmosphere. The reaction mixture was stirred at 100 C or 150 C (see schemes) for 20 h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 20h;Inert atmosphere;
In a typical experiment, the bromopyridine (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc (4 mL) under an argon atmosphere. The reaction mixture was stirred at 100 C or 150 C (see schemes) for 20 h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
With PdCl(C3H5)(dppb); potassium acetate; In N,N-dimethyl acetamide; at 150℃; for 20h;Inert atmosphere;
In a typical experiment, the bromopyridine (1 mmol), heteroaromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc (4 mL) under an argon atmosphere. The reaction mixture was stirred at 100 C or 150 C (see schemes) for 20 h. After evaporation of the solvent, the product was purified by silica gel column chromatography.
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