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Structure of 38749-79-0 * 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.
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 5, p. 871 - 880
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2006, vol. 49, # 9, p. 789 - 799
2
[ 68-12-2 ]
[ 38749-79-0 ]
[ 60032-57-7 ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 1 h;
To a solution of 3-bromo-2-methylpyridine (148; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 °C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 0C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-methylnicotinaldehyde 149 (2.18 g, 31percent).
31%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 1 h;
Example 21. Synthesis of 2-(2-methylpyridin-3-yl)-N-(thiazol-2-yl)-[l,2,4]triazolo[l,5- a]pyridine-8-carboxamide (Compound 239):Step 1) Preparation of 2-methylnicotinaldehyde (89): To a solution of 3-bromo-2-methylpyridine (88; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 0C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 0C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-methylnicotinaldehyde 89 (2.18 g, 31percent).
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 2989 - 3004
4
[ 557-21-1 ]
[ 38749-79-0 ]
[ 1721-23-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 175℃; for 2 h; Microwave irradiation; Inert atmosphere
3-Bromo-2-methylpyridine (344 mg, 2 mmol), Zn(CN)2 (235 mg, 2 mmol) and Pd(PPh3)4 (75 mg, 0.06 mmol) were dissolved in DMF (5 mL). The mixture was vacuumed for N2 three times, The reaction solution was reacted in the microwave (175° C.) for 2 h under N 2 protection. After cooling, it was diluted with EtOAc (60 mL). After washing with saturated saline, dry over anhydrous sodium sulfate. Concentration by filtration and column chromatography of the residue provided the title compound as a white solid (212 mg, yield 90percent).
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2006, vol. 49, # 9, p. 789 - 799
7
[ 67-56-1 ]
[ 201230-82-2 ]
[ 38749-79-0 ]
[ 65719-09-7 ]
Yield
Reaction Conditions
Operation in experiment
93.6%
at 80℃; for 16 h;
A mixture of 3-bromo-2-methylpyridine (5.0 g, 29.0 mmol), Pd(dppf)C12 (2.1 g, 2.9 mmol) and Et3N (8.8 g, 87 mmol) in MeOH (250 mL) was stirred at 80 °C and 5OPsi under CO for 1 6h. Solid was then filtered out and the filtrate was concentrated. The residue was purified by column chromatography (PE:EA=5: 1) to give the desired product (4.1 g, 93.6percent). ‘H NMR (CD3OD, 400MHz) (ppm): 8.57 - 8.42 (m, 1H), 8.08 (d, 1=8.0 Hz, 1H),7.10 (dd, 1=4.8, 7.8 Hz, 1H), 3.81 (s, 3H), 2.73 (s, 3H). LCMS (mlz): 152.0 [M+H]+
Reference Example 182 3-bromo-2-methylpyridine; 2-Methylpyridine (46.6 g) was added dropwise to aluminum chloride (200 g) and the mixture was stirred at 100° C. To a mixture was added dropwise bromine (40.0 g) at the same temperature over 1 hr, and the mixture was further stirred for 30 min. After cooling, the reaction mixture was poured into ice water, concentrated hydrochloric acid was added until the mixture was acidified. The obtained solution was washed with ethyl acetate, and the aqueous layer was basified with a 8 mol/L aqueous sodium hydroxide solution. After extraction with diethyl ether, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-diethyl ether=10:1) to give the title compound as a colorless oil (yield 5.09 g, 12percent). 1H-NMR (CDCl3)δ: 2.67 (3H, s), 6.98-7.03 (1H, m), 7.78-7.82 (1H, m), 8.40-8.44 (1H, m).
Stage #1: With lithium hexamethyldisilazane In diethyl ether; hexane for 1 h;
Lithium hexamethyldisilazane (436 mL, 0.44 mmol, 1 M solution in hexanes) was dissolved in diethyl ether (1 L). Compound 26, 3-bromo-2-methylpyridine, (25.0 g, 0.14 mmol) was added. The solution was stuffed for 1 h. Diethyl carbonate (26.0 mL, 0.22 mol) was added and the solution was stirred overnight. The reaction solution was washed three times with half-saturated aqueous sodium chloride (3 x 250 mL) and dried with magnesium sulfate. The solvent was evaporated and the reminder was dissolved in hexanes (200 mL). The solution was filtered through silica pad (10 g), the pad was rinsed with additional hexanes (100 mL) and the solvent was evaporated. The remaining oil was stirred in high vacuum for 1 hour till there were no further bubbles visible. The product was a yellow liquid(37.7 g). LCMS: [M + Hj = 244.1.
37.7 g
Stage #1: With lithium hexamethyldisilazane In diethyl ether; hexane for 1 h;
[0117] Lithium hexamethyldisilazane (436 mL, 0.44 mmol, 1 M solution in hexanes) was dissolved in diethyl ether (1 L). Compound 1 , 3-bromo-2-methylpyridine, (25.0 g, 0.14 mmol) was added. The solution was stirred for 1 h. Diethyl carbonate (26.0 mL, 0.22 mol) was added and the solution was stirred overnight. The reaction solution was washed three times with half- saturated aqueous sodium chloride (3 χ 250 mL) and dried with magnesium sulfate. The solvent was evaporated and the reminder was dissolved in hexanes (200 mL). The solution was filtered through silica pad (10 g), the pad was rinsed with additional hexanes (100 mL) and the solvent was evaporated. The remaining oil was stirred in high vacuum for 1 hour till there were no further bubbles visible. The product was a yellow liquid (37.7 g). LCMS: [M + H]+ = 244.1.
With selenium(IV) oxide In 1,4-dioxane for 48 h; Reflux
Dissolve 3-bromo-2-methylpyridine (258 mg, 1.5 mmol) in dioxane (5 mL) and add selenium dioxide while stirring (666 mg, 6.0 mmol), the mixture was refluxed for 48 h, allowed to cool, and the filtrate was concentrated. The residue was purified by column chromatography to give a pale yellow solid. (175 mg, 63percent yield).
55%
With selenium(IV) oxide In 1,4-dioxane at 120℃; for 18 h;
3-Bromopicolinaldehyde (B5.1) (0362) A mixture of 3-bromo-2-methylpyridine (5 g, 29 mmol), SeO2 (17.5 mg, 116 mmol) in dioxane (70 mL) was heated to 120° C. and stirred for 18 h. The mixture was concentrated and purified by silica gel (PE:EA=4:1) to give the title compound (3 g, 55percent) as a white solid. LC-MS: [M+H]+=188.1.
55%
With selenium(IV) oxide In 1,4-dioxane at 120℃; for 18 h;
A mixture of 3-bromo-2-methylpyridine (5 g,2gmmol), SeQ2 (17.5 mg, ll6mmol) in dioxane (70 mL) was heated to 120°C andstirred for 18 h. The mixture was concentrated and purified by silica gel (PE:EA = 4:1)to give the title compound (3 g, 55percent) as a white solid. LC-MS: [M+H] = 188.1.
Reference：
[1] Patent: US2006/199817, 2006, A1, . Location in patent: Page/Page column 50
[2] British Journal of Pharmacology, 2018, vol. 175, # 17, p. 3470 - 3485
17
[ 38749-79-0 ]
[ 155058-02-9 ]
Reference：
[1] Patent: WO2015/200677, 2015, A2,
18
[ 38749-79-0 ]
[ 754131-60-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
With N-Bromosuccinimide In tetrachloromethane for 4 h; Reflux
A mixture of 6a (1 g, 5.8 mmol), benzoylperoxide (101 mg, 0.4 mmol) and NBS (1.1 g, 6.39 mmol) in CCI4 (58 mL) was heated under reflux for 4 h. The reaction mixture was cooled to rt, quenched with H20 and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by CC on silica gel, eluting with PE:EA = 15:1 to afford 6b (1.1 g, 78percent yield) as a yellow oil.
30%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 48 h; Inert atmosphere; Reflux
Operations: 100g of compound 1 (3-bromo-2-methyl pyridine, TCI (Shanghai) Chemical Industry Co., Ltd.) wasdissolved in carbon tetrachloride. 155g of N-bromosuccinimide and 5g of benzoyl peroxide were added and refluxed for48h under nitrogen protection and cooled to filter off insoluble substances. After being added with an appropriate amountof ethyl acetate, the organic phase was washed with diluted hydrochloric acid once, then washed with a saturatedaqueous solution of sodium bicarbonate, and finally washed and extracted with saturated brine. The organic phase wasdried, filtered and distilled under reduced pressure to obtain a pale yellow oily substance, isolated by column chromatographyto obtain compound 2 (43g, yield 30percent). MS: m/z 251.8.
30%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 48 h; Inert atmosphere; Reflux
100 g of compound 1 (3-bromo-2-methylpyridine, TCI (Shanghai) Chemical Industry Co., Ltd.) was dissolved in carbon tetrachloride. 155 g of N-bromosuccinimide and 5 g of benzoyl peroxide were added and refluxed for 48 h under nitrogen protection and cooled to filter off insoluble substances. After being added with an appropriate amount of ethyl acetate, the organic phase was washed with diluted hydrochloric acid once, then washed with a saturated aqueous solution of sodium bicarbonate, and finally washed and extracted with saturated brine. The organic phase was dried, filtered and distilled under reduced pressure to obtain a pale yellow oily substance, isolated by column chromatography to obtain compound 2 (43 g, yield 30percent). MS: m/z 251.8.
To a stirred solution of LiHMDS(87.2 mL, 521.12 mmol, 1.5 equiv.) in THF(200 mL) was added 3-bromo-2-methylpyridine(10 g, 58.13 mmol, 1 equiv.) dropwise at 0 degrees celsius under nitrogen atmosphere. The mixture was stirred at rt for 2 h. diethyl carbonate(10.3 g, 87.20 mmol, 1.5 equiv.) was added to the mixture at 0 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. To the mixture was added water (200 mL). The resulting mixture was extracted with EtOAc(2 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL),dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 2-(3-bromopyridin-2- yl)acetate(13 g, 91.62%) as colorless oil.
37.7 g
Lithium hexamethyldisilazane (436 mL, 0.44 mmol, 1 M solution in hexanes) was dissolved in diethyl ether (1 L). Compound 26, 3-bromo-2-methylpyridine, (25.0 g, 0.14 mmol) was added. The solution was stuffed for 1 h. Diethyl carbonate (26.0 mL, 0.22 mol) was added and the solution was stirred overnight. The reaction solution was washed three times with half-saturated aqueous sodium chloride (3 x 250 mL) and dried with magnesium sulfate. The solvent was evaporated and the reminder was dissolved in hexanes (200 mL). The solution was filtered through silica pad (10 g), the pad was rinsed with additional hexanes (100 mL) and the solvent was evaporated. The remaining oil was stirred in high vacuum for 1 hour till there were no further bubbles visible. The product was a yellow liquid(37.7 g). LCMS: [M + Hj = 244.1.
37.7 g
[0117] Lithium hexamethyldisilazane (436 mL, 0.44 mmol, 1 M solution in hexanes) was dissolved in diethyl ether (1 L). Compound 1 , 3-bromo-2-methylpyridine, (25.0 g, 0.14 mmol) was added. The solution was stirred for 1 h. Diethyl carbonate (26.0 mL, 0.22 mol) was added and the solution was stirred overnight. The reaction solution was washed three times with half- saturated aqueous sodium chloride (3 chi 250 mL) and dried with magnesium sulfate. The solvent was evaporated and the reminder was dissolved in hexanes (200 mL). The solution was filtered through silica pad (10 g), the pad was rinsed with additional hexanes (100 mL) and the solvent was evaporated. The remaining oil was stirred in high vacuum for 1 hour till there were no further bubbles visible. The product was a yellow liquid (37.7 g). LCMS: [M + H]+ = 244.1.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; for 24h;Reflux; Inert atmosphere;
Dissolve <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (126 mg, 0.733 mmol) in toluene (1 mL) and add a solution of phenylboronic acid (268 mg, 2.198 mmol) in ethanol (1.5 mL) while stirring. Additional 2M sodium carbonate solution (2.93 mL) was added, Additional Pd[P(Ph)3]4 (110 mg, 0.088 mmol) was added. After the mixture was evacuated for N2 three times, it was refluxed for 24 h under N2 atmosphere. After allowing to cool, the liquid was separated, the organic layer was separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. Column chromatography gave a yellow oil (105 mg, yield 86%).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 16h;Reflux;
NBS (2.85 g, 16.0 mmol) and benzoyl peroxide (282 mg, 0.872 mmol) were added to a solution of 3a (1.25 g, 7.27 mmol) in CCl4 (15 mL). The mixture was heated to reflux for 4 h. Then, another portion of NBS (1.0 g, 5.62 mmol) and benzoyl peroxide (100 mg, 0.310 mmol) were added and the reaction mixture was heated to reflux for another 12 h. The reaction mixture was filtered to remove the insoluble materials, and concentrated in vacuo. The crude product was purified by fc (4 cm, EtOAc:cyclohexane 1:10). Pale yellow oil (EtOAc:cyclohexane 1:4, Rf = 0.30), yield 2.16 g (90%). 1H NMR (400 MHz, CDCl3): delta (ppm) = 7.12-7.21 (m, 2H, 5-H-Py, PyCH), 7.86 (dd, J = 8.1/1.5 Hz, 1H, 4-H-Py), 8.68 (dd, J = 4.5/1.4 Hz, 1H, 6-H-Py).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 30h;Reflux;
Intermediate 40: (S)-(3-(Prop-l-yn-l-yl)pyridin-2-yl)(4-(trifluoromethyl)- phenyl)methanamine hydrochlorideStep- 1. 3-Bromo-2-dibromethyl-pyridineTo a solution of 3-bromo-picoline (25 g, 0.145 mol) in CCI4 was added NBS (51.66 g, 0.29 mol) and benzoylperoxide (2.5 g, 0.018 mol). The resulting mixture was then gradually heated to reflux for 30 h. The reaction mixture was cooled to rt, the succinamide was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography using silica (100-200 mesh) with EtOAc: hexane (1 :9) as eluent to furnish 40.0 g pure 3-bromo-2-dibromomethyl-pyridine. 1H-NMR (400 MHz, CDCI3) delta ppm 7.67 (d, 1H), 7.86 (d, 1H), 7.15 (t, 2H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 30h;Reflux;
Step-1. 3-Bromo-2-dibromethyl-pyridineTo a solution of 3-bromo-picoline (25 g, 0.145 mol) in CCI4 was added N- bromosuccinimide (51.66 g, 0.29 mol) and benzoylperoxide (2.5 g, 0.018 mol). The mixture was then gradually heated to reflux and stirred for 30 h. The reaction miture was then cooled to rt, the succinimide was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting product was purified by flash column chromatography using silica (100-200 mesh) with EtOAc: hexane (0.1 :09) as eluent to furnish pure 3-Bromo-2-dibromomethyl- pyridine. 1H-NMR (400 MHz, CDC13): 7.66-7.68(d, 1H), 7.84-7.88(d, 1H), 7.13-7.17(t, 2H).
With selenium(IV) oxide; In 1,4-dioxane; for 48h;Reflux;
Dissolve 3-bromo-2-methylpyridine (258 mg, 1.5 mmol) in dioxane (5 mL) and add selenium dioxide while stirring (666 mg, 6.0 mmol), the mixture was refluxed for 48 h, allowed to cool, and the filtrate was concentrated. The residue was purified by column chromatography to give a pale yellow solid. (175 mg, 63% yield).
55%
With selenium(IV) oxide; In 1,4-dioxane; at 120℃; for 18h;
3-Bromopicolinaldehyde (B5.1) (0362) A mixture of 3-bromo-2-methylpyridine (5 g, 29 mmol), SeO2 (17.5 mg, 116 mmol) in dioxane (70 mL) was heated to 120 C. and stirred for 18 h. The mixture was concentrated and purified by silica gel (PE:EA=4:1) to give the title compound (3 g, 55%) as a white solid. LC-MS: [M+H]+=188.1.
55%
With selenium(IV) oxide; In 1,4-dioxane; at 120℃; for 18h;
A mixture of 3-bromo-2-methylpyridine (5 g,2gmmol), SeQ2 (17.5 mg, ll6mmol) in dioxane (70 mL) was heated to 120C andstirred for 18 h. The mixture was concentrated and purified by silica gel (PE:EA = 4:1)to give the title compound (3 g, 55%) as a white solid. LC-MS: [M+H] = 188.1.
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux;
A mixture of 6a (1 g, 5.8 mmol), benzoylperoxide (101 mg, 0.4 mmol) and NBS (1.1 g, 6.39 mmol) in CCI4 (58 mL) was heated under reflux for 4 h. The reaction mixture was cooled to rt, quenched with H20 and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by CC on silica gel, eluting with PE:EA = 15:1 to afford 6b (1.1 g, 78% yield) as a yellow oil.
30%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 48h;Inert atmosphere; Reflux;
Operations: 100g of compound 1 (<strong>[38749-79-0]3-bromo-2-methyl pyridine</strong>, TCI (Shanghai) Chemical Industry Co., Ltd.) wasdissolved in carbon tetrachloride. 155g of N-bromosuccinimide and 5g of benzoyl peroxide were added and refluxed for48h under nitrogen protection and cooled to filter off insoluble substances. After being added with an appropriate amountof ethyl acetate, the organic phase was washed with diluted hydrochloric acid once, then washed with a saturatedaqueous solution of sodium bicarbonate, and finally washed and extracted with saturated brine. The organic phase wasdried, filtered and distilled under reduced pressure to obtain a pale yellow oily substance, isolated by column chromatographyto obtain compound 2 (43g, yield 30%). MS: m/z 251.8.
30%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 48h;Inert atmosphere; Reflux;
100 g of compound 1 (<strong>[38749-79-0]3-bromo-2-methylpyridine</strong>, TCI (Shanghai) Chemical Industry Co., Ltd.) was dissolved in carbon tetrachloride. 155 g of N-bromosuccinimide and 5 g of benzoyl peroxide were added and refluxed for 48 h under nitrogen protection and cooled to filter off insoluble substances. After being added with an appropriate amount of ethyl acetate, the organic phase was washed with diluted hydrochloric acid once, then washed with a saturated aqueous solution of sodium bicarbonate, and finally washed and extracted with saturated brine. The organic phase was dried, filtered and distilled under reduced pressure to obtain a pale yellow oily substance, isolated by column chromatography to obtain compound 2 (43 g, yield 30%). MS: m/z 251.8.
With N-Bromosuccinimide; In tetrachloromethane; for 144h;Heating / reflux;
3-Bromo-2-methylpyridine (10.0 g, 58.1 mmol), diphenylperoxyanhydride (2.82 g, 11.6 mmol), l-bromopyrrolidine-2,5-dione (10.9 g, 61.0 mmol) were refluxed in 233 mL of carbon tetrachloride for 144 hours. The reaction mixture was cooled to ambient temperature and washed with water (3 x 200 mL). The organic layer was dried over Na2SOphi filtered, concentrated, and purified by silica gel chromatography eluting with 0-30% EtOAc in hexanes to provide 3 -bromo-2-(bromomethyl)pyridine.The above pyridine (5.13 g, 20.4 mmol) was stirred in 50.1 mL of a 5.6:1 solution of ethanolrdeionized water. To this mixture was added sodium cyanide (1.20 g, 24.5 mmol), which was stirred for 2 hours and 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (3 x 100 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield (3- bromopyridin-2-yl)acetonitrile.The (3-bromopyridin-2-yl)acetonitrile (2.00 g, 10.2 mmol) and tert-butyl bis(2- chloroethyl)carbamate (2.46 g, 10.2 mmol) were dissolved in 102 mL of DMSO. The reaction was purged with a stream of nitrogen and cooled to 18 0C. To this reaction was added sodium hydride (0.564 g, 22.3 mmol), which was then warmed to 50 0C and stirred for 18 hours. The mixture was diluted with dichloromethane (150 mL), washed with water (3 x 150 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield tert-butyl 4-(3-bromopyridin-2-yl)-4-cyanopiperidine-l-carboxylate. <n="35"/>The above carboxylate (290 mg, 0.79 mmol) was dissolved in 7.9 mL of a 1 :1 solution of dry EtOAc: dichloromethane and cooled to 0 0C. Anhydrous HCl gas was then bubbled through the solution for 5 minutes. The reaction was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was taken up in dichloromethane (10 mL) and slowly neutralized with a saturated sodium bicarbonate solution. The mixture was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (6 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to yield 4-(3-bromopyridin-2-yl)piperidine-4-carbonitrile.In a 2-5 mL Emrys process vial, a mixture of the ethyl 1 -formyl-4-oxo-4H- quinolizine-3 -carboxylate (150 mg, 0.61 mmol), 4-pyridin-2-ylpiperidine-4-carbonitrile (179 mg, 0.67 mmol), glacial acetic acid (0.21 mL, 3.67 mmol) and 3.1 mL of dichloroethane was stirred vigorously. To the stirring mixture was added resin-bound MP-cyanoborohydride (600 mg, 1.22 mmol). The mixture was heated via Emrys Optimizer microwave to 120 0C for 20 minutes. Filtration and solvent removal provided crude material, which was purified by preparative reverse phase HPLC to afford ethyl l-[4-(3-bromopyridin-2-yl)-4-cyanopiperidin-l-yl]methyl}- 4-oxo-4H-quinolizine-3-carboxylate.The ethyl 1 - { [4-(3 -bromopyridin-2-yl)-4-cyanopiperidin- 1 -yljmethyl } -4-oxo-4H- quinolizine-3 -carboxylate (30 mg, 0.061 mmol) was dissolved in DMSO (1.0 mL), treated with lithium hydroxide (0.15 mL, 0.80 mmol), and warmed to ambient temperature for 96 hours. The reaction mixture was purified by preparative reverse phase HPLC to yield the title compound as the trifluoroacetate salt that gave a proton NMR spectrum consistent with theory and a low resolution mass spectrum (ES+) m/z of 468.8 calculated for M+H+ [C22H19BrN4O3]: 1H NMR (400 MHz, CD3OD) delta 9.57 (d, J= 6.8 Hz, IH), 8.75 (s, IH), 8.59 (m, IH), 8.46 (d, J= 8.9 Hz, IH), 8.16-8.22 (m, 2H), 7.73 (t, J= 7.1 Hz, IH), 7.37 (dd, J= 4.6 Hz, IH), 3.77 (bs, 2H), 3.59 (t, J= 12.0 Hz, 2H), 2.84 (m, 2H), 2.65 (m, 2H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Heating / reflux; light;
To a mixture of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (46. 5g, 0. 27MOL) in CCl4 (800ML) was added NBS (53g, 0. 297MOL) and benzoylperoxide (4.7g) and refluxed for 2h in presence of light. The reaction mixture was cooled to 50C and filtered off the solid succinimide. The filtrate was concentrated and the crude 6-BROMO-2-BROMOMETHYLPYRIDINE was used for the follow- up reaction. MS (ESI) : 251.8 ; MS (ESI-) : 249.8
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 31h;Reflux;
Example 1: Synthesis of 3-(4-Fluorophenyl)-imidazo[l,5-a]pyridine-8-carboxylic acid (1); To a room temperature solution of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (2.60 g, 15.1 mmol) and N-bromosuccinimide (NBS) (2.90 g, 16.3 mmol) in CC14 is added benzoyl peroxide (150 mg, 1.08 mmol). The mixture is heated at reflux for 7 hours, cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (EtOAc) (3 x 30 mL). The combined organic layers are washed with brine (3 x 30 mL), dried over magnesium sulfate, filtered and concentrated. LCMS analysis indicated starting material and the desired product. The residue is dissolved in CC14 (40 mL) and NBS (1.7 g, 9.6 mmol) and benzoyl peroxide (100 mg, 0.72 mmol) is added, and the mixture is warmed at reflux. After 24 hours, the mixture is cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers are washed with brine (3 x 30 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a mixture of dichloromethane in hexanes (25:75, then 3:7) to afford 3- bromo-2-bromomethyl-pyridine.
[3-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-yl](2,4-dichlorophenyl)methanone[ No CAS ]
[ 38749-79-0 ]
[3-amino-6-(2-methyl-3-pyridinyl)-1-benzofuran-2-yl](2,4-dichlorophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38.5%
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 80℃;
Step 2: Preparation of the tile compound: [3-amino-6-(2-methvl-3->vridinvl)-1- benzofuran-2-yll 2, 4-dichlorophenyl) methanone; A solution of [3-amino-6- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1-benzo- furan-2-yl] (2, 4-dichlorophenyl) methanone (65 mg, 0.15 mmol) in toluene (1.0 mL) and ethanol (1.0 mL) was degassed with argon for 30 min. At this time, 3-bromo-2- methylpyridine (33.6 mg, 0.20 mmol, 1.3 eq) was added followed by [1,1'- bis (diphenylphosphino)-ferrocene] dichloro-palladium (iI), complex with dichloromethane (1: 1) (12.3 mg, 0.02 mmol, 0.1 eq) and 2M aqueous Na2CO3 (0.38 mL). The reaction was bubbled with argon for another 15 min and then heated to 80 C overnight. The reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and purified on the MPLC (Biotage) eluted with 45 to 65% ethyl acetate-hexane to afford 23 mg (38.5 %) of a yellow solid as the product. 1H-NMR (DMSO-d6) 6 8.46 (dd, J = 4. 5,1. 5 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1 H), 7.64 to 7.56 (m, 5H), 7.46 (s, 1H), 7.31 to 7.27 (m, 2H), 2.41 (s, 3H); LC-MS (ES MH+ = 397/399, RT = 2.34 min).
38.5%
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; water; toluene; at 80℃;
Step 2: Preparation of the tile compound: r3-amino-6-(2-methyl-3-pyridinyl)-1-benzofuran-2- yl)(2.4-dichlorophenyl)-methanone. A solution of [3-amino-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-benzo-furan-2-yl](2,4- dichlorophenyl)methanone (65 mg, 0.15 mmol) in toluene (1.0 mL) and ethanol (1.0 mL) was degassed with argon for 30 min. At this time, <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (33.6 mg, 0.20 mmol, 1.3 eq) was added followed by [l,r-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II), complex with dichloromethane (1 :1) (12.3 mg, 0.02 mmol, 0.1 eq) and 2M aqueous Na2CC*3 (0.38 mL). The reaction was bubbled with argon for another 15 min and then heated to 80 0C overnight. The reaction was diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and purified on the MPLC (Biotage) eluted with 45 to 65% ethyl acetate - hexane to afford 23 mg (38.5 %) of a yellow solid as the product. 1H-NMR (DMSO-d6) delta 8.46 (dd, J = 4.5, 1.5 Hz, IH), 8.11 (d, J = 8.4 Hz, IH), 7.75 (d, J = 2.1 Hz, 1 H), 7.64 to 7.56 (m, 5H), 7.46 (s, IH), 7.31 to 7.27 (m, 2H), 2.41 (s, 3H); LC-MS (ES MH+ = 397/399, RT = 2.34 min).
To a solution of 3-bromo-2-methylpyridine (4.00 g, 23 mmol), triisopropyl borate (6.40 mL, 28 mmol) in 50 mL of 4/1 toluene/THF (4/1, 50 mL) at -78 C. was added was added butyllithium (17 mL, 28 mmol), dropwise. The mixture was allowed to warm up to 30 min at -70 C. LCMS and then to 20 C. HCl (2M) was added to bring the solution to pH1. Then water (20 mL) was added and the mixture was extracted with toluene. The aqueous layer was neutralized with 1 M NaOH and extracted with dichloromethane. The aqueous layer was concentrated to dryness and the white solid was washed with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2.10 g of 2-methylpyridin-3-ylboronic acid as a yellow oil. ES+=138.2 (M+H)
ethylenediamine tetraacetic acid, disodium salt[ No CAS ]
[ 623-00-7 ]
[ 594-19-4 ]
[ 38749-79-0 ]
[ 122957-52-2 ]
Yield
Reaction Conditions
Operation in experiment
20%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); Zinc chloride; In tetrahydrofuran; hexane; water; pentane;
PREPARATION 37 3-(4-cyanophenyl)-2-methylpyridine t-Butyllithium (1.8 molar in pentane) (18.1 ml, 32.6 mmol) was added dropwise to a stirred solution of 4-bromobenzonitrile (2.81 g, 15.4 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at -60+-5 C. After stirring for 20 minutes at this temperature a solution of dry zinc chloride (4.62 g, 33.8 mmol) in anhydrous tetrahydrofuran (55 ml) was added via a cannula and the stirred solution warmed to +10 C. over 10 minutes, whereupon tetrakis(triphenylphosphine)palladium (0.5 g, 0.43 mmol) and <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (3.19 g, 18.5 mmol) were added. The clear, red solution was then stirred under reflux for 5.5 hours. On cooling to ambient temperature, the reaction mixture was concentrated to ca. 50 ml under reduced pressure and the residue partitioned between methylene chloride (300 ml) and a solution of ethylene diamine tetraacetic acid disodium salt (8 g) and sodium carbonate (10 g) in water (500 ml). The organic extract was separated, dried over magnesium sulphate and concentrated to a dark oil under reduced pressure. This oil was chromatographed on Merck 60 Kieselgel (Trade Mark), eluding with 0%?100% ether in hexane. Product-containing fractions were combined and concentrated under reduced pressure to give the title compound as an oil (0.6 g, 20%) which solidified on standing. 1 H-NMR (CDCl3), inter alia: 2.52 (3H, s), 7.26 (1H, m), 7.48 (2H, d, J=9 Hz), 7.53 (1H, m), 7.78 (2H, d, J=9 Hz), 8.58 (1H, m).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 18h;Heating / reflux;
The 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt used in the method described above was prepared as follows: (i) A solution of 1 ,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13) and 3-bromo-2- methylpyridine (515 mg, 3.00 mmol) in 1 ,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give 1 ,1-dimethylethyl 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4- imidazolidinecarboxylate (738 mg, 85%). LC/MS [M+H]+ = 292.
(trans)-ethyl 2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate[ No CAS ]
[ 38749-79-0 ]
ethyl (cis)-2-oxo-3-(2-methyl-3-pyridinyl)-1-oxa-3-azaspiro[4.5]decane-8-carboxylate[ No CAS ]
ethyl (trans)-3-(2-methyl-3-pyridinyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With potassium phosphate;copper(l) iodide; trans-cyclohexanediamine; In 1,4-dioxane; at 110 - 130℃; for 6h;
Intermediate 56: Ethyl (trans)-3-(2-methyl-3-pyridinyl)-2-oxo-1-oxa-3-azaspiro[4.51decane- 8-carboxylate; <n="56"/>To a stirred solution of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (1.01 ml, 8.77 mmol) and ethyl (trans)-2- oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (prepared in an analogous method to Intermediate 38, 1.66 g, 7.30 mmol) in anhydrous 1 ,4-dioxane (22 ml), CuI (70 mg, 0.365 mmol), trans-cyclohexanediamine (88 mul, 0.730 mmol) and potassium phosphate tribasic (3.10 g, 14.6 mmol) were added and the mixture was heated under a nitrogen atmosphere at 115 0C (external temperature) for 4 hours. Additional CuI (693 mg, 3.65 mmol) and trans-cyclohexanediamine (0.875 ml, 0.730 mmol) were added and the external temperature was increased to 130 0C (internal T= 1 1O0C). Stirring was carried on for further 2 hours. The mixture was diluted with EtOAc and washed with water (2x20 ml), the aq. layer was back-extracted with ethyl acetate and the combined organic extracts were dried over Na2SO4, filtered and concentrated under vacuum to obtain a residue. The crude was purified by gradient elution of a NH column (0-100% EtOAccyclohexane) to give: 1 ) a yellowish oil as mixture of trans isomer with traces of cis isomer 2) a colourless oil as a mixture of both isomers and 3) a yellowish solid as cis isomer. The mixed fractions 1 ) and 2) were combined and separated (twice) by NH chromatography eluting with 0-50% EtOAdcyclohexane to give the title compound as white solid (478 mg, 20%). 1 H-NMR (400 MHz, CDCI3): delta 1.28 (t, 3H), 1.72-1.82 (m, 2H), 1.93-2.06 (m, 4H), 2.09-2.18 (m, 2H), 2.50-2.59 (m, 4H), 3.69 (s, 2H), 4.16 (q, 2H), 7.20-7.24 (m, 1 H), 7.58 (dd, 1 H), 8.50 (dd, 1 H); UPLC-MS: 0.53 min, m/z 319 [M+H]+.
Intermediate 131 : (+/-)-Ethyl hvdroxy(2-methyl-3-pyridinyl)acetate:; 7.27 mL of nBuLi solution in hexanes (11.63 mmole, Aldrich) were added to 2.91 mL of isopropylmagnesium chloride 2.0M in diethylether (5.81 mmole) diluted in 24 mL of THF at O0C (int. T0C= 30C). The mixture was stirred at O0C for 15 min. Then the solution was cooled to -100C (int. T0C= -150C) and a solution of 2 g of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (11.63 mmole, Aldrich) in 11.5 mL of THF was added dropwise. The mixture was stirred at -100C for 0.5 h. Then 4.75 mL of ethyl glyoxylate 50% in toluene (23.25 mmole, Fluka) were added and the solution was stirred for 2.5 h at O0C (int. T0C= 20C). The mixture was then poured into 100 mL of a saturated K2CO3 solution. The resulting precipitate was then filtered off and the cake was washed with 100 mL of AcOEt. The resulting biphasic solution was transferred to a separatory funnel and the aqueous phase was extracted twice with 50 mL of AcOEt. The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude was then purified by flash chromatography on silica gel with the following eluent: A: CH+3% TEA/B: AcOEt+3%TEA: 0%B for 1 min, 0% to 75%B in 14 min, 75%B for 7 min. Evaporation of the solvents under reduced pressure gives the title compound as a yellow oil (1.136 g, 50%). 1H-NMR (400 MHz, CDCI3): delta 1.25 (3H, t), 2.68 (3H, s), 4.16-4.35 (2H, m), 5.37 (1 H, s), 7.18 (1 H, dd), 7.67 (1 H, dd), 8.48 (1 H, dd); LC-MS [XTerra MC C18, 30x4.6mm, 2.5 mum, gradient: A <n="150"/>NH4CO3 5mM, pH 10 (NH4OH)/B: CH3CN: 0 to 50%B in 0.4 min, 50% to 95%B in 3.6 min, 95%B for 1 min, 95% to 0%B in 0.1 min, flow: 1.5 mL/min]: Rt = 1.23 min (100%) m/z (ES) = 196 [M+H]+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 2h;Heating / reflux;
A mixture of 3-bromo-2-methylpyridine (0.13 mL; 1.16 mmol; 1 eq.), methyl 3-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (353 mg; 1.28 mmol; 1.1 eq.), potassium carbonate (803 mg; 5.81 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (134 mg; 0.12 mmol; 0.1 eq.) in toluene (1 mL) and water (1 mL) was refluxed for 2 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of celite which was further washed with toluene (20 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (10 mL). The organic layer was washed with a sat. aq. NaHCO3, water and brine, dried over MgSO4 and concentrated in vacuo. The residue (250 mg; 1.04 mmol; 1 eq.) was taken up in EtOH (7.5 mL) and sodium hydroxide (5M; 0.62 mL; 3.1 1 mmol; 3 eq.). <n="76"/>The reaction mixture was stirred at 600C for 2 hours then concentrated in vacuo. The residue was taken up in water (50 ml_) and the aqueous phase was washed with Ethyl acetate (2 x 20 ml.) then acidified pH 2 with cone. HCI. The solution was concentrated in vacuo to ca. 15 ml_, the precipitate filtered off and washed with ACN to afford the title compound (190 rmg, 72%) as a beige solid.HPLC (Method A) : Rt 0.88 min (purity 97.1 %). 1H NMR (DMSO-d6, 300 MHz) delta 13.04 (s, 1 H), 8.78-8.77 (d, J = 5.4 Hz, 1 H), 8.16-8.13 (m, 1 H), 7.98-7.95 (dd, J = 1.9, 8.0 Hz, 1 H), 7.77-7.76 (m, 2H), 7.56-7.54 (d, J = 8.0 Hz, 1 H), 2.37 (s, 3H), 2.13 (s, 3H).
With potassium acetate;[1,1-bis(diphenylphosphino)ferrocene]palladium(II) bis methylene chloride; In N,N-dimethyl-formamide; at 80℃; for 16h;
Intermediate 1: 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 3-Bromo-2-pinnacol (1 g, 5.8 mmol) was dissolved in DMF (20 mL). To this was added potassium acetate (2 g, 20.3 mmol) followed by 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.9 g, 7.5 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) bis methylene chloride (0.47 g, 10% mol). The reaction was heated to 80 C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and brined then dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in ethyl acetate. A greenish/black oil 0.2 g was recovered.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃; for 16h;
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 3-Bromo-2-pinnacol (1 g, 5.8 mmol) was dissolved in DMF (20 mL). To this was added potassium acetate (2 g, 20.3 mmol) followed by 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1.9 g, 7.5 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)bis methylene chloride (0.47 g, 10% mol). The reaction was heated to 80 C. for 16 hrs then poured into water and extracted with ethyl acetate. The organic layer was separated and brined then dried over magnesium Examples 121-125 were made according to the procedure given in scheme 1 (Example 19) using 2-fluoro-4-trifluoromethyl nitrobenzene and the appropriate boronic acid or pinnacle boronate (method B, intermediate 14A).
With potassium acetate;{1,1-bis(diphenylphosphino)ferrocene} palladium (II)-bis-dichloromethane; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere of argon;
3-Bromo-2-picoline (1 g, 5.8 mmol) was dissolved in dry DMF (20 mL). To this was added potassium acetate (2 g, 3.5 eq), followed by bis(pinacolato)diboron (1.9 g, 1.3 eq). Argon was bubbled through the reaction vessel for 1 min and {1,1-bis(diphenylphosphino)ferrocene} palladium (II)-2CH2Cl2 (0.47 g, 10 mole %) was added. The reaction was sealed and heated to 80 C. for 16 h, then cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate and the organic layer separated, washed with brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in ethyl acetate. 0.2 g of greenish oil was recovered; MS (ESI) 220.1 [M+1]+; 1H NMR (400 MHz, d6-DMSO) delta ppm 8.45 (m, 1H), 7.88 (m, 1H), 7.14 (m, 1H), 2.57 (s, 3H), 1.26 (s, 12H).
To a solution of 3-bromo-2-methylpyridine (148; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 0C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-methylnicotinaldehyde 149 (2.18 g, 31%).
31%
Example 21. Synthesis of 2-(2-methylpyridin-3-yl)-N-(thiazol-2-yl)-[l,2,4]triazolo[l,5- a]pyridine-8-carboxamide (Compound 239):Step 1) Preparation of 2-methylnicotinaldehyde (89): To a solution of 3-bromo-2-methylpyridine (88; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at -78 0C. The reaction mixture was stirred at this temperature for Ih. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at -78 0C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-methylnicotinaldehyde 89 (2.18 g, 31%).
With N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 80℃; for 4h;Inert atmosphere;
Reference Example 30 3- (Benzylsulfanyl) -2-methylpyridineTo a solution of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (1.0 g) in toluene (12 ?iL) were added phenylmethanethiol (794 mg) , N, N- diisopropylethylamine (1.65 g) , tris (dibenzylideneacetone) dipalladium(O) (213 mg) and 4,5- bis (diphenylphosphino) -9, 9-dimethylxanthene (269 mg) , and the mixture was stirred under an argon atmosphere at 800C for 4 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9: 1?3 : 1) to give the title compound as a yellow solid (yield 742 mg, 59%) .1H-NMR(CDCl3)O: 2.56(3H,s), 4.08(2H,s), 7.03 (IH, dd, J=I .6, 5. OHz) ,7.21-7.34 (5H,m) , 7.48 (IH, dd, J=7.8, 1.6Hz) ,8.30(lH,dd, J=4.8,1.6Hz) .
59%
With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 3h;
General procedure: A mixture of compound 6a (1.73 g, 6.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (121 mg, 0.132 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg, 0.26 mmol), N-ethyldiisopropylamine (1.88 g, 14.5 mmol) and benzyl mercaptane (861 mg, 6.93 mmol) in toluene (15 mL) was stirred at 80 C for 3 h. The reaction mixture was filtered through a short pad of silica gel, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 1/0-19/1) to afford compound 7a (1.63 g, quant.) as a yellow oil: 1H-NMR (CDCl3) d 4.12 (2H, s), 7.21-7.36 (5H, m), 7.53 (1H, t, J = 2.1 Hz), 8.36 (2H, d, J = 1.9 Hz).
44%
Benzylmercaptan (664 mg, 0.63 mL, 5.34 mmol) was dissolved in 8.5 mL DMF under an atmosphere of N2. NaH( 214 mg 60% as an oil dipersion, 5.34 mmol) was added portionwise with stirring, then stirred for an additional 15 mins. To the solution was added <strong>[38749-79-0]3-bromo-2-methyl-pyridine</strong> (102a, mg, 4.11 mmol) in one portion and the mixture heated in an oil bath at 130 C for 4 h. The reaction mixture was cooled to RT and partitioned between H2O (50 mL) and hexane (50 mL). The hexane layer was separated, washed with H2O (50 mL), dried over MgS04, then concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with EtOAc: hexane (1: 2) to afford 522 mg (44%) of 102b as a viscous liquid: ms (ES+) m/z 216 (M+H)+.
With potassium tert-butylate;bis(dibenzylideneacetone)-palladium(0); XPhos; In tert-butyl alcohol; at 150℃; for 0.5h;Inert atmosphere; microwave irradiation; sealed tube;
Step 4: 9-Chloro-10-[3-(dimethylamino)propyl]-2-[(2-methylpyridin-3-yl)amino]-5,7- dihydro-6H-pyrimido[5,4-J][l]benzazepin-6-one; To a mixture of 2-amino-9-chloro-10-[3-(dimethylamino)propyl]-5,7-dihydro-6H- pyrimido[5,4-(fl[l]benzazepin-6-one (0.10 g, 0.29 mmol), Xphos (8.6 mg, 0.018 mmol), tris(dibenzylideneacetone)dipalladium (4.7 mg, 0.0052 mmol) and <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (50 mg, 0.29 mmol) in a dry, sealed microwave tube under an atmosphere of argon was added tert-biy alcohol (1.0 mL) followed by a 1.0 M solution of potassium /ert-butoxide in terf-butyl alcohol (0.58 mL, 0.58 mmol). The mixture was heated under microwave irradiation at 150 0C for 30 min. The reaction mixture was allowed to cool to rt and then added to water (50 mL). The precipitated solid was collected via suction filtration, washed with water, and dried to produce 9-chloro-10-[3-(dimethylamino)propyl]-2-[(2- methylpyridin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-J][l]benzazepin-6-one (95 mg, 0.21 mmol, 75%) as a brown solid. LCMS (FA): m/z = 453.5 (M+Eta).
(1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one[ No CAS ]
[ 38749-79-0 ]
[ 1247004-92-7 ]
Yield
Reaction Conditions
Operation in experiment
25%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 125℃; for 2h;Microwave irradiation; Inert atmosphere;
Example A 150. (1 R.2S)-2-G-((E)-2-(6-methylpyridin-3-yl)vinyl)-l H-indazol-6-yl)spiro [cyclopropane- l,3'-indolinl-2'-one0 To a mixture of (l R*,2S*)-2-(3-vinyl-l H-indazol-6-yl)spiro[cyclopropane-l,3'- indolin]-2'-one (60.2 mg, 0.2 mmol) and <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (34.4 mg, 0.2 mmol) in DMF (1.5 mL) was added 1Pr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125 0C. Purification by prep-HPLC gave the title5 compound as a light yellow solid (25 mg, 25%). NMR indicated 6% of the branched isomer. 1H NMR (400 MHz, CD3OD) delta 8.90 (s, IH), 7.74 (dd, J = 8.4 Hz, 1.6 Hz, IH), 8.02 (d, J = 8.4 Hz, I H), 7.87 (d, J = 8.4 Hz, I H), 7.78 (d, J = 16.8 Hz, I H), 7.55 (d, J = 16.8 Hz, I H), 7.49 (s, I H), 7.07-7.00 (m, 2H), 6.94 (d, J = 8.0 Hz, I H), 6.55 (t, J = 7.6 Hz, I H), 5.97 (d, J = 7.6 Hz, I H), 3.34 (t, J = 8.4 Hz, IH, partially overlapping withQ MeOH residue), 2.78 (s, 3H), 2.23 (dd, J = 7.6 Hz, J = 4.8 Hz, I H), 2.18 (dd, J = 8.8 Hz, J = 4.8 Hz, I H); MS ESl 393.1 [M + H]+, calcd for [C25H20N4O + H]+ 393.2.
3-Bromo-2-methylpyridine (500 mg) was dissolved in tetrahydrofuran (15 ml). A 1.58 M solution (2 ml) of n-butyllithium/hexane was added to the solution at -78C, and the mixture was stirred for 30 min. 4,5-Dimethylfurfural (350 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for additional one hr. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with an ethyl acetate-hexane system to give (4,5-dimethyl-furan-2-yl)-(2-methyl-pyridin-3-yl)-methanol (251 mg, yield 40%). (4,5-Dimethyl-furan-2-yl)-(2-methyl-pyridin-3-yl)-methanol (251 mg) was dissolved in chloroform(5 ml), manganese dioxide (1.51 g) was added to the solutiion, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography with an ethyl acetate-hexane system to give (4,5-dimethyl-furan-2-yl)-(2-methyl-pyridin-3-yl)-methanone (203 mg, yield 81%). (4,5-Dimethyl-furan-2-yl)-(2-methyl-pyridin-3-yl)-methanone (203 mg) was dissolved in methanol (2 ml), 28% aqueous ammonia (2 ml) was added to the solution, and the mixture was stirred in a sealed tube at 160C overnight. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with an acetone-hexane system to give 5,6,2'-trimethoxy-[2,3']bipyridinyl-3-ol (12 mg, yield 6%).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃;
To a solution of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (5g, 29.1 mmol) in DCM (50 ml) was added portionwise at 0C m-chloroperbenzoic acid (70%, 8.6 g, 34.9 mmol). The solution was stirred at 0C for three hours and then at room temperature overnight. The mixture was filtered, the residue was washed with DCM and the combined DCM phases were quenched with a 10% solution of sodium thiosulfate. The phases were separated, the organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, diethyl ether, then DCM/methanol 95:5) to yield 4.44 g (23.6 mmol, yield 81 %) MS(multi-mode) m/z = 190.0 [M+1]+.
69.5%
With peracetic acid; In dichloromethane; at 20 - 30℃; for 3h;Product distribution / selectivity;
Example 13-Bromo-2-methylpyridine N-oxide synthesisIn a 5-l. four-necked round bottom flask equipped with agitation, a thermometer, a condenser and a dropping funnel, was placed <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (110 grams, 1.18 moles) and dichloromethane (2 .L). The mixture was stirred, and per-acetic acid (900 grams, 20%, 2.37 moles) was added at such a rate that the temperature was maintained at 30 C. After the addition, the mixture was stirred for 3 hrs. at 20-30 C. The reaction was quenched with sodium sulfite solution when the raw material was detected at less than 2%.To another 10-l. four-necked round bottom flask was added sodium sulfite (180 grams) dissolved in water (1100 grams). The mixture was stirred for 20 min., and the reaction mixture was added to the 10-l. flask at a rate such that the temperature did not exceed 30 C. After the addition, the mixture was stirred 1 hr. at 30 C. Then sodium hydroxide solution (320 grams, 50%) was added drop-wise into the mixture while the temperature was maintained at below 30 C. After phase separation, the aqueous layer was extracted with dichloromethane (130 grams). The extraction was repeated twice and the organic phases were combined, and its pH was adjusted to 14 with a sodium hydroxide solution (50%). Water (200 ml) was added as well. The organic phase was washed with brine, and concentrated by removal of the solvent. The residue was crystallized in ethyl acetate (400 grams). Off-white needle solid was obtained (155 grams, 69.5%).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 16h;
Step 1: To a solution of <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (5.0 g, 28.7 mmol) in dichloromethane (100 mL) at 0 C in a 250 mL 3 neck RBF, was added m-CPBA (10.25 g, 57.5 mmol). The resulting solution was stirred at room temperature for 16 h. The reaction solution was concentrated to remove the solvent. The crude product was purified by column chromatography (30% EtOAc in petroleum ether) to yield the intermediate N-oxide compound which was taken up in triethylamine (50 mL) and TMS-CN (50 mL) in a 250 mL sealed tube and heated at 80 C for 8 h. The reaction solution was concentrated. The crude product was purified by column chromatography (10% EtOAc in petroleum-ether) to yield 5-bromo-6- methylpicolinonitrile. 1H NMR (300 MHz, MeOD): delta 8.15 (d, J = 8.16 Hz, 1H), 7.59 (d, J = 8.13 Hz, 1H), 2.67 (s, 3H).
With caesium carbonate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane;4-{1-[4-(carboxymethylcarbamoyl)-2,5-difluorophenyl]piperidin-4-ylideneaminooxy}piperidine-1-carboxylic acid isopropyl ester; In toluene; at 80℃; for 20h;
EXAMPLE 4ISOPROPRYL 4-(2'-METHYL-2,3,5,6-TETRAHYDRO-[1 ,3']BIPYRIDINYL-4- YLIDENEAMINOOXY)PIPERIDINE- 1 -CARBOXYLATEStep 4A : Isopropryl 4-(2'-Methyl-2.3.5.6-tetrahvdro-ri.3'1bipyridinyl-4- ylideneaminooxy)piperidine- 1 -carboxylate (4-1) Compound 2d (30 mg, 0.11 mmol), <strong>[38749-79-0]3-bromo-2-methyl-pyridine</strong> (0.16 mmol), cesium carbonate (72 mg, 0.22 mmol), PddppfCl2 (10 mg), and triisobutylphosphatrane (15 muL) were combined in toluene (0.5 mL). The mixture was heated at 80 0C for 2Oh. The mixture was concentrated under a stream of nitrogen and the residue was partitioned between DCM and water. The DCM layer was concentrated and taken up in methanol and purified by preparative HPLC to afford 4-1 : LC-MS 375.4 (MH+), tR = 7.88 (Method 6). EC50: 4804 nM.
With N,N,N,N,-tetramethylethylenediamine; di-tert-butyl[dichloro({di-tert-butyl[4-(dimethylamino)phenyl]phosphaniumyl})palladio][4-(dimethylamino)phenyl]phosphanium; zinc; In water; at 20℃; for 48h;Inert atmosphere;
General procedure: In a 5 mL round-bottom flask under argon containing zinc powder (197 mg, 3 mmol) and PdCl2(Amphos)2 (7 mg, 0.01 mmol) was added 2% PTS solution in water (1.5 mL). N,N,N',N'-Tetramethylethylenediamine (TMEDA, 232 mg, 2 mmol) was added at rt followed by the addition of the alkyl halide (2 mmol) and the heteroaromatic halide (0.5 mmol). The flask was stirred vigorously at rt for the indicated time. The product was extracted with EtOAc.11 Silica gel (1 g) was added to the combined organic phase and solvents were removed under vacuum. The resulting dry, crude silica was introduced on top of a silica gel chromatography column to purify the product.
General procedure: For 17: compound 16 (4.2 g, 24.4 mmol) was dissolved in anhydrous THF (100 mL) and LDA (2 M, 15 mL, 30 mmol) was added at -78 C over 5 min. The mixture was stirred at -78 C for an additional 45 min, a solution of allyl bromide (2.0 mL, 30 mmol) in THF (10 mL) was added drop-wise over 15 min. After stirring at -78 C for another 2 h, aqueous NaHCO3 was added to quench the reaction and the mixture was warmed up to RT. Most of the solvent was removed in vacuo and the resulting residue was partitioned into ethyl acetate (50 mL) and brine (50 mL). The aqueous layer was further extracted with ethyl acetate (3 × 50 mL) and the combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, hexane:ethyl acetate, 10:1) to afford 17 (4.8 g, 92% yield) as a pale yellow oil.
To a solution of diisopropylamine (2.6 mL, 18.6 mmol) in dry Et2O (6 mL) stirred at 0 C under argon was added dropwise a solution of 2.5 M n-BuLi in hexanes (7.4 mL, 18.6 mmol). The solution was stirred at 0 C for 30 min. The flask was cooled to -20 C and a solution of <strong>[38749-79-0]2-methyl-3-bromopyridine</strong> (3.19 g, 18.6 mmol) in Et2O (9 mL) was added dropwise. The resulting red mixture was stirred at -20 C, under argon, for 2 h. A solution of thiolane 9 (1.78 g, 7.42 mmol) in THF (11 mL) was added dropwise and kept stirring at -20 C for 1 h. The reaction flask was allowed to warm up to room temperature and was quenched slowly with H2O (30 mL). The mixture was extracted with EtOAc (3×75 mL), washed with saturated NH4Cl (30 mL), saturated NaHCO3 (30 mL), brine (30 mL), and dried with Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes) to yield 11 as an off-white solid (2.66 g, 87%, mp 71-73 C). [alpha]21.2D -91.9 (c 1.0, CHCl3). 1H NMR (CDCl3): delta=8.41 (dd, J=1.5, 4.5 Hz, 1H), 7.88 (dd, J=1.5, 8.0 Hz, 1H), 7.06 (dd, J=4.5, 8.0 Hz, 1H), 6.31 (s, 1H), 5.58 (s, 1H), 3.43-3.35 (m, 3H), 3.25-3.19 (m, 1H), 3.11 (d, J=15.5 Hz, 1H), 2.98 (d, J=15.5 Hz, 1H), 2.50-2.44 (m, 1H), 2.34 (m, 1H), 2.26-2.17 (m, 2H), 1.89-1.82 (m, 1H), 1.77 (m, 1H), 1.61-1.58 (m, 1H), 1.48 (m, 1H), 1.18 (s, 3H). 13C NMR (CDCl3): delta=159.3, 147.4, 146.6, 140.8, 124.4, 122.7, 122.6, 82.7, 66.0, 47.1, 40.4, 40.2, 39.7, 38.9, 33.5, 29.6, 26.0, 19.8. FTIR (thin film) 3362, 2922, 1428, 1066, 1033 cm-1. HRMS (ES) calcd for C18H22BrNOS2: 411.0326 (M+), found 412.0388 (MH+).
potassium 6-fluoropyridine-2-trifluoroborate[ No CAS ]
[ 38749-79-0 ]
[ 1356336-19-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate; In ethanol; at 85℃; for 16h;Inert atmosphere;
General procedure: A 10-mL Schlenk tube was charged with Pd(OAc)2 (1.7 mg, 0.0075 mmol, 3.0 mol %), SPhos (6.2 mg, 0.015 mmol, 6.0 mol %), Na2CO3 (53.0 mg, 0.50 mmol, 2.0 equiv), potassium 6-fluoropyridine-2-trifluoroborate (101.5 mg, 0.50 mmol, 2.0 equiv) and heteroaryl halides (0.25 mmol, 1.0 equiv), followed by the addition of ethanol (2.0 ml). The reaction was carried out at 85 C for 16 h under the protection of nitrogen gas. Then, the reaction mixture was allowed to cool down to room temperature and the reaction solution was filtered through a thin pad of silica gel (eluting with ethyl acetate) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate/hexane=1:2-1:80).
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 70℃;Inert atmosphere;
3-Bromo-2-methylpyridine (1.2 mmol, 206 mg), morpholine (1.44 mmol, 125 mg), Pd2(dba)3 (0.024 mmol, 22 mg), (±) BINAP (0.048 mmol, 30 mg), NaOtBu (1.68 mmol, 161 mg), and toluene (4 mL) were added to the dried reaction flask and replaced with N2 for 5 min. The reaction solution was reacted at 70 under N 2 atmosphere until the starting material disappeared. Let it cool to room temperature Diethyl ether (10 mL) was added, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was subjected to column chromatography to give the title compound as a yellow oil (yield 90%).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere;
3-Bromo-2-methylpyridine (500 mg) and tert-butyl piperazine-1-carboxylate (650 mg) were dissolved in toluene (7.5 ml), and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one_palladium (3:2) (40 mg), 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine) (18 mg), and 2-methylpropan-2-ol sodium (391 mg) were added thereto in this order under a nitrogen atmosphere, followed by warming to 100 C. and stirring overnight. The reaction mixture was subjected to liquid separation with CHCl3 and water, the organic layer was dried over Na2SO4, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CHCl3 to 5% MeOH/CHCl3) to obtain tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (790 mg) as a pale yellow oil.
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In 1,4-dioxane; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;
To a solution of ethyl 2-(4-hydroxyphenyl)acetate (1.36 g, 7.55 mmol) in 6 mL of 1,4-dioxane were added <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (1.0 g, 5.8 mmol), CuI (330 mg, 1.74 mmol), Cs2CO3 (5.67 g, 17.4 mmol) and N,N-dimethylglycine (180 mg, 1.74 mmol) under nitrogen. The resulting mixture was sealed and heated in a microwave (120 C for 60 min). After cooling to rt, water (30 mL) was added and the reaction mixture was extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (30 mL x 3), and dried over Na2SO4. After removal of solvent, the residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1) to obtain title compound (600 mg, yield: 38%) as a yellow oil. LCMS-P1: 272 [M+H]+; Rt: 1.293 min.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 100℃; for 24h;
To a stirred solution of methyl 2-(l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl)acetate (500 mg, 2.2 mmol) in dry 1,4-dioxane (25 mL) were added <strong>[38749-79-0]3-bromo-2-methyl pyridine</strong> (390 mg, 2.2 mmol) followed by NN'-dimethylethylenediamine (160 mg, 1.8 mmol) and K3PO4 (960 mg, 4.5 mmol). The solution was degassed with N2 for 5 min. Cul (173 mg, 0.91 mmol) was added and the reaction mixture was heated to 100 C for 24 h. The reaction mixture was filtered through Celite and the filtrated was concentrated under reduced pressure and diluted with EtOAc. The solution was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resultant residue was purified by column chromatography (5% MeOH/CH2Cl2) to afford the title compound (260 mg, 37%) as a pale yellow liquid. TLC: 100% EtOAc, Rf= 0.3. lH NMR (400 MHz, MeOD-d4) delta ppm 8.44 - 8.43 (m, 1H), 8.01 - 7.93 (m, 1H), 7.81 - 7.78 (m, 1H), 7.49 - 7.31 (m, 3H), 4.07 - 4.00 (m, 1H), 3.85 - 3.73 (m, 3H), 3.71 - 3.69 (m, 3H), 3.21 - 3.20 (m, 2H), 2.49 (s, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In tetrahydrofuran; at 80℃; for 0.666667h;Inert atmosphere; Microwave irradiation; Sealed tube;
3-Bromo-2-methylpyridine (258 mg, 1.5 mmol), tert-butyl (1 S,4S)-3,6- diazabicyclo[2.2.1 ]heptane-3-carboxylate (397 mg, 2 mmol), Pd2(DBA)3 (30 mg, 0.033 mmol), sodium tert-butoxide (160 mg, 1 .66 mmol), BINAP (60 mg, 0.096 mmol) were placed in anhydrous THF (5 ml), purged with argon and heated under microwave heating at 80C in a closed vial for 40 minutes. The mixture was filtered through kieselguhr, concentrated under reduced pressure and purified by column chromatography (silica, gradient from 0 to 50% ethyl acetate in DCM) to yield 230 mg of an orange solid (0.80 mmol, yield 53%). MS(ESI) m/z = 290.1 [M+1]+.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In tetrahydrofuran; water; for 72h;Inert atmosphere; Reflux;
3-Bromo-2-methylpyridine (172 mg, 1 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate (309 mg, 1 mmol) were dissolved in THF (10 ml) and combined with a solution of sodium carbonate (425 mg, 4 mmol) in water (1 ml). The mixture was purged with argon, PdCI2(PPh3)2 (35 mg, 0.05 mmol) was added and the mixture was stirred under reflux for three days, diluted with ethyl acetate (30 ml), the phases were separated and the organic layer was washed with brine and dried (sodium sulfate). After concentration under reduced pressure the residue was purified with column chromatography (silica, gradient of 0 to 30% ethyl acetate in DCM) to yield 209 mg (0.76 mmol, yield 76%) MS(multi-mode) m/z = 275.2 [M+1]+.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water;Inert atmosphere; Reflux;
3-Bromo-2-methylpyridine (1.9g, 11.04mmol) and 3,5-dichlorophenyl boronic acid (3.16g, 16.57mmol) dissolved in degassed THF (60mL) were placed into a 250mL two necked round bottom flask. A solution of potassium carbonate (3.05g, 22.09mmol) in water (20mL) was added slowly to the solution, and bubbled with nitrogen for 30min. Finally, tetrakis(triphenylphosphine)palladium(0) (1.26g, 1.17mmol) was added to the above reaction mixture, then heated under reflux under nitrogen overnight. The solution was cooled to room temperature and the organics were extracted using ethyl acetate and washed with distilled water. The solution was dried over magnesium sulfate and evaporated to remove solvent. The product was further purified by flash chromatography on silica gel using methylene chloride/n-hexane as an eluent to produce 2.0g (76% yield) of 2-(3,5-dichlorophenyl)-3-methylpyridine.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 0.5h;Microwave irradiation;
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100C for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate = 0:100 to 20:80, gradient) to obtain the title compound (388 mg, 72%) as a brown solid. 1H-NMR (400 MHz, CDCl3) delta: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.44-1.54 (2H, m), 1.57-1.62 (1H, m), 1.65-1.69 (1H, m), 2.47 (3H, s), 2.52-2.58 (1H, m), 2.65-2.73 (1H, m), 3.41 (2H, s), 3.53 (2H, dd, J = 17.8, 10.0 Hz), 4.09-4.15 (1H, m), 4.32-4.40 (1H, m), 7.12-7.61 (6H, m), 8.48-8.51 (1H, m)
1-(2-methyl-1-benzofuran-3-yl)heptafluorocyclopentene[ No CAS ]
[ 38749-79-0 ]
[ 1585983-42-1 ]
Yield
Reaction Conditions
Operation in experiment
30%
To a stirred anhydrous THF (40mL) solution of compound 7a (0.69g, 4.00mmol) was added dropwise a 2.4molL-1n-BuLi/hexane solution (1.67mL, 4.00mmol) at 195K under argon atmosphere. After 30min, THF (10mL) containing compound 6 (1.43g, 4.40mmol) was added and the reaction mixture was stirred for 2h at this low temperature. The reaction was allowed to slowly warm to the room temperature and quenched by water. The product was extracted with ether. The combined organic layers was dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (v/v=3/1) as the eluent to give 0.12g diarylethene 1o as a pale red solid in 30% yield. mp 69-70C; IR (upsilon, KBr, cm-1): 785, 843, 879, 992, 1067, 1125, 1140, 1156, 1195, 1250, 1278, 1317, 1342, 1401, 1455, 1648, 3131, 3436; 1H NMR (400MHz, CDCl3): delta 2.10 (s, 3H, -CH3), 2.22 (s, 3H, -CH3), 7.22-7.29 (m, 3H, benzofuran-H, pyridine-H), 7.39 (d, 1H, J=8.0Hz, benzofuran-H), 7.46 (d, 1H, J=7.6Hz, benzofuran-H), 7.70 (d, 1H, J=8.0Hz, pyridine-H), 8.51-8.52 (m, 1H, pyridine-H); 13C NMR (100MHz, CDCl3): delta 13.4, 22.8, 104.4, 111.2, 119.7, 120.8, 123.1, 123.6, 124.7, 126.3, 136.8, 150.4, 154.2, 155.5, 156.7; Calcd for C20H13F6NO (%): Calcd C, 60.46; H, 3.30; N, 3.53. Found C, 60.57; H, 3.35; N, 3.51.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20℃; for 2h;Reflux; Inert atmosphere;
General procedure: Pd(PPh3)4 (3 mol%) was added to a suspension of the appropriate benzoxazole 7 and (het)aryl bromide (1 equiv) in 1 M aq K2CO3 (3equiv) and 1,4-dioxane (0.15 M) at r.t. The mixture was stirred at reflux for 2 h then cooled to r.t. H2O was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel,hexane-EtOAc or CHCl3-MeOH).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 20℃; for 2h;Reflux; Inert atmosphere;
General procedure: Pd(PPh3)4 (3 mol%) was added to a suspension of the appropriate benzoxazole 7 and (het)aryl bromide (1 equiv) in 1 M aq K2CO3 (3equiv) and 1,4-dioxane (0.15 M) at r.t. The mixture was stirred at reflux for 2 h then cooled to r.t. H2O was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried (NaSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel,hexane-EtOAc or CHCl3-MeOH).
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; at 105℃; for 12h;
Preparation 8.2: 2,-methyl-[3,3'-bipyridin]-4-amine 7q [00281] A mixture of (4-amino-3-pyridyl)boronic acid hydrochloric acid (100 mg, 0.5734 mmol), <strong>[38749-79-0]3-bromo-2-methyl-pyridine</strong> (108.5 mg, 0.64 mmol), NaHC03 (860 mu, of 2 M, 1.72 mmol) and palladium triphenylphosphane (66.26 mg, 0.05734 mmol) in dioxane (4 mL) was heated at 105C for 12h. The mixture was then cooled to room temperature and partitioned between DCM and water. The organic layer was filtered through a SCX column, eluting with a 2M solution of H3 in MeOH. The eluate was concentrated in vacuo to give the title compound 7q (60 mg, 56% Yield).
8-bromo-2-methylindolizine (35). A mixture of cloroacetone (17 mmol), LiBr (17 mmol) in acetonitrile (10 mL) was stirred at room temperature for 15 min. Then, a solution of 2-bromo-3-methylpyridine (19 mmol) in acetonitrile (10 mL) was added and the resulting mixture was heated at reflux for 24 h. The mixture was cooled to room temperature and the solvent was removed under reduce pressure. The residue was diluted with water extracted with diethylether. The aqueous was treated with K2CO3 (96 mmol) and heated at 80 C. for 2 h. The mixture was cooled to room temperature and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give 35. (34%) 1H NMR (400 MHz, CDCl3) delta 7.76 (dt, J=6.9, 0.8 Hz, 1H), 7.20-7.07 (m, 1H), 6.83 (dd, J=7.1, 0.7 Hz, 1H), 6.40 (s, 1H), 6.25 (t, J=7.0 Hz, 1H), 2.39 (s, 3H). LC-MS (ES) for C9H8BrN [M+1]+ 209.11.
3-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: (2,2-difluorobenzo[d][1,3]dioxol-4-yl)boronic acid; 3-bromo-2-picoline With triethylamine In water at 23 - 25℃; for 0.166667h; Inert atmosphere;
Stage #2: With 3-(t-butyl)-4-(2,6-dimethoxyphenyl)-2-(2,4,6-triisopropylbenzyl)-2,3dihydrobenzo[d][1,3]oxaphosphole; palladium diacetate In water; toluene at 25 - 50℃; for 12h; Inert atmosphere;
78%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate monohydrate; methylmagnesium chloride at 45℃; for 24h;
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); triethylamine; at 80℃; under 2585.81 Torr; for 16h;
A mixture of 3-bromo-2-methylpyridine (5.0 g, 29.0 mmol), Pd(dppf)C12 (2.1 g, 2.9 mmol) and Et3N (8.8 g, 87 mmol) in MeOH (250 mL) was stirred at 80 °C and 5OPsi under CO for 1 6h. Solid was then filtered out and the filtrate was concentrated. The residue was purified by column chromatography (PE:EA=5: 1) to give the desired product (4.1 g, 93.6percent). ?H NMR (CD3OD, 400MHz) (ppm): 8.57 - 8.42 (m, 1H), 8.08 (d, 1=8.0 Hz, 1H),7.10 (dd, 1=4.8, 7.8 Hz, 1H), 3.81 (s, 3H), 2.73 (s, 3H). LCMS (mlz): 152.0 [M+H]+
2-[3-{3-(2-methylpyridyl)-5-(9-phenanthryl)phenyl}]-4,6-diphenyl-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 13h;Inert atmosphere;
A stream of argon, 4,6-diphenyl-2- [5- (9-phenanthryl) -3- (4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) phenyl] - 1,3,5-triazine (1.35g, 2.2mmol), 3- bromo-2-methylpyridine (0.30 mL, 2.7 mmol), and tetrakis (triphenylphosphine) palladium (76.7 mg, 0. weighed 066mmol), was suspended in tetrahydrofuran (22mL). The mixture 2.0M- aqueous potassium carbonate solution (3.3 mL, 6.6 mmol) after the mixture was heated at 70 C.. 13 hours. After cooling, water was added, and the precipitated solid was filtered off and washed with water, methanol, a solid with hexane. By further purified by recrystallization (toluene)2- [3- {3- (2-methylpyridyl) -5- (9-phenanthryl) phenyl}] - 4,6-diphenyl-1,3,5-triazineIt was obtained (Compound the A-37) as a white solid (Yield 1.24g, 97% yield).
With palladium diacetate; In tetrahydrofuran; at 0℃;
In a three-necked flask was added 250 mL of anhydrous tetrahydrofuran,<strong>[38749-79-0]3-bromo-2-methylpyridine</strong> and 4.0 g of palladium acetate,The system will be cooled to 0 ,A solution of cyclobutylmagnesium bromide in tetrahydrofuran (55.0 g) was slowly added dropwise.After dripping,Continue to react.After the reaction,Adding 800 mL of ammonium chloride aqueous solution,Extracted with ethyl acetate (200 mL x 3)Sodium bicarbonate,Saturated brine washing,Dried over anhydrous sodium sulfate,And concentrated to 38.7 g (90.4%) of 2-methyl-3-cyclobutylpyridine.
Multi-step reaction with 2 steps
1: tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / toluene / 3 h / 80 °C
2: N-chloro-succinimide; acetic acid / water / 2 h / 20 °C
Multi-step reaction with 2 steps
1.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 0.25 h
1.2: 4 h / 130 °C
2.1: chlorine; acetic acid / water / 0.58 h / 0 °C
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0) / 2 h / 100 °C
2: acetic acid; N-chloro-succinimide / water / 2 h / 20 °C
Stage #1: 3-bromo-2-picoline With n-butyllithium In tetrahydrofuran at -70℃; for 1h;
Stage #2: With 1,4-diazabicyclo[2.2.2]octane-triethylenediamine-bis(sulfur dioxide) In tetrahydrofuran at -70℃; for 1h;
Stage #3: With sulfuryl dichloride In tetrahydrofuran at -70 - 25℃; for 2h;
B.3 Example B.3 (0274) 2-methylpyridine-3-sulfonyl chloride
To a solution of 3-bromo-2-methylpyridine (500 mg, 2.91 mmol) in THF (10 mL) was added n- butyllithium (1.74 mL, 4.36 mmol) at -70 °C. Then the mixture was stirred at -70 °C for 1 h and DABCO-bis(sulfur dioxide) (1.05 g, 4.36 mmol) was added. The mixture was stirred at -70 °C for 1 h again. Then to the mixture was added sulfuryl chloride (1.96 g, 14.53 mmol, 5 eq) and the reaction mixture was allowed to slowly warm to 25 °C and stirred for 2 h. To the mixture was added 20 mL water and extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude compound 2- methylpyridine-3-sulfonyl chloride (500 mg, 2.61 mmol, 90% yield) was obtained as a brown oil.
diethyl 2-(2-methyl-3-pyridinyl)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With benz<b>oxazole; copper(l) iodide; triethylamine; In dimethyl sulfoxide; at 60℃; for 0.25h;
(1) <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> was dissolved in DMSO at a concentration of 1 mol / L to give solution a; (2) diethyl malonate, benzoxazole, The molar ratio of diethyl malonate to <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> in DMSO was 1.5: 1, the molar ratio of benzoxazole to <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> was 0.4: The molar ratio of triethylamine to <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> was 8: 1 to give solution b; (3) adding solid catalyst cuprous iodide to a fixed bed microchannel reaction apparatus, 2-methylpyridine is 0.4: 1; (4) The solution a and the solution b are simultaneously pumped into the fixed bed microchannel reaction apparatus after the treatment in step (3), and then the microcirculation reaction in the reaction apparatus (Diameter of 0.5mm, length of 20m) reaction.The flow rate ratio of solution a and solution b is controlled at 1: 1, flow rate 1ml / min, holding residence time 15min, reaction at 60 ; (5) collecting outflow liquid, EA / water extraction, combining organic phase, adding anhydrous sulfuric acid The product was purified by silica gel column chromatography and separated from petroleum ether / ethyl acetate as a mobile phase. The product was purified in 74% yield;
74%
With benz<b>oxazole; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 50℃; for 6h;Inert atmosphere; Sealed tube;
General procedure: Under Ar atmosphere, DMSO (2 mL), ArBr 1 (1.0 mmol), diethyl malonate 2 (1.5 mmol), CuI (0.1mmol), benzoxazole (0.2 mmol) and K3PO4 (3 mmol) were successively added into a sealed tube.The mixture was stirred at 50C for about 3-9 h. When the reaction completed indicated by TLC,the reaction mixture was poured into saturated ammonium chloride aqueous solution (20 mL)and extracted with ethyl acetate (3×20 mL).The combined organic phase was washed with saturated ammonium chloride aqueous solution(2×20 mL) and water (2×20 mL). Then the separated organic layer was dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel using hexane/ethyl acetate to afford the desired product.
1,2-di(2-methyl-3-pyridyl)perfluorocyclopentene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
General procedure: To a stirred anhydrous THF (20ml) of compound 513 (1.045g, 5.00mmol) was added dropwise a 2.5M n-BuLi/ hexane solution (2.2ml, 5.50mmol) at 195K under argon atmosphere. After 40min, octafluorocyclopentene (C5F8) (0.40ml, 2.88mmol) was added and the reaction mixture was stirred for 1hat this low temperature. The reaction was allowed to slowly warm to the room temperature and quenched by water. The product was extracted with ethyl acetate, and then dried with MgSO4, filtered, and evaporated in vacuo. The crude product was purified by column chromatography using petroleum ether/ ethyl acetate (v/v=4/1) as the eluent to give 0.96g compound 1o as yellow solid in 48% yield.
With tetrakis(triphenylphosphine) palladium(0); In m-xylene; at 130℃; for 35h;
The 3 - bromo -2 - methyl pyridine (40.8 g, 240 mmol), 2 - tributyltin - pyridine (82.8, 225 mmol) and four triphenyl phosphate palladium (6.52 g, 5 . 62 mmol) is put into the with 720 ml m-xylene reaction bottle. The mixture degassing, then heating to 130 C is continued after 35 hours. The reaction mixture is cooled to room temperature, then 15% hydrochloric acid solution to extraction. The aqueous phase first washing with ethyl ether, then 50% aqueous sodium hydroxide solution to neutralize, chloroform extraction, the combined organic layer, and drying by anhydrous magnesium sulphate, concentrated via column chromatography to obtain 2 - methyl -3 - (pyridine -2 - yl) pyridine (33.8 g, yield 83%)
60%
With bis-triphenylphosphine-palladium(II) chloride; lithium chloride; In toluene; at 120℃; for 72h;Inert atmosphere; Schlenk technique;
Under nitrogen atmosphere, <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (0.69 mL, 5.37 mmol), 2-(tributhylstannyl)pyridine(3.07 mL, 8.05 mmol), LiCl(1.14g, 26.85 mmol), and Pd(PPh3)2Cl2 (0.19g, 0.27 mmol) were charged into a a Schlenk flask and then toluene(50 ml) was added to this reaction mixture. This mixture was refluxed at 120 C for 3 days. After the reaction was completed, solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with. H2O. The organic layer was dried over anhydrous MgSO4 and concentrated. The product was purified by column chromatography (ethylacetate/dichloromethane = 2/1, Rf = 0.2) to give 60% yield of white solid. 1H NMR (400 MHz, CD2Cl2, delta): 8.62 (m, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.71 (td, J = 8, 1.6 Hz, 1H), 7.65(dd, J = 7.6, 1.6 Hz, 1H),7.34(d, J = 8 Hz, 1H), 7.21 (m, 1H), 7.14 (m, 2H) 2.52 (s, 3H).
2-(3-bromo-2-pyridyl)-1-(3-furyl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 16h;
2.1 2.1 2-(3-Bromo-2-pyridyl)-1-(3-furyl)ethanone
2.1 2-(3-Bromo-2-pyridyl)-1-(3-furyl)ethanone:LHMDS (1.06 mol/L in THF, 300 mL) is added to a solution of 3-bromo-2-methyl-pyridine (50.0 g) in dry THF (500 mL) maintained at 0 °C,followed by the dropwise addition of ethyl furan-3-carboxylate (45.0 g) in THF. The reaction mixture is warmed to ambient temperature and stirred for 16 h. Citric acid (15% m/m) is added and the mixture is extracted with EtOAc (3x). The combined organics are dried over Na2504, solid parts are removed by filtration and the remaining solution is concentrated under reduced pressure. The resulting crude product (87.0 g) is used directly in the next step. MS (ESI) m/z265.9 [M + Hj.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 175℃; for 2h;Microwave irradiation; Inert atmosphere;
3-Bromo-2-methylpyridine (344 mg, 2 mmol), Zn(CN)2 (235 mg, 2 mmol) and Pd(PPh3)4 (75 mg, 0.06 mmol) were dissolved in DMF (5 mL). The mixture was vacuumed for N2 three times, The reaction solution was reacted in the microwave (175 C.) for 2 h under N 2 protection. After cooling, it was diluted with EtOAc (60 mL). After washing with saturated saline, dry over anhydrous sodium sulfate. Concentration by filtration and column chromatography of the residue provided the title compound as a white solid (212 mg, yield 90%).
61.1 Step 1: 3-Methoxy-2-methylpyridine
Dissolve 3-bromo-2-methylpyridine (860 mg, 5 mmol) in DMSO (10 mL). CH3ONa (20 mmol, 1.080 g) was added and the mixture was reacted at 100°C for 12 h, allowed to cool, water added and extracted three times with ether. Combine organic layers, dry over anhydrous sodium sulfate, filter and concentrate, Column chromatography of the residue gave the title compound as a yellow oil (43% yield).
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 3h;Inert atmosphere;
Under N 2 atmosphere, <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (172 mg, 1 mmol), cyclopropylboronic acid (112 mg, 1.3 mmol), To a solution of potassium phosphate (743 mg, 3.5 mmol) and tricyclohexylphosphine (28.0 mg, 0.1 mmol) in toluene (4.0 mL) and water (200 muL) was added palladium acetate (12.0 mg, 0.05 mmol). The mixture was reacted at 100C for 3 hours. Let it cool to room temperature. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate, residual Column chromatography gave the title compound as a pale yellow oil (121 mg, 91% yield).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 2h;Inert atmosphere;
<strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (880 mg, 5.12 mmol), isopropenylboronic acid (661 mg, 7.69 mmol) and potassium carbonate (3.64 g, 26.32 mmol) were dissolved in a mixture of DME (46 mL) and water (5.12 mL) The solution was evacuated by N2 three times, and Pd(dppf)2Cl2.CH2Cl2 (460 mg, 0.56 mmol) was added under N2 protection. The mixture was allowed to react for 2 h at 90 C. After cooling, it was extracted three times with ether. The ether extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title compound as a brown oil (444 mg, yield 65%).
With tetrabutyl-ammonium chloride; palladium diacetate; sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;Inert atmosphere;
3-Bromo-2-methylpyridine (1.72 g, 10 mmol), acrylonitrile (3.29 mL, 50 mmol), Pd(OAc) 2 (244 mg, 1 mmol), n-Bu4NCl (2.78 g, 10 mmol) and NaHCO 3 (4.2) g, 50 mmol) dissolved in 15 mL DMF. The mixture was exposed to microwaves at 110C for 5 h under N2 protection. After cooling, the DMF was evaporated to dryness, the residue partitioned between water and DCM, the organic phase dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by column chromatography to give the title compound as a white gum (1.33 g, 93% yield).
With tetrabutyl-ammonium chloride; palladium diacetate; sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;Microwave irradiation; Inert atmosphere;
3-Bromo-2-methylpyridine (1.72 g, 10 mmol), acrylonitrile (3.29 mL, 50 mmol), palladium acetate (244 mg, 1 mmol), tetra-n-butylammonium chloride (2.78 g, 10 mmol) and sodium bicarbonate (4.2 g, 50 mmol) dissolved in 15 mL of N,N-dimethyl Formamide (DMF). The mixture was placed under microwave protection at 110C for 5 h under N2 protection. After cooling, spin down DMF and the residue Separate the mixture with water and dichloromethane (DCM), dry the organic phase over anhydrous sodium sulfate, concentrate by filtration, and purify the residue by column chromatography. The product was a white gum (1.33 g, yield 93%).
(S)-isopropyl 2-(6-amino-4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate[ No CAS ]
[ 38749-79-0 ]
(S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin--yl)-5-(4-(4-fluorophenethoxy)phenyl)-2-methyl-6-((2-methylpyridin-3-yl)amino)pyridin-3-yl)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
A mixture of (S)-isopropyl 2-(6-amino-4-(4,4-dimethylpiperidin-1-yl)-S-(4-(4-fluorophenethoxy)phenyl)-2-methylpyridin-3 -yl)-2-(tert-butoxy)acetate (0.025 g, 0.041mmol), <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (8.52 mg, 0.050 mmol), Xantphos (1.433 mg, 2.476imol), tris(dibenzylideneacetone)dipalladium(0) (0.756 mg, 0.825 imol), and cesiumcarbonate (0.019 g, 0.058 mmol) in dioxane (1 mL) was degassed and heated at 100 Cfor 5 h. The reaction mixture was cooled to ambient temperature, filtered through a pad of celite, and concentrated in vacuo. The residue was taken up in ethanol (1 mL) and 5 MNaOH (0.083 mL, 0.4 13 mmol) was added. The mixture was heated at 100 C for 1 h, cooled to ambient temperature, and filtered. The crude mixture was purified viapreparative HPLC to afford the desired product (18.2 mg, 67%). LCMS (M+1) = 655.4.
tert-butyl (3-(2-methylpyridin-3-yl)prop-2-yn-1-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
To a Biotage 2.0-5.0 ml_ microwave tube containing N-Boc-propargylamine (413 mg, 2.66 mmol) under a blanket of argon was added degassed DME/EtOH 50:50 (2.5 ml_) followed by cuprous iodide (46.0 mg, 0.242 mmol) followed by (0248) tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol). To the vigorously stirred suspension was added triethylamine (734 mg, 7.26 mmol). The tube was purged with argon, stirred at ambient temperature for ten minutes followed by the addition of a solution of 3-bromo- 2-methylpyridine (416 mg, 2.42 mmol). The tube was purged with argon, capped and placed in a Biotage Initiator-·- microwave and heated to 150 C for 15 minutes on normal absorption level. The contents of the flask were filtered through a compressed bed of celite and the crude material was eluted with dichloromethane. The solvent was removed in vacuo and the residue was chromatographed on silica gel (EtOAc/Hex, 25:75, v/v Rf = 0.167) to afford F-Boc (192 mg, 32.0% yield) as a red oil: 1 H NMR (500 MHz, CDCI3) d = 8.34 (d, J = 3.6 Hz, 1 H), 7.55 (dd, J = 1.5, 7.7 Hz, 1 H), 6.98 (dd, J = 4.9, 7.5 Hz, 1 H), 5.31 (br. s., 1 H), 4.13 (d, J = 4.9 Hz, 2 H), 2.56 (s, 3 H), 1.40 (s, 9 H).
3-(2-chloro-4-methoxyphenyl)-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 0.5h;Microwave irradiation;
3-bromo-2-methyl-pyridine (50 mu, 0.44 mmol), <strong>[219735-99-6]2-chloro-4-methoxyphenylboronic acid</strong> (124 mg, 0.66 mmol), potassium carbonate (182 mg, 1.32 mmol) andtetrakis(triphenylphosphine)palladium(0) (26 mg, 0.022 mmol) in water (0.5 mL) and DME (1.5 mL) was microwave irradiated at 110 C for 30 min. After organic solvent was removed in vacuo, the residue was extracted with EtOAc and washed successively with water and brine. The organic layer was dried over Na2S04and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (MeOH/DCM) to obtain 82 mg of 3-(2-Chloro-4-methoxy- phenyl)-2-methyl-pyridine
tert-butyl 3-(2-methylpyridin-3-yl)-4-oxopiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In tetrahydrofuran; toluene; at 45℃; under 760.051 Torr;Inert atmosphere;
A mixture of /-BuONa (5.79 g, 60.2 mmol) and Pd(OAc)2 (901 mg, 4.02 mmol) in THF (80 mL) was stirred at l5C for 15 minutes. Tri-/67 /-butyl phosphine (10% in toluene, 16.25 g, 8.03 mmol), <strong>[38749-79-0]3-bromo-2-methyl-pyridine</strong> (7.60 g, 44.2 mmol) and tert- butyl 4- oxopiperi dine- l-carboxy late (8.00 g, 40.2 mmol) were added. The reaction mixture was stirred at 45C overnight under argon atmosphere. The reaction mixture was subsequently diluted with EtOAc and washed with water. The organic layer was dried over Na^SCE. (1508) filtered, and concentrated under reduced pressure to give crude product. The crude product was purified by automated flash silica column chromatography (60 g column) eluting with a gradient of 0-50% EtOAc in petroleum ether to give the title compound as a yellow oil (4.3 g, 37%). ESI-MS [M+H]+ calc?d for C16H22N2O3, 291.17; found, 291.2.
2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde[ No CAS ]
[ 38749-79-0 ]
2-methyl-4-(2-methylpyridin-3-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.5%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
To a stirred solution of 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzaldehyde (250 mg, 1.0 mmol) and <strong>[38749-79-0]3-bromo-2-methylpyridine</strong> (206 mg, 1.2 mmol) in dioxane (4 ml_), cesium carbonate (975 mg, 3.01 mmol) and water (0.4 mL) were added at RT. The reaction mixture was flushed with nitrogen for 10 minutes before addition of tetrakis(triphenyiphosphine)palladium(0) (1 15 mg, 0.1 mmol). Then the resulting reaction mixture was heated at 100 C overnight. It was filtered through celite and the filtrate was concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 15-20% EtOAc in PE) to afford the title compound. Yield: 75.5 % (160 mg, pale yellow gummy solid). 1H NMR (400 MHz, DMSO -ofe): d 10.28 (s, 1 H), 8.51 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.65-7.56 (m, 2H), 7.55-7.44 (m, 1 H), 7.56-7.58 (m, 1 H), 2.67 (s, 3H), 2.21 (s, 3H). LCMS: (Method A) 212.1 (M+H), Rt. 1.17 min, 77.1 % (Max).
Stage #1: trifluoromethylsulfonic anhydride; 5-(diphenylphosphaneyl)-2-(trifluoromethyl)pyridine; 3-bromo-2-picoline In dichloromethane at -50℃; for 1h; Inert atmosphere;
Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at -78 - 20℃; for 0.333333 - 0.5h; Inert atmosphere;
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous sodium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 4.5h; Inert atmosphere;
1.12.1 Step 1: Tert-butyl (3-fluoro-4-(2-methylpyridin-3-yl)phenyl)carbamate, Tert-butyl (3-fluoro-4-(2- methylpyridin-3-yl)phenyl)carbamate
A solution of 3-bromo-2-methylpyridine (900 mg, 5.23 mmol), tert-butyl (3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1764 mg, 5.23 mmol) and 2M aq. Na2CO3 (8.50 mL, 17 mmol) in dioxane (39 mL) was purged with argon. PdCl2(dppf)DCM (302 mg, 0.366 mmol) was added and the mixture heated to 100 °C for 4.5 hours. After cooling to RT the mixture was diluted with EtOAc, washed twice with saturated NaHCO3 solution and brine. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica (0 % to 63 % EtOAc in heptane) to yield the title compound (2.0 g, quantitative yield) as a yellow foam. LC-MS: Rt = 0.97 min; MS m/z = 303 [M+H]+ (Method 1).
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