Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 3430-17-9 | MDL No. : | MFCD00239380 |
Formula : | C6H6BrN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PZSISEFPCYMBDL-UHFFFAOYSA-N |
M.W : | 172.02 | Pubchem ID : | 220832 |
Synonyms : |
2-Bromo-3-picoline
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.9 |
TPSA : | 12.89 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.76 cm/s |
Log Po/w (iLOGP) : | 1.85 |
Log Po/w (XLOGP3) : | 2.24 |
Log Po/w (WLOGP) : | 2.15 |
Log Po/w (MLOGP) : | 1.58 |
Log Po/w (SILICOS-IT) : | 2.54 |
Consensus Log Po/w : | 2.07 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.87 |
Solubility : | 0.231 mg/ml ; 0.00134 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.15 |
Solubility : | 1.23 mg/ml ; 0.00714 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.26 |
Solubility : | 0.0948 mg/ml ; 0.000551 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.56 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With sodium amide In 5,5-dimethyl-1,3-cyclohexadiene at 118 - 120℃; for 1 h; Inert atmosphere | Example 2 To the reaction tank was charged 650g of xylene as a solvent, heated up to 115 ~ 120 deg. C heated under reflux until complete removal of the water; under nitrogen, the solvent was cooled to 70 deg. C, sodium amide was added 22g, and then the solution was heated to 118 to 120 deg. C, was added dropwise under reflux 102g of 2-bromo-3-methylpyridine, the addition was complete, the reaction maintaining the temperature at reflux 1H; After the reaction, the reaction solution was cooled to 45 deg. C, and then poured into ice water, separation of the upper solvent layer; xylene was concentrated at atmospheric pressure, the remaining 220g, stirring cooling to 10 ~ 15 deg. C, crystallization give the desired product 2- methyl-6-amino-5-bromopyridine 100g, content 99.3percent, yield 90.1percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 12 h; | To a stirred solution of 2-bromo-3-methylpyridine (50g) in dichloromethane (500mL) was added 3-chloroperbenzoic acid (bOg) at about room temperature. The reactionmixture was stirred for about 1 2h at about room temperature and was filtered. The filtrate was quenched in to saturated sodium thiosulfate solution. The reaction mixture was stirred for about lh at about room temperature. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water and saturated brine solution, dried and concentrated underreduced pressure at about 40°C. The solid was purified by column chromatography (5-7percent methanol in ethyl acetate). Yield: 33g (60percent)‘H NMR (300MHz, CDC13): ö 8.30-8.29 (m,1H), 7.14-7.12(m,2H), 2.47 (s,3H)IR: 3382, 3051, 1670, 1436, 1410, 1275, 1240, 1067, 958, 786, 695, 599 cmMass [M+H] : 188.09 |
47% | With sodium hydroxide; 3-chloro-benzenecarboperoxoic acid In dichloromethane; ethyl acetate | EXAMPLE 89A 2-bromo-3-methylpyridine 1-oxide A solution of 2-bromo-3-methylpyridine (10.0 mL, 0.0898 mol) in dichloromethane (150 mL) at 0° C. was treated with mCPBA (~77percent, 22.1 g, 0.0987 mol) in three equivalent portions. The mixture was warmed to room temperature, stirred for 18 hours, cooled to 0° C., and treated with 1N NaOH (50 mL). The organic phase was washed with 1N NaOH and saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate and 9:1 ethyl acetate/methanol to provide 7.83 g (47percent) of the desired product. MS (DCI/NH3) m/z 187.9 (M+H)+; 1H NMR (CDCl3) δ8.28-8.26 (m, 1H), 7.15-7.09 (m, 2H), 2.46 (s, 3H). |
47% | With sodium hydroxide; 3-chloro-benzenecarboperoxoic acid In dichloromethane; ethyl acetate | EXAMPLE 89A 2-bromo-3-methylpyridine 1-oxide A solution of 2-bromo-3-methylpyridine (10.0 mL, 0.0898 mol) in dichloromethane (150 mL) at 0° C. was treated with mCPBA (~77percent, 22.1 g, 0.0987 mol) in three equivalent portions. The mixture was warmed to room temperature, stirred for 18 hours, cooled to 0° C., and treated with 1N NaOH (50 mL). The organic phase was washed with 1N NaOH and saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate and 9:1 ethyl acetate/methanol to provide 7.83 g (47percent) of the desired product. MS (DCI/NH3) m/z 187.9 (M+H)+; 1H NMR (CDCl3) δ 8.28-8.26 (m, 1H), 7.15-7.09 (m, 2H), 2.46 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium permanganate In water for 5 h; Heating / reflux | 2-bromo-3-methylpyridine (25.0 mL, 213 mmol) was added to a solution of potassium permanganate (87.7 g, 555 mmol) in 800 ML of water and the mixture was stirred under reflux. After 5 hours, 600 mL of water was distilled off and the remaining suspension was filtered. The residue was washed with two 50 mL portions of hot water and the combined filtrates were acidified with concentrated HC1. The white precipitate was filtered and dried in a vacuum oven to give 26.8 g of 2-bromonicotinic acid (62percent yield). DIPHENYLPHOSPHORYLAZIDE was added to a solution of 2-bromonicotinic acid (15.0 g, 74.0 mmol) and triethylamine (11.4 mL, 81. 4 mmol) in 140 mL of anhydrous tert-butanol. The reaction mixture was stirred under reflux for 2 hours, cooled to room temperature, and concentrated in VACUO. The residue was dissolved in 150 ML of ethyl acetate and washed with three 50 mL portions of water, three 50 mL portions of saturated aqueous sodium bicarbonate, and with two 50 mL portions of brine. The organic layer was dried over magnesium sulfate (MGS04), filtered, and concentrated in vacuo. The residue crystallized upon standing to give 15.3 g of the title product (76percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | at 80℃; for 16 h; | A mixture of 2-bromo-3-methylpyridine (5.0 g, 29.0 mmol), Pd(dppf)C12 (2.1 g, 2.9 mmol), and triethylamine (8.8 g, 87 mmol) in methanol (250 mL) was stirred at 80 °C under CO atmosphere (50 psi) for 16 h. The mixture was filtered and the filtrate concentrated in vacuo, then purified by column chromatography on Si02 to give the desired product (4.1 g, 93.6percent). LCMS (mlz): 152.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: With potassium <i>tert</i>-butylate In tert-Amyl alcohol at 100℃; for 40 h; Schlenk technique; Inert atmosphere Stage #2: at 20℃; for 24 h; |
General procedure: In a dry Schlenk tube 2-bromo-6-methylpyridine (5.98 g, 35.0 mmol) was dissolved in 100 mL oft-AmylOH and KOt-Bu (39.3 g , 350.0 mmol) was added. The mixture was stirred at 100 °C for 40 h. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of HCO2H. The solution was stirred for 24 h at rt, then the pH was set to about 6 using 3N aq. KOH solution. The extraction was performed using CHCl3 (3×) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was transferred to a column chromatography (8percentMeOH in DCM) to afford 1 (white solid), 2.75 g (72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 40℃; for 8 h; UV-irradiation; Inert atmosphere | This intermediate was generated by a modified procedure based on thatdisclosed in Rebek, J., et al., I Am. Chem. Soc., 107, 7487 (1985)). A three-neckround bottom flask with a stir bar was flame dried, cooled under vacuum and purged with N2. To the flask were added 2-bromo-3-methylpyndine (5.2 mL, 29.1 mmol), N-bromosuccinimide (5.5 g, 32.0 mmol), and degassed benzene (126 mL). The flask was fitted with a condenser, heated to 40 °C and AIBN (0.24 g, 1.5 mmol) was addedin several portions. The reaction was irradiated using a sun lamp as it was stirred at40 °C. The reaction was monitored using TLC and HPLC and was stopped after 80percentconversion of the pyridine reagent (approximately 8 hrs). The reaction wasconcentrated under reduced pressure, then redissolved in 4:1 DCM/EtOAc (120 mL)and extracted once with 50 mL of a saturated solution of NaHCO3(aq), water and asaturated solution of NaCl(aq). The organic phase was dried over anhydrous sodiumsulphate, filtered and concentrated. Upon standing the residue could not be fully redissolved in DCM and the resultant suspension was filtered to remove the insoluble solid. The filtrate was concentrated to near dryness and the residue was purified by normal phase flash chromatography (EtOAc/Hexanes) to give the title compound I-i(3.0 g, 11.9 mmol, 41percent) as a yellow solid. ‘H NMR (400 MHz, CDC13) ö 8.33 (1H, dd, J5,2 Hz), 7.78 (1H, dd, J7,2 Hz), 7.28 (1H, dd, J=5,4 Hz), 4.57 (2H, s), MS (LC/MS) m/z observed 249.97, expected 249.89 [M+Hj |
41% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene at 40℃; for 8 h; Inert atmosphere; Irradiation | This intermediate was generated by a modified procedure based on that disclosed in Rebek, J., et al., J Am. Chem. Soc., 107, 7487 (1985)). A three-neck round bottom flask with a stir bar was flame dried, cooled under vacuum and purged with N2. To the flask were added 2-bromo-3-methylpyridine (5.2 ml, 29.1 mmol), N-bromosuccinimide (5.5 g, 32.0 mmol), and degassed benzene (126 ml). The flask was fitted with a condenser, heated to 40°C and AIBN (0.24 g, 1.5 mmol) was added in several portions. The reaction was irradiated using a sun lamp as it was stirred at 40°C.The reaction was monitored using TLC and HPLC and was stopped after 80percent conversion of the pyridine compound (approximately 8 hrs). The reaction was concentrated under reduced pressure, then redissolved in DCM/EtOAc (120 ml, 4:1 (v/v)) and extracted once with 50 ml of NaHCO3 (satd, aqueous) water and brine. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated. Upon standing the residue could not be fully redissolved in DCM and the resultant suspension was filtered to remove the insoluble solid. The filtrate was concentrated to near dryness and the residue was purified by normal phase flash chromatography (EtOAc/Hexanes) to give the title compound I-4 (3.0 g, 11.9 mmol, 41percent) as a yellow solid. H1 NMR (400 MHz, CDCl3) δ 8.33(1H, dd, J=5.2 Hz), 7.78(1H, dd, J=7.2 Hz), 7.28(1H, dd, J=5.4 Hz), 4.57(2H, s), MS (EC/MS) m/z observed 249.97, expected 249.89 [M+H]. |
34% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3 h; Reflux | A mixture of 2-bromo-3-methylpyridine (2.0 mL, 17.9mmoli), NBS (3.5 g,19.7 mmoli) and benzoyl peroxide (1.8 g, 10.2 mmoli) in CCl4 (180 mL) was refluxed for 3 h. After cooling, the mixture was poured into H2O (100 mL) and extracted with CHCl3 (3 x 50 ml). The organic phase was evaporated under reduced pressure and purified by column chromatography (eluting with CE/EtOAc 8/2) to give 2-bromo-3-bromomethylpyridine (yield34percent), as an oil; 1H NMR (300 MHz, DMSO-d6): δ 8.35 (dd, J= 4.7 and 1.7 Hz, 1 H, 6-H); 8.05 (dd, J= 7.5 and 1.7 Hz, 1 H, 4-H); 7.49 (dd, J = 7.5 and 4.7 Hz, 1 H, 5-H); 4.72 (s,2 H, CH2Br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78℃; for 1 h; |
To 2-bromo-3-methylpyridine (1.3 mE, 11.7 mmol) in THF (35 mE) at —78° C. was added n-BuEi (2.5 M in hexanes, 5.6 mE, 14 mmol). Afier 30 mi tri-n-butyltin chloride (3.8 mE, 14 mmol) was added. After 1 hat —78° C., the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10percent aq KF. The organic layer was dried (Mg504). Purification via silica gel chromatography (0-15percent EtOAc in heptane) gave the title compound (1.2 g, 27percent). MS (ESI) mass calcd. for C18H33NSn, 382.2; mlz found 384.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium permanganate; water for 20h; Heating; | |
70% | With potassium permanganate In water Heating; | |
62% | With potassium permanganate In water for 5h; Heating / reflux; | 2 2-bromo-3-methylpyridine (25.0 mL, 213 mmol) was added to a solution of potassium permanganate (87.7 g, 555 mmol) in 800 ML of water and the mixture was stirred under reflux. After 5 hours, 600 mL of water was distilled off and the remaining suspension was filtered. The residue was washed with two 50 mL portions of hot water and the combined filtrates were acidified with concentrated HC1. The white precipitate was filtered and dried in a vacuum oven to give 26.8 g of 2-bromonicotinic acid (62% yield). DIPHENYLPHOSPHORYLAZIDE was added to a solution of 2-bromonicotinic acid (15.0 g, 74.0 mmol) and triethylamine (11.4 mL, 81. 4 mmol) in 140 mL of anhydrous tert-butanol. The reaction mixture was stirred under reflux for 2 hours, cooled to room temperature, and concentrated in VACUO. The residue was dissolved in 150 ML of ethyl acetate and washed with three 50 mL portions of water, three 50 mL portions of saturated aqueous sodium bicarbonate, and with two 50 mL portions of brine. The organic layer was dried over magnesium sulfate (MGS04), filtered, and concentrated in vacuo. The residue crystallized upon standing to give 15.3 g of the title product (76% yield). |
43% | With potassium permanganate In water Reflux; Acidic conditions; | |
With potassium permanganate; water | ||
With potassium permanganate In water | ||
With potassium permanganate Heating; | ||
With potassium permanganate In water | 1.A N-(2'-Aminosulfonyl-[1,1']biphen-4-yl)-2-(3'-amidinophenyl)nicotinamide, trifluoroacetic Acid Salt Part A. Preparation of 2-bromonicotinic Acid. Potassium permanganate (18.4 g, 116 mmol) was dissolved in water (400 mL) and added to 2-bromo-3-methylpyridine (10.0 g, 58 mmol) and refluxed for 16 hours. After cooling to room temperature, the slurry was filtered through a celite plug and rinsed with water and chloroform. The entire filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted again with CHCl3 and acidified with 6N HCl to pH 1. A white solid was obtained on standing (2.08 g of product). The pH of the remaining aqueous was adjusted to pH 4 with 2M NaOH and 2M HCl, then concentrated to <100 mL. A white precipitate was filtered. The pH was adjusted to 4 and the mixture filtered again, combining the isolated solids for a total of 3.88 g of product. The filtrate was concentrated again to <100 mL and adjusted to pH 1.5 and an additional quanitity of white solid was obtained (1.80 g), for a combined yield of 3 crops, (8.76 g, 66%). 1 H NMR (DMSO-d6): δ 13.76 (bs, 1H), 8.46 (m, 1H), 8.09 (dd, 1H, J=7.7, J'=2.2), 7.51 (m, 1H). | |
With potassium permanganate In water at 100℃; for 23h; | 1 Step 1: Synthesis of Compound WXO41-2 10508] Under 20° C., potassium permanganate (9.46 g,59.87 mmol, 1.03 eq) was added to the aqueous (200.00 mE) solution of WXO41-1 (10.00 g, 58.13 mmol, 6.49 mE, 1.00 eq). The mixture was stirred for 1 h at 100° C., added with potassium permanganate (9.46 g, 59.87 mmol, 1.03 eq) and stirred for 16 h, then added with potassium permanganate (9.46 g, 59.87 mmol, 1.03 eq) again and continuously stirred for 6 h. Afier reaction, the reaction liquid was filtered to remove the undissolved substance, added with water (100 mE), adjusted with hydrochloric acid (4M) to pH=3-4, and extracted with ethyl acetate three times (200 mE each time). The organic phase was washed with saturated sodium chloride solution (200 mE), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain WXO41 -2.10509] ‘H NMR (400 MHz, MeOD) ö ppm: 7.50 (dd, J=7.78, 4.77 Hz, 1H), 8.15-8.20 (m, 1H), 8.42-8.48 (m, 1H). | |
With potassium permanganate In water Reflux; Acidic conditions; | ||
With potassium permanganate In water Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-bromo-3-picoline With magnesium In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Reflux; Stage #2: With dilithium tetrachlorocuprate(II); oxygen In tetrahydrofuran at 20℃; for 2h; | |
80% | With nickel(II) chloride hexahydrate; iodine; acetic acid; lithium chloride; zinc In N,N-dimethyl-formamide at 50 - 60℃; for 6h; | |
77% | With bis(triphenylphosphine)nickel(II) chloride; tetraethylammonium iodide; zinc In tetrahydrofuran at 60℃; for 72h; |
65% | With manganese; zirconocene dichloride; [(2,9-dimethyl-1,10-phenanthroline)dichloro nickel(II)]; lithium chloride In 1,2-dimethoxyethane at 50℃; for 48h; Inert atmosphere; | General procedure: To a suspension of a NiCl2-complex (0.01 mmol, 0.02 equiv), Zr(cp)2Cl2 (Strem, 99%; 7.3 mg, 0.025 mmol, 0.05 equiv), Mn powder (Aldrich, 99.99%; 54.9 mg, 1.0 mmol, 2.0 equiv) and LiCl (Aldrich, anhydrous, ground powder; 42.4 mg, 1.0 mmol, 2.0 equiv) in DME (Aldrich, anhydrous, 99.5%; 1.0 mL) was added an iodide (0.5 mmol) under nitrogen. The mixture was stirred at rt under nitrogen until the reaction completed (TLC). Except for the dipyridyls, the mixture was loaded on silica gel directly, and the flash chromatography on silica gel gave the homo-coupling product. For dipyridyls, the reaction was quenched with aq. NH4OH (27% w/w, 0.6 mL), stirred for 10 min, extracted with CH2Cl2 (10 mL × 3), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give the homocoupling product. For alkenyl halide substrates (Fig. 3 and Table 3), the reaction was done in 0.2 mmol scale (C: 0.5 M) with added toluene (42 μl, 0.4 mmol, 2.0 equiv) as an internal standard. After the reaction was completed, a small portion (50 μL) of the mixture was passed through a small silica pad, and eluted with CDCl3 (1 mL). The yield was estimated from 1H NMR (600 MHz, CDCl3). |
58% | In N,N-dimethyl-formamide at 20℃; constant current intensity 200 mA; | |
42.5% | at 220 - 240℃; for 1h; | 1.A' Copper powder (8.1665 g) was washed with dilute aqueous nitric acid solution, and was transferred to a reaction vessel after roughly drying the powder. The copper powder was dried by heating with a heat gun (300° C.) under reduced pressure, and allowed to stand until the temperature is decreased to room temperature. 2-Bromo-3-methylpyridine (3.4 mL) was added to the reaction vessel, and the outside temperature of the reaction vessel was raised to 220° C. After increasing the outside temperature to 240° C. in 1 hour, the vessel was cooled to room temperature. The metal powder was dissolved by adding concentrated nitric acid, and the reaction solution was made to be weakly alkaline by adding aqueous 6 N sodium hydroxide solution. The reaction mixture was filtered through celite using ether as an elution solvent, and the filtrate was extracted three times with ether. The extract was concentrated under reduced pressure, and was purified by column chromatography (Merck silica gel 60, elution solvent; chloroform/methanol=30/1) to obtain 3,3'-dimethyl-2,2'-bipyridyl (1.862 g, 42.5%). |
19% | With 4-methylisopropylbenzene; copper; sodium chloride for 2h; Heating; | |
With copper at 240℃; | ||
72 % Chromat. | With sodium iodide; nickel dibromide; zinc In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; | |
With potassium acetate In ethanol | 31 Synthesis of 3,3'-dimethyl-2,2'-bipyridine Example 31 Synthesis of 3,3'-dimethyl-2,2'-bipyridine This example shows that 2-bromo-3-methylpyridine can be coupled in the presence of a weak base, KOAc and Pd(OAc)2. Placed 172 mg(1.0 mmol) of 2-bromo-3-methylpyridine in a reaction tube together with 281 mg (1.11 mmol) of the pinacol ester of diboronic acid, 22.5 mg Pd(OAc)2 and 300 mg (3.06 mmol) of KOAc After addition of 5 ml ethanol the mixture was warmed to 80° C. After 6 h the gc of an aliquot of the reaction mixture (extracted with ether/water) indicated the formation of the 3,3'-dimethyl-2,2'-bipyridine. | |
Inert atmosphere; | ||
Multi-step reaction with 3 steps 1.1: water / 24 h / Reflux; Inert atmosphere 2.1: copper(II) bis(trifluoromethanesulfonate) / 1,2-dichloro-ethane / 16 h / 95 °C / Sealed tube; Inert atmosphere 3.1: n-butyllithium / tetrahydrofuran; hexane / 0.53 h / -78 °C / Sealed tube; Inert atmosphere 3.2: 2 h / -78 °C / Sealed tube; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-bromo-3-picoline With thiourea In ethanol at 20℃; for 5h; Heating / reflux; Stage #2: With sodium hydroxide In ethanol; water for 1h; Heating / reflux; | A. A2. A.2.4 A.2 Synthesis of sulfonyl chlorides; A.2.4 Synthesis of 3-Methyl-pyridine-2-sulfonyl chloride; 3-Methyl-pyridine-2-thiol Thiourea (174 mmol) was added to a solution of 2-bromo-3-methylpyridine [(87] mmol) in ethanol (500 mL). The reaction mixture was refluxed for 5 h, cooled to RT, treated with an aqueous solution of sodium hydroxide (25%, 1.0 mL) and refluxed for additional 60 min. The mixture was concentrated in vacuo to 50 mL, water (300 mL) and ethyl acetate (300 mL) were added, the layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). Brine (50 [ML)] was added to the combined organic layers, the layers were separated and the solvents were removed in vacuo. The crude oil was crystallized from ether to give 7.1 g (56.7 mmol, 65%) of the thiol as pale yellow crystals. LC-MS: rt = 0. [48] min, 126 (M+1, ES+). |
52% | ||
31.3% | Stage #1: 2-bromo-3-picoline With thiourea In ethanol Heating / reflux; Stage #2: With sodium hydroxide; ethanol; water for 1h; Heating / reflux; | 141.A Example 141; (S)-I^5-(5(3- methylpyridin-2-ylthioV3-(2-methylpyridin-3-yloxy)pyridin-2-ylam ino)1.2.4- thiadiazol-3-yl)ethane- 1.2-diol hydrochloride; Step A: Thiourea (22.1 g, 291 ramol) was added to a solution of 2-bromo-3- methylpyridine (25.0 g, 145 mmol) in ethanol (500 mL) and refluxed overnight. The reaction was cooled to ambient temperature, and a 25% aqueous solution of sodium hydroxide (2.33 ml, 14.5 mmol) was added. The reaction was heated at reflux for an hour and cooled. A waxy solid formed. The reaction mixture was partitioned between ethyl acetate (600 mL) and water (1 L), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated. The solids were triturated with ether (150 mL) for an hour and filtered to afford 3-methylpyridine-2-thiol (5.69 g, 45.5 mmol, 31.3 % yield) as a yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In benzene; at 40℃; for 8h;UV-irradiation; Inert atmosphere; | This intermediate was generated by a modified procedure based on thatdisclosed in Rebek, J., et al., I Am. Chem. Soc., 107, 7487 (1985)). A three-neckround bottom flask with a stir bar was flame dried, cooled under vacuum and purged with N2. To the flask were added 2-bromo-3-methylpyndine (5.2 mL, 29.1 mmol), N-bromosuccinimide (5.5 g, 32.0 mmol), and degassed benzene (126 mL). The flask was fitted with a condenser, heated to 40 C and AIBN (0.24 g, 1.5 mmol) was addedin several portions. The reaction was irradiated using a sun lamp as it was stirred at40 C. The reaction was monitored using TLC and HPLC and was stopped after 80%conversion of the pyridine reagent (approximately 8 hrs). The reaction wasconcentrated under reduced pressure, then redissolved in 4:1 DCM/EtOAc (120 mL)and extracted once with 50 mL of a saturated solution of NaHCO3(aq), water and asaturated solution of NaCl(aq). The organic phase was dried over anhydrous sodiumsulphate, filtered and concentrated. Upon standing the residue could not be fully redissolved in DCM and the resultant suspension was filtered to remove the insoluble solid. The filtrate was concentrated to near dryness and the residue was purified by normal phase flash chromatography (EtOAc/Hexanes) to give the title compound I-i(3.0 g, 11.9 mmol, 41%) as a yellow solid. ?H NMR (400 MHz, CDC13) oe 8.33 (1H, dd, J5,2 Hz), 7.78 (1H, dd, J7,2 Hz), 7.28 (1H, dd, J=5,4 Hz), 4.57 (2H, s), MS (LC/MS) m/z observed 249.97, expected 249.89 [M+Hj |
41% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In benzene; at 40℃; for 8h;Inert atmosphere; Irradiation; | This intermediate was generated by a modified procedure based on that disclosed in Rebek, J., et al., J Am. Chem. Soc., 107, 7487 (1985)). A three-neck round bottom flask with a stir bar was flame dried, cooled under vacuum and purged with N2. To the flask were added 2-bromo-3-methylpyridine (5.2 ml, 29.1 mmol), N-bromosuccinimide (5.5 g, 32.0 mmol), and degassed benzene (126 ml). The flask was fitted with a condenser, heated to 40C and AIBN (0.24 g, 1.5 mmol) was added in several portions. The reaction was irradiated using a sun lamp as it was stirred at 40C.The reaction was monitored using TLC and HPLC and was stopped after 80% conversion of the pyridine compound (approximately 8 hrs). The reaction was concentrated under reduced pressure, then redissolved in DCM/EtOAc (120 ml, 4:1 (v/v)) and extracted once with 50 ml of NaHCO3 (satd, aqueous) water and brine. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated. Upon standing the residue could not be fully redissolved in DCM and the resultant suspension was filtered to remove the insoluble solid. The filtrate was concentrated to near dryness and the residue was purified by normal phase flash chromatography (EtOAc/Hexanes) to give the title compound I-4 (3.0 g, 11.9 mmol, 41%) as a yellow solid. H1 NMR (400 MHz, CDCl3) delta 8.33(1H, dd, J=5.2 Hz), 7.78(1H, dd, J=7.2 Hz), 7.28(1H, dd, J=5.4 Hz), 4.57(2H, s), MS (EC/MS) m/z observed 249.97, expected 249.89 [M+H]. |
34% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Reflux; | A mixture of 2-bromo-3-methylpyridine (2.0 mL, 17.9mmoli), NBS (3.5 g,19.7 mmoli) and benzoyl peroxide (1.8 g, 10.2 mmoli) in CCl4 (180 mL) was refluxed for 3 h. After cooling, the mixture was poured into H2O (100 mL) and extracted with CHCl3 (3 x 50 ml). The organic phase was evaporated under reduced pressure and purified by column chromatography (eluting with CE/EtOAc 8/2) to give 2-bromo-3-bromomethylpyridine (yield34%), as an oil; 1H NMR (300 MHz, DMSO-d6): delta 8.35 (dd, J= 4.7 and 1.7 Hz, 1 H, 6-H); 8.05 (dd, J= 7.5 and 1.7 Hz, 1 H, 4-H); 7.49 (dd, J = 7.5 and 4.7 Hz, 1 H, 5-H); 4.72 (s,2 H, CH2Br). |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Heating / reflux; | Example 12 Step 1 A mixture of 2-bromo-3-methylpyridine (1114 mul, 10 mmol), NBS (1780 mg, 10 mmol), and benzoyl peroxide (45 mg) in CCI4 was refluxed for 3 h. After cooling to rt, the suspension was filtered. Purification of the residue by SiO2 chromatography (EtOAc/hexane) gave the desired compound (600 mg). ESI-MS: m/z 250, 252, and 254 (C6H5Br2N-H+) | |
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; for 18h;Heating / reflux; | solution of 2-bromo-3-methylpyridine (1.0 mL, 8.98 mmol), benzoyl peroxide(217 mg, 0.90 mmol), and N-bromosuccinimide (1.76 g, 9.88 mmol) in 40 mL of chloroform was heated at reflux for 18h. At which point the solution was cooled to room temperature and the solution was diluted with 100 mL of water. The separated organic layer was then washed with NaCO3(aq) and brine, dried over MgSO4, and concentrated in vacuo. The orange oil crude product is used directly in the next step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 12h; | To a stirred solution of 2-bromo-3-methylpyridine (50g) in dichloromethane (500mL) was added 3-chloroperbenzoic acid (bOg) at about room temperature. The reactionmixture was stirred for about 1 2h at about room temperature and was filtered. The filtrate was quenched in to saturated sodium thiosulfate solution. The reaction mixture was stirred for about lh at about room temperature. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water and saturated brine solution, dried and concentrated underreduced pressure at about 40C. The solid was purified by column chromatography (5-7% methanol in ethyl acetate). Yield: 33g (60%)?H NMR (300MHz, CDC13): oe 8.30-8.29 (m,1H), 7.14-7.12(m,2H), 2.47 (s,3H)IR: 3382, 3051, 1670, 1436, 1410, 1275, 1240, 1067, 958, 786, 695, 599 cmMass [M+H] : 188.09 |
7.83 g (47%) | With sodium hydroxide; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; ethyl acetate; | EXAMPLE 89A 2-bromo-3-methylpyridine 1-oxide A solution of 2-bromo-3-methylpyridine (10.0 mL, 0.0898 mol) in dichloromethane (150 mL) at 0 C. was treated with mCPBA (~77%, 22.1 g, 0.0987 mol) in three equivalent portions. The mixture was warmed to room temperature, stirred for 18 hours, cooled to 0 C., and treated with 1N NaOH (50 mL). The organic phase was washed with 1N NaOH and saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate and 9:1 ethyl acetate/methanol to provide 7.83 g (47%) of the desired product. MS (DCI/NH3) m/z 187.9 (M+H)+; 1H NMR (CDCl3) delta8.28-8.26 (m, 1H), 7.15-7.09 (m, 2H), 2.46 (s, 3H). |
7.83 g (47%) | With sodium hydroxide; 3-chloro-benzenecarboperoxoic acid; In dichloromethane; ethyl acetate; | EXAMPLE 89A 2-bromo-3-methylpyridine 1-oxide A solution of 2-bromo-3-methylpyridine (10.0 mL, 0.0898 mol) in dichloromethane (150 mL) at 0 C. was treated with mCPBA (~77%, 22.1 g, 0.0987 mol) in three equivalent portions. The mixture was warmed to room temperature, stirred for 18 hours, cooled to 0 C., and treated with 1N NaOH (50 mL). The organic phase was washed with 1N NaOH and saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate and 9:1 ethyl acetate/methanol to provide 7.83 g (47%) of the desired product. MS (DCI/NH3) m/z 187.9 (M+H)+; 1H NMR (CDCl3) delta 8.28-8.26 (m, 1H), 7.15-7.09 (m, 2H), 2.46 (s, 3H). |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 30℃; for 16.33h; | 2-bromo 3-methyl pyridine (25 g) was dissolved in dichloromethane (250 mL) at 30C and cooled to 0C. m-chloroperbenzoic acid (65.58 g) was added to the above solution slowly portion wise in 20 minutes at 0C. The reaction mixture was warmed to 30C and stirred for 16 hours. The reaction mixture was quenched with saturated sodium sulfite (2 x 50 mL) and extracted with dichloromethane (200 mL). The organic layer was washed with saturated sodium bicarbonate solution (2 x 60 mL), then with brine solution (50 mL) and dried over sodium sulfate and concentrated the solution to obtain 18 g of 2-bromo 3-methyl pyridine N-oxide as brown color solid having 92.19% purity by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-Bromosuccinimide; dibenzoyl peroxide In dichloromethane at 80℃; for 4h; Inert atmosphere; | 2-bromo-3-(dibromomethyl)- Pyridine 21 Under N2 to a well stirred solution of 2-bromo-3-methyl-pyridine 1 (2.0 g, 11.7mmol,1.0 equiv) in dichloromethane (10.0 mL) bromosuccinimide (4.6 g, 25.7 mmol,2.2 equiv) and benzoyl peroxide (339.0 mg, 1.4 mmol, 0.12 equiv) were addedsuccessively in several portions. After addition, the resulted reaction mixture wasstirred at 80 for 4 h. The precipitated succinimide was filtered off and the filtratewas concentrated under reduced pressure. The crude product was purified by flashchromatography on silica gel (eluent: EtOAc / petroleum ether =1:9) to givecompound 2 (3.7 g, 90% yield) as colorless oil. 1H NMR(CDCl3): 8.08-8.37 (m,2H),7.66 (m, 1H),7.01 (s, 1H). |
90% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4h; Reflux; | 3 2-Bromo-3-(dibromomethyl)pyridine (4d) NBS (2.85 g, 16.0 mmol) and benzoyl peroxide (282 mg, 0.872 mmol) were added to a solution of 3d (1.25 g, 7.27 mmol) in CCl4 (15 mL). The mixture was heated to reflux for 4 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 = 0.41), yield 2.16 g (90%). 1H NMR (400 MHz, DMSO-d6): δ (ppm) = 7.27 (s, 1H, PyCH), 7.61 (dd, J = 7.8/4.7 Hz, 1H, 5-H-Py), 8.42-8.33 (m, 2H, 4-H-Py, 6-H-Py). |
83% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium phosphate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In m-xylene at 110℃; for 20h; | |
77% | With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In m-xylene at 110℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating / reflux; | 42.1 Step 1 : N,N-diethyl-4-methoxy-2-(3-methylpyridin-2-yl)benzamide; A three-necked flask charged with Pd(PPh3)4 (10.5 g, 9 mmol) was purged with nitrogen for 15 minutes. DME (500 mL) was then added, followed by 2-bromo-3-methylpyridine (20 mL, 0.18 mol). The solution was stirred at room temperature for 10 minutes, after which a solution of {2- [(diethylamino)carbonyl]-5-methoxyphenyl}boronic acid (0.28 mol, Can. J. Chem. 2000, 78, 905) in DME (300 mL) was added via addition funnel, followed by addition of sodium carbonate (2 M, 550 mL), also via addition funnel. The mixture was stirred at reflux for 5h, after which it was quenched with 25% ammonium acetate. The aqueous phase was extracted with ethyl acetate, the organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The material was purified by flash chromatography on silica (40-90% ethyl acetate in hexanes) to provide N,N-diethyl-4-methoxy-2-(3-methylpyridin-2-yl)benzamide (53.8 g, quant.) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: KMnO4; H2O 2: SOCl2 / Behandeln des Reaktionsprodukts mit wss. NH3 in Dioxan oder in Benzol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With barium dihydroxide; triphenylphosphine In 1,2-dimethoxyethane; water at 85℃; for 18.1667h; | 2-(4-Methoxy-phenyl)-3-methyl-pyridine A solution of 3-methyl-2-bromopyridine (1.0 mL, 9.0 mmol), DME (32 mL), water (13.5 mL), barium hydroxide octahydrate (8.55 g, 27.1 mmol), 4-methoxyphenylboronic acid (2.76 g, 18.1 mmol) and triphenyl phosphine (0.49 g, 1.87 mmol) was stirred rapidly, and nitrogen was bubbled into the solution for 10 min. Bis[triphenylphosphine]palladium (II) chloride (0.63 g, 0.90 mmol) was added, and the mixture was warmed to 85° C. using an oil bath and stirred for 18 h. The mixture was poured onto ice, and extracted three times with EtOAc. The combined organic extracts were washed with water and saturated aqueous NaCl, dried over Na2SO4, then filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (85:15 to 70:30 hexanes/EtOAc) to provide compound 1 (1.5 g, 84%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ8.51 (dd, J=4.8, 1.2 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.46-7.51 (m, 2H), 7.14 (dd, J=7.6, 4.8 Hz, 1H), 6.95-7.01 (m, 2H), 3.86 (s, 3H) 2.37 (s, 3H); ESI MS m/z=200 [C13H13NO+H]+. |
82% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene Inert atmosphere; Reflux; | |
80% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 12h; |
52% | With potassium phosphate tribasic heptahydrate; oxygen; palladium diacetate In isopropyl alcohol at 80℃; | |
4.2. Materials General procedure: Pyridine substrates 7 and 8 were prepared according to literatureprocedures. Substrates 1-6 and 9 were synthesized via Suzuki coupling of 2-bromo-3-methylpyridine with the correspondingarylboronic acids. Pyridine substrates 11e13 were alsoprepared Suzuki couplings of 2-bromopyridine derivatives with otolylphenylboronicacid. Substrate 10 was prepared by Suzuki coupling of 2-methoxyphenylboronic acid with 2-chloropyridine.Potassium 2,6-dimethylphenyltrifluoroborate and potassium 3-acetylphenyltrifluoroborate were synthesized from the correspondingboronic acids and KHF2. | ||
With palladium diacetate; triphenylphosphine In ethanol at 80℃; for 4h; | General procedure for synthesis of 2-arylpyridines General procedure: All the 2-arylpyridines were synthesized through the coupling between corresponding arylboronic acids and 2-bromopyridines according to literature procedures [1]: A mixture of Pd(OAc)2 (3 mol%),PPh3(6 mol%), arylboronic acid (7 mmol) and 2-bromopyridine (7 mmol) were dissolved in ethanol (6 mL) in a 50 mL round-bottom flask and heated to 80 °C for 4 h. Then the reaction mixture was diluted with ethyl acetate (10 mL) and washed by distilled water (15 mL) for three times. The crude organic layers were collected and dried then the solvent was removed by evaporation. The product was obtained through column chromatography purification with EtOAc/hexane (1/20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 2.08333h; | 129.b 2-(3-Methylpyridine-2-yl)acetonitrile: To a solution of n-BuLi (2.5 N in hexanes, 7.92 mL, 19.8 mmol) at -78° C. under N2 was added dry THF (75 mL), followed immediately by a solution of dry MeCN (1.15 mL, 21.78 mmol) in anhydrous THF (30 mL) over a 5-min period. The resulting reaction mixture was stirred continuously at -78° C. for 1 h. Then 2-bromo-3-methylpyridine (516 mg, 3 mmol) was added. The resulting reaction mixture was stirred at -78° C. for 1 h, then warmed to room temperature, and quenched with water. The organic solvent was evaporated in vacuo, dissolved in CH2Cl2. The organic layer was washed with brine, dried (MgSO4), concentrated, purified via column chromatography (20% EtOAc in hexanes) to afford the product quantitatively: m/e=133 [M+1]. |
91% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 4h; | Intermediate 63: (3-methyl-2-pyridinyl)acetonitrile; To a solution of 511 μl_ of dry acetonitrile (12 mmole) in 15 ml. of dry THF, 7.25 ml. of n- BuLi (1 1.6 mmole, 1.6 M solution in hexane, Aldrich) were added at -78°C and under N2 A solution of 0.5 g of 2-bromo-3-methylpyridine (2.9 mmole, Aldrich) in 15 mL of dry THF was added dropwise. The mixture was stirred at -780C for 2 h and was then warmed to RT and stirred for 2 h. 10 mL of water and 30 mL of AcOEt were added to the mixture, the organic layer was separated, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude thus obtained was purified on FlashMaster silica cartridge (CH/AcOEt 1 :1 as an eluent) to give the title compound as a yellow oil (350 mg, 91%). 1H-NMR (400MHz, DMSO-d6): δ 2.40 (3H, s), 3.91 (2H, s), 7.22 (1 H, dd), 7.54 (1 H, d), 8.45 (1 H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 4.0h; | To a mixture of 2, 6-dichloropyridine (3.28 g, 22.2 mmol) and bis (PINACOLATO) diboron (6.2 g, 24.4 mmol) was added 1, 10-phenanthroline (0.24 g, 1. 3 mmol) and CHLORO-1, 5-CYCLOOCTADIENE iridium (I) dimer (0.44 g, 0.66 mmol) under nitrogen followed by anhydrous 1, 2-dichloroethane. Nitrogen was bubbled through the mixture for 5 min and the reaction was then heated with stirring at 100 C for 15 h under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature, poured onto DIETHYLETHER/4N sodium hydroxide (50 ML/200 ML) and the phases separated. The aqueous phase was acidified with 6N hydrochloric acid and the resulting solid was filtered, washed with water and dried on the sinter to yield <strong>[408492-27-3]pinacol 2,6-dichloropyridine-4-boronate</strong> (3.5 g, 58 %) as a grey solid, MS: (ES (M+1)) 274/276. LH NMR (360 MHz, DMSO) 8 1.30 (12H, s), 7.57 (2H, s) ppm. To a mixture of the boronate (3.7 g, 13.5 mmol) and 2-bromo-3-methylpyridine (2.3 g, 13.4 mmol) in anhydrous dioxane (25 ml) was added (1, 1 - bis (diphenylphosphino) ferrocene) dichloropalladium (0.45 g, 0.61 mmol) and saturated aqueous sodium carbonate solution (14 ml). Nitrogen was bubbled through the mixture for 5 min and the reaction was then heated with stirring at 100 C for 4 h under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature, poured onto water (200 ml) and the pH adjusted to pH = 7 by addition of IN HC1. The solid was filtered, washed with water and dried to yield the title compound (3.2 g, quant. ) as a brown solid, MS: (ES (M+1)) 239/241. 1H NMR (360 MHz, DMSO) 6 2.38 (3H, s), 7.44 (1H, dd, J7.6 and 4.7), 7.76 (2H, s), 7.81 (1H, d, J7. 6), 8,55 (1H, d, J4.7) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: 4-fluoro-N,N-diethyl-benzamide With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 0.583333h; Stage #2: With zinc(II) chloride In tetrahydrofuran; cyclohexane at -78℃; for 1h; Stage #3: 2-bromo-3-picoline In tetrahydrofuran; cyclohexane at 20℃; for 16h; Heating / reflux; | 10.A To a solution of sec-butyllithium (1.4 M in cyclohexane, 17.6 mL, 24.6 mmol) and N,N,N',N'-tetramethylethylenediamine (3.38 mL, 22.4 mmol) in THF (26 mL) at -78 °C was added a solution of N,N-diethyl-4-fluorobenzamide (4.37 g, 22.4 mmol) in THF (25 mL) over 5 minutes. After 30 minutes, ZnC12 (0.5 M in THF, 89.6 mL, 44.8 mmol) was added. The reaction was held at - 78 °C for 1 hour and then was allowed to warm to room temperature. Upon reaching room temperature, the mixture was then added to a solution of 2-bromo-3-methylpyridine (2.63 mL, 22.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.29 g, 1.12 mmol) in THF (25 mL) and the resulting mixture was heated to reflux for 16 hours. The reaction was cooled to ambient temperature and poured into saturated NaHC03. The aqueous portion was extracted with three portions of diethyl ether. The combined extracts were washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed (30-50% ethyl acetate/hexanes) to afford N,N-diethyl-4-fluoro-2- (3-methylpyridin-2-yl) benzamide (2.97 g, 46%). ¹H NMR (CDC13, 400 MHz) : No. 8.40 (d, J= 4.7 Hz, 1H); 7.55 (d, J= 7.6 Hz, 1H); 7.35 (dd, J= 8.6,5.7 Hz, 1H) ; 7.18 (dd, J= 7.8, 4.7 Hz, 1H) ; 7.13 (dt, J = 8.4,2.5 Hz, 1H) ; 7.06 (dd, J= 9.2, 2.5 Hz, 1H); 3.50-2.SO (br, 4H) ; 2.25 (s, 3H) ; 0.99 (t, J = 7.1 Hz, 3H) ; 0.74 (t, J= 7.1 Hz, 3H). MS (ES) 287 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 65℃; for 9h; | 3.1 In a 150 mL autoclave were added sequentially 10 g (55 mmol) of 2-bromo-3-methylpyridine, 1.2 g (1.7 mmol) of (Ph3P)2PdCl2, 50 mL of CH3CN, 8 mL (87 mmol) of aniline, and 18 mL (116 mmol) of DBU. The autoclave was sealed, evacuated, purged with nitrogen and charged with carbon monoxide to 80 psi. The reaction mixture was heated to 65°C for 9 h with periodical refilling of carbon monoxide as necessary, and then cooled to r.t. The contents of the autoclave was vented under vacuum, flushed with nitrogen and transferred into a separatory funnel with the aid of water and EtOAc. The phases were separated and the aqueous phase was extracted with 100 mL of EtOAc. The combined extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from hot i-PrOH and water and the precipitated was filtered and dried at 50°C to give 6.9 g (59%) of the amide as white solid. The solution yield was determined to be 76%. Mp. 66-67°C. 1H NMR (CDCl3): δ 10.23 (bs, 1H), 8.37 (dd, J = 4.6 Hz, 0.8 Hz, 1H), 7.71 (m, 2H), 7.62 (dd, J = 6.95 Hz, 1H), 7.31-7.36 (m, 3H), 7.10 (t, J = 7.42 Hz, 1H), 2.79 (s, 3H). 13C NMR (CDCl3): δ 163.52, 146.70, 145.21, 141.28, 138.02, 136.13, 128.94, 125.95, 123.97, 119.62, 20.80. R: 3330 (w), 2920 (s), 1680 (m) cm-1. Analysis. Calcd for C13H12N2O: C, 73.58, H, 5.66, N, 13.21; found: C, 73.29, H, 5.76, N, 12.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 8h; Inert atmosphere; | 5.1.6. [4-(3-Methylpyridin-2-yl)phenyl]methanol (11a) Under argon gas atmosphere, to a mixture of 2-bromo-3-methylpyridine (9a; 860 mg, 5.00 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (10; 836 mg, 5.50 mmol) in 1,2-dimethoxyethane (DME; 30 mL) were added Pd(PPh3)4 (289 mg, 0.25 mmol)and 1 M Na2CO3 aqueous solution (12.5 mL, 12.5 mm ol), and the mixture was stirred at 90 C for 8 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated in vacuo and purified by silica gel column chromatography (0-5% MeOH in CHCl3) to give 11a (906 mg, 91%) as a pale yellow solid. 1H NMR (DMSO-d6) d 2.32 (s, 3H), 4.56 (d, 2H, J = 5.7 Hz), 5.23(t, 1H, J = 5.7 Hz), 7.28 (dd, 1H, J = 7.6, 4.7 Hz), 7.40 (d, 2H,J = 8.3 Hz), 7.50 (d, 2H, J = 8.3 Hz), 7.69-7.73 (m, 1H), 8.45-8.48(m, 1H); MS (ESI) m/z 200 [M+H]+. |
47% | With sodium carbonate In water; toluene | Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic Acid Intermediate 14: 4-(3-methyl-2-pyridinyl)benzoic Acid A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol), 4-(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh3)4 (9.5 g, 0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene (750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated the toluene layer and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to yield [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrazine hydrate | R.2.52 2-Hydrazino-3-methylpyridine Reference Example 2-52 2-Hydrazino-3-methylpyridine Following the procedure described in Reference Example 2-48, the title compound was prepared from 2-bromo-3-methylpyridine and hydrazine monohydrate (60% yield). NMR (DMSO-d6) δ: 2.03 (3H, s), 4.10 (2H, br s), 6.53 (1H, dd, J=5.2 Hz, 7.4 Hz), 7.09 (1H, br s), 7.23 (1H, dd, J=1.0 Hz, 7.4 Hz), 7.94 (1H, dd, J=1.0 Hz, 5.2 Hz). |
52% | With hydrazine hydrate at 100℃; for 20h; | Intermediate 68. 2-Hydrazinyl-3-methylpyridine A mixture of 2-bromo-3-methylpyridine (1 .50 g, 8.7 mmol) and hydrazine monohydrate (4.3 mL,87 mmol) was stirred at 100 00 for 20 hrs. The reaction mixture was allowed to cool to r.t. Theresultant precipitate was collected by filtration and washed with H20. The solid material wasdissolved in DCM (50 mL) and dried (phase separating cartridge). The solvent was removedunder reduced pressure to give the title compound as a white solid (0.56 g, 52%).1H NMR (ppm)(400 MHz, CDCI3): 2.08 (3H, s), 4.00-4.00 (2H, m), 5.63-5.49 (IH, m), 6.69-6.60 (1 H, m), 7.30 - 7.22 (1 H, m),8.08 (1 H, d, J=3.8 Hz) |
36% | With hydrazine hydrate In ethanol at 105℃; for 40h; | 2-Hydrazinyl-3-methylpyridine (37). A solution of 2-bromo-3-methyl pyridine (1.54g, 8.98mmol) and 80% hydrazine hydrate (74.5mmol, 4.72g) in EtOH (3mL) was stirred at 105°C for 40h. After evaporating EtOH, the resulting slurry was filtered and washed with diisopropyl ether (9mL). The solid was collected, dissolved in CH2Cl2, dried over anhydrous Na2SO4 and evaporated to give compound 37 as a white solid (394mg, 36%). Mp=122-130°C; 1H NMR (400MHz, CDCl3) δ 8.08 (dd, J=5.0, 0.9Hz, 1H), 7.25 (m, 1H), 6.65 (dd, J=7.1, 5.1Hz, 1H), 5.51 (br s, 1H), 4.03 (br s, 2H), 2.08 (s, 3H),; 13C NMR (100MHz, CDCl3) δ 158.4, 144.9, 137.1, 116.9, 114.4, 16.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With {2,6-bis[(di-1-piperidinylphosphino)amino]phenyl}palladium(II) chloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate; butan-1-ol at 100℃; for 4h; | |
96% | With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In ethanol at 100℃; for 15h; Inert atmosphere; | |
89% | With tris-(dibenzylideneacetone)dipalladium(0); tripotassium phosphate monohydrate; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 16h; Sealed tube; Inert atmosphere; |
83% | With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 100℃; for 12h; | |
81% | With tripotassium phosphate tribasic; tetrabutylammonium bromide In lithium hydroxide monohydrate at 85℃; for 1h; Green chemistry; | General Procedure for the Suzuki-Miyaura Coupling Reaction. General procedure: To a 10-mL reaction vial, heteroaryl halide (1.0 mmol), boronic acid (1.2 mmol), K3PO4 (2.0 mmol), tetra-butylammonium bromide (TBAB) (0.5 mmol), and 4 (0.1 mol %) in water (3.5 mL) were added. The reaction mixture was stirred at 85 °C and the reaction progress was monitored by GC-MS analysis. After completion of the reaction, it was diluted with H2O and CH2Cl2. The organic layer was separated from mixture, the dried organic layer over MgSO4, and evaporated under reduced pressure. The crude reaction product was purified using column chromatography on silica-gel to afford the corresponding product with isolated yield up to 98%. |
76% | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 70℃; for 12h; | |
74% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 80℃; for 14h; Inert atmosphere; Schlenk technique; | |
69% | With tripotassium phosphate tribasic In ethanol; lithium hydroxide monohydrate at 100℃; for 8h; | 2.4. General procedure for Suzuki coupling reaction catalyzed bypolymer anchored-Pd(II) D General procedure: A dried round bottomed flask equipped with a magnetic stirring bar was charged with 10mg Polymer anchored-Pd(II) D catalyst (PS-NPPZ-Pd) (0.0045mmol/Pd), 2-halopyridine (0.5mmol), phenylboronic acid (0.6mmol) and K3PO4 (1.0mmol) were added to a reaction vessel. The mixture was stirred in 4mL of H2O: EtOH (1:1) at 100°C for 8h and then cooled to room temperature. The catalyst was filtered and the filtrate was extracted with ethyl acetate (3×10mL). The combined organic layers were extracted with water, and dried over anhydrous Na2SO4. The organic layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography by using ethyl acetate/hexane (10:90) as eluent to give the corresponding coupled products. The products were characterized by 1H NMR, 13C NMR and HRMS analysis. |
67% | With potassium carbonate In toluene at 100℃; for 24h; Inert atmosphere; | Procedure for 1-Pd NPs-catalyzed Suzuki coupling General procedure: : 4-Methoxybiphenyl 2 General procedure: (Table 2, entry 3): 1-Pd NPs (3.6 mg, 0.0075 mmol) was added to a frame driedflask and filled with N2 gas. To the flask were added phenylboronic acid (83mg, 0.68 mmol), potassium carbonate (106 mg, 0.76 mmol), and4-bromoanisole (47 μl, 0.37 mmol), and dry toluene (1.0 ml), then the reactionmixture was heated at 100 oC. After stirring for 5 h, the reaction mixture was cooled to room temperature, filtered, extracted with hexane, washed with brine. The combinedorganic layer was dried over Na2SO4, evaporated. The crude material was purified by silica gelcolumn chromatography (hexane to hexane:EtOAc 100:1) to give 2. |
With potassium carbonate In tetrahydrofuran; lithium hydroxide monohydrate for 8h; Heating / reflux; | ||
With potassium phosphate tribasic trihydrate; palladium (II) chloride In toluene at 100℃; | ||
With anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 2h; Inert atmosphere; | P5.a To a stirred solution of 2-bromo-3-methylpyridine (30 g, 174 mmol) in dimethoxyethane (1 .3 I) was added in one portion phenylboronic acid (42.5 g, 349 mmol) at ambient temperature, followed by an aqueous solution of sodium carbonate (3 M in water, 233 ml, 698 mmol). The mixture was degassed with argon for about 30 minutes, after which [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (4.3 g, 5.0 mmol) was added under argon atmosphere. The reaction was stirred at 95°C for 2 hours. The crude mixture was diluted with ethyl acetate and water and the organic layer was decanted. It was washed once with an aqueous solution of sodium hydroxide (0.5 M) and once with brine. The organic layer was collected, dried with sodium sulphate andconcentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1 : 3). The title compound was obtained as a pale orange oil. 1H-NMR (CDCI3): δ = 2.37 (s, 3H), 7.19 (dd, 1 H), 7.37-7.41 (m, 2H), 7.42-7.49 (dd, 1 H), 7.52-7.56 (m, 2H), 7.60 (d, 1 H), 8.55 (d, 1 H). | |
With anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 2h; Inert atmosphere; | 5.a a) Synthesis of 3-methyl-2-phenyl-pyridine To a stirred solution of 2-bromo-3-methylpyridine (30 g, 174 mmol) in dimethoxyethane (1.3 L) was added in one portion phenylboronic acid (42.5 g, 349 mmol) at room temperature, followed by an aqueous solution of sodium carbonate (3 M in water, 233 mL, 698 mmol). The mixture was degassed with argon for about 30 minutes, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (4.3 g, 5.0 mmol) was added, under argon. The reaction was stirred at 95° C. for 2 hours. The crude mixture was diluted with ethyl acetate and water and the organic layer was decanted. It was washed once with an aqueous solution of sodium hydroxide (0.5 M) and once with brine. The organic layer was collected, dried with sodium sulphate and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3). The title compound was obtained as a pale orange oil. 1H-NMR (CDCl3): δ=2.37 (s, 3H), 7.19 (dd, 1H), 7.37-7.41 (m, 2H), 7.42-7.49 (dd, 1H), 7.52-7.56 (m, 2H), 7.60 (d, 1H), 8.55 (d, 1H). | |
With anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 2h; Inert atmosphere; | P5.a a) Preparation of 3-methyl-2-phenyl-pyridine: To a stirred solution of 2-bromo-3-methylpyridine (30 g, 174 mmol) in dimethoxyethane (1.3 l) was added in one portion phenylboronic acid (42.5 g, 349 mmol) at ambient temperature, followed by an aqueous solution of sodium carbonate (3 M in water, 233 ml, 698 mmol). The mixture was degassed with argon for about 30 minutes, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (4.3 g, 5.0 mmol) was added under argon atmosphere. The reaction was stirred at 95° C. for 2 hours. The crude mixture was diluted with ethyl acetate and water and the organic layer was decanted. It was washed once with an aqueous solution of sodium hydroxide (0.5 M) and once with brine. The organic layer was collected, dried with sodium sulphate and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3). The title compound was obtained as a pale orange oil. 1H-NMR (CDCl3): δ=2.37 (s, 3H), 7.19 (dd, 1H), 7.37-7.41 (m, 2H), 7.42-7.49 (dd, 1H), 7.52-7.56 (m, 2H), 7.60 (d, 1H), 8.55 (d, 1H). | |
With potassium phosphate heptahydrate; oxygen; palladium diacetate In isopropanol at 80℃; | ||
4.2. Materials General procedure: Pyridine substrates 7 and 8 were prepared according to literatureprocedures. Substrates 1-6 and 9 were synthesized via Suzuki coupling of 2-bromo-3-methylpyridine with the correspondingarylboronic acids. Pyridine substrates 11e13 were alsoprepared Suzuki couplings of 2-bromopyridine derivatives with otolylphenylboronicacid. Substrate 10 was prepared by Suzuki coupling of 2-methoxyphenylboronic acid with 2-chloropyridine.Potassium 2,6-dimethylphenyltrifluoroborate and potassium 3-acetylphenyltrifluoroborate were synthesized from the correspondingboronic acids and KHF2. | ||
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; lithium hydroxide monohydrate; toluene for 12h; Reflux; | ||
With palladium diacetate; triphenylphosphine In ethanol at 80℃; for 4h; | Generalprocedure for synthesis of2-arylpyridines General procedure: All the 2-arylpyridines were synthesized through the couplingbetween corresponding arylboronic acids and 2-bromopyridines according toliterature procedures [1]: A mixture of Pd(OAc)2 (3 mol%),PPh3(6 mol%), arylboronic acid (7 mmol) and 2-bromopyridine (7mmol) were dissolved in ethanol (6 mL) in a 50 mL round-bottom flask and heatedto 80 oC for 4 h. Then the reaction mixture was diluted with ethylacetate (10 mL) and washed by distilled water (15 mL) for three times. Thecrude organic layers were collected and dried then the solvent was removed byevaporation. The product was obtained through column chromatographypurification with EtOAc/hexane (1/20). | |
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; lithium hydroxide monohydrate; toluene for 12h; Inert atmosphere; Reflux; | ||
With palladium diacetate; triphenylphosphine In ethanol at 80℃; for 4h; | General procedure for synthesis of 2-arylpyridines General procedure: All the 2-arylpyridines were synthesized through the coupling between corresponding arylboronic acids and 2-bromopyridines according to literature procedures [1]: A mixture of Pd(OAc)2 (3 mol%),PPh3(6 mol%), arylboronic acid (7 mmol) and 2-bromopyridine (7 mmol) were dissolved in ethanol (6 mL) in a 50 mL round-bottom flask and heated to 80 °C for 4 h. Then the reaction mixture was diluted with ethyl acetate (10 mL) and washed by distilled water (15 mL) for three times. The crude organic layers were collected and dried then the solvent was removed by evaporation. The product was obtained through column chromatography purification with EtOAc/hexane (1/20). | |
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; lithium hydroxide monohydrate; toluene for 12h; Reflux; Inert atmosphere; | ||
With anhydrous sodium carbonate In 1,2-dimethoxyethane; lithium hydroxide monohydrate at 95℃; for 2h; Inert atmosphere; | 5.a To a stirred solution of 2-bromo-3-methylpyridine (30 g, 174 mmol) in dimethoxyethane (1.3 L) was added in one portion phenylboronic acid (42.5 g, 349 mmol) at room temperature, followed by an aqueous solution of sodium carbonate (3 M in water, 233 mL, 698 mmol). The mixture was degassed with argon for about 30 minutes, after which [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (4.3 g, 5.0 mmol) was added, under argon. The reaction was stirred at 95°C for 2 hours. The crude mixture was diluted with ethyl acetate and water and the organic layer was decanted. It was washed once with an aqueous solution of sodium hydroxide (0.5 M) and once with brine. The organic layer was collected, dried with sodium sulphate and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1 : 3). The title compound was obtained as a pale orange oil. 1H- NMR (CDCl3): δ = 2.37 (s, 3H), 7.19 (dd, IH), 7.37-7.41 (m, 2H), 7.42-7.49 (dd, IH), 7.52-7.56 (m, 2H), 7.60 (d, IH), 8.55 (d, IH). | |
With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; lithium hydroxide monohydrate; toluene for 12h; Inert atmosphere; Schlenk technique; Reflux; | ||
90 %Chromat. | With tetrabutylammonium bromide; potassium carbonate In ethanol; lithium hydroxide monohydrate at 50℃; for 1h; | Suzuki Coupling Reaction; General Procedure General procedure: Aryl halide (1.0 mmol), arylboronic acid (1.5 mmol), TBAB (0.5 mmol), K2CO3 (2.0 mmol), and catalyst 4 (0.1 mol%) were mixed in H2O/EtOH (2 mL/2 mL). The mixture was stirred at r.t. in an air atmosphere. The reaction progress was monitored by GC. After reaction completion, the mixture was diluted with H2O and Et2O. The organic layer was separated from mixture, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude reaction product was purified using column chromatography on silica gel to afford the corresponding product in good yield. |
91 %Chromat. | With tetrabutylammonium bromide; potassium carbonate In ethanol; lithium hydroxide monohydrate at 50℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.4% | With sodium t-butanolate In toluene at 95℃; | 7.1 Example 7Preparation of 2-{r3-ethyI-4-(6-methoxypyridin-3-yI)-l-(3-methyIpyridin-2-yI)-lH- pyrazol-5-vnamino}-5-(trifluoromethoxy)benzoic acidStep 1: Preparation of diphenylmethanone (3-methylpyridin-2-yl)hydrazone; A mixture of 2-bromo-3 -methyl pyridine (10.76 g, 62.55 mmol), benzophenone hydrazone (11.16 g, 56.87 mmol) and Xantphos (1.65 g, 2.84 mmol) in toluene (100 mL) was degassed by passing nitrogen through for 0.5 h. To the mixture was added sodium t-butoxide (13.12 g, 136.48 mmol) followed by Pd(OAc)2 (0.64 g, 2.84 mmol) and the mixture was stirred at 950C overnight. Some red solid was observed. The reaction mixture was concentrated to a third of its original volume. The red solid formed was collected by filtration, washed with hexanes, then dried under vacuum to give the desired compound (10.20 g, 62.4%). 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.96 (IH, d, J = 8 Hz), 7.90 (lH,s), 7.66-6.76 (1 IH, m), 6.79-6.76 (IH, t, J = 4.5 Hz), 2.20 (3H,S); LC-MS m/z 288.1 (MH+), HPLC RT (min) 2.38 {method (A)}. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate In 1,4-dioxane for 18h; Heating / reflux; | 25.i The 3-methyl-1-(3-methyl-2-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 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2- oxo-S-^phenylmethy^oxyJcarbonylJ^-imidazolidinecarboxylic acid) and 2-bromo-3- methylpyridine (515 mg, 3 mmol) in 1 ,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.5 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 0-100% ethyl acetate in isohexane to give 1 ,1-dimethylethyl 3-methyl-1-(3-methyl-2-pyridinyl)-2-oxo-4- imidazolidinecarboxylate (700 mg, 80%). LC/MS [M+H]+ = 292. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Synthesis of t°rf-butyl-3-(3-methylpyridin-2-yl)benzoate (compound 4).1. toluene, 2M K2CO3tBu[00259] 2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 0C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 0C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). <n="55"/>The organic layer is concentrated to afford crude compound 4 (82%) that is used directly in the next step. | |
82% | 2-Bromo-3-methylpyridine (1.0 eq.) was dissolved in toluene (12 vol). K2CO3 (4.8 equivalents) and water (3.5 volumes) were added in that order. The resulting mixture was heated to 65 C under a stream of N 2 and held for 1 hour. Then 3-(t-butoxycarbonyl)phenylboronic acid (1.05 equivalents) and Pd(dppf)Cl2CH2Cl2 (0.015 eq.) were added and the mixture was heated to 80 C. After 2 hours, the heater was turned off, water (3.5 vol) was added and the layers were separated. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous m. The aqueous phase was made basic with 50% aq. EtOAc (2 EtOAc). The organic layer was concentrated to give crude 3-(3-methylpyridin-2-yl)benzoic acid butyl ester (82%) which was used directly in the next step. | |
2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 0C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 0C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). <n="24"/>The organic layer is concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that is used directly in the next step. |
2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 0C under a stream of N2 for 1 hour. 3-(?-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 0C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer is concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that is used directly in the next step. | ||
Preparation of tert-butyl-3-(3-methylpyridin-2-yl)benzoate 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. | ||
2-Bromo-3-methylpy:ridine (1.0 eq) was dissolved in toluene (12 vol). K2C03 (4.8eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 oc under astream ofN2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (L05 eq) andPd(dppf)Ch·CH2CI2 (0.(H5 eq) were then added and the mixture was heated to 80 oc After 2hours, the heat was turned oft~ water was added (3.5 vol), and the layers were allowed toseparate. The organic phase was then washed with water (3.5 vol) and extracted with 10%)aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic withS0%1 aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer wasconcentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was useddirectly in the next step. | ||
[00299] 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2C03 ( 4.8 eq)was added, followed by water (3.5 vol). The resulting mixture was heated to 65 oc under astream ofN2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) andPd(dppf)Cb·CH2Cb (0.015 eq) were then added and the mixture was heated to 80 C. After 2hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed toseparate. The organic phase was then washed with water (3.5 vol) and extracted with 10%aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer wasconcentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was useddirectly in the next step. | ||
[00314] 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2C03 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C under a stream of N2 for 1 hour. 3-(^-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2 CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude /er^-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. | ||
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; toluene; at 80℃; for 2h;Inert atmosphere; | 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. 2-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; toluene; at 80℃; for 2h;Inert atmosphere; | Preparation of tert-butyl-3-(3-methylpyridin-2-yl)benzoate 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. | |
10 g of 2-bromo-3-methyl pyridine was dissolved in 120 ml of toluene. 38.5 g ofpotassium carbonate was added followed by 35 ml of water and the mixture heated to65 C under N2 atm for 1 hour. 13.55 g (t-butoxycarbonyl)phenylboronic acid and 0.72 gPd(dppf)C12 were added. The reaction mixture was heated to 80 C. After completion ofreaction, the reaction mass was cooled, 35 ml water was added and stined for 15 mm.The layers were separated. The organic layer was washed with 35 ml water and extracted with 230 ml 10% methane sulfonic acid. The aqueous layer was basified with 50% NaOH and extracted with 100 ml ethyl acetate. The organic layer was concentrated under vacuum to afford 13 g crude tert-butyl-3(3-methylpyridin-2-yl)benzoate (83.3 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | Stage #1: 2-bromo-3-picoline With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: 2,5-difluorobenzaldehyde In tetrahydrofuran at 0 - 20℃; Stage #3: With thionyl chloride; water; ammonium chloride more than 3 stages; | 14 Referential Example 14: 2-[Chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride Referential Example 14: 2-[Chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2.0 ml) solution of 2-bromo-3-methylpyridine (510 mg, 3 mmol) under ice cooling and the mixture was stirred at room temperature for 60 minutes.. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution.. The temperature of the reaction mixture was then raised gradually to room temperature.. After addition of a saturated aqueous solution of ammonium chloride, the resulting mixture was extracted with ethyl acetate.. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=8:1) to yield a mixture containing the title compound.. To the resulting mixture were added thionyl chloride (2.0 ml) and a drop of dimethylformamide, followed by stirring at room temperature for 14 hours.. Distillation of excess thionyl chloride under reduced pressure yielded a white precipitate.. The resulting white precipitate was triturated with hexane and diethyl ether, whereby the title compound (101 mg, 12%) was obtained.1H-NMR (400MHz, CDCl3) δ: 2.37(3H,s), 6.95-7.10(2H,m), 7.28 (1H,s), 7.7-7.8(2H,m), 8.11(1H,d,J=6.3Hz), 8.72(1H,d,J=4.9Hz). IR (ATR) cm-1: 1612, 1496, 1294, 1232, 821. mp: 118-119°C. MS m/z: 254 (M++H). |
12% | Stage #1: 2-bromo-3-picoline With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: 2,5-difluorobenzaldehyde In tetrahydrofuran at 0 - 20℃; Stage #3: With thionyl chloride; water; ammonium chloride more than 3 stages; | 4 Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2.0 ml) solution of 2-bromo-3-methylpyridine (510 mg, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution, 2,5-difluorobenzaldehyde (328 µl, 3 mmol) was added dropwise under ice cooling. The temperature of the reaction mixture was then raised to room temperature gradually. After addition of a saturated aqueous solution of ammonium chloride, the resulting mixture was extracted with ethyl acetate. After the solvent was dried, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=8:1) to give a mixture containing the title compound. Thionyl chloride (2.0 ml) and one drop of dimethylformamide were added to the mixture. The resulting mixture was stirred at room temperature for 14 hours. Excess thionyl chloride was distilled off under reduced pressure to yield a white precipitate. The resulting precipitate was triturated with hexane and diethyl ether to give the title compound (101 mg, 12%). 1H-NMR(400MHz,CDCl3)δ: 2.37(3H,s), 6.95-7.10(2H,m), 7.28(1H,s), 7.7-7.8(2H,m), 8.11(1H,d,J=6.3Hz), 8.72(1H,d,J=4.9Hz). mp: 118 to 119°C. MSm/z: 254 (M++H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 2-bromo-3-picoline With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: With zinc(II) chloride In tetrahydrofuran; hexane at 0℃; for 1.08333h; Stage #3: C18H16ClN5O In tetrahydrofuran; hexane for 4h; Heating / reflux; | 8.A To a solution of 2-bromo-3-methylpyridine (4.85 g, 28.2 mmol) in dry THF (8.0 mL) cooled to-70 °C was added n-BuLi (1.6 M solution in hexane, 17.6 mL, 28.2 mmol) dropwise. The reaction mix was stirred at-70 °C for 30 min, then ZnCI2 (0. 5 M solution in THF, 66.0 mL, 34 mmol) was added over 5 min. The mixture was allowed to warm to 0 °C over 1 hr, then Cmpd 1f (1.66 g, 4.70 mmol) and tetrakis (triphenylphosphine) palladium (0) (326 mg, 0.28 mmol) were added. The mixture was then heated to reflux for 4 hr. The cooled reaction mixture was quenched with water, the THF was evaporated and the resulting aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed on silica gel using 1: 3 hexanes/ethyl acetate to give 8-1 free base (1.6 g, 83 %) as a yellow solid. To a solution of 8-1 (1.6 g, 3.9 mmol) in 7: 1 ethyl acetate/chloroform (100 mL) was added hydrogen chloride (4.0 mL of a 2. 0 M solution in ether, 8.0 mmol) at 0 °C. The suspension was diluted with ether, then the solid was collected on a fritted glass filter and rinsed with ether to obtain 8-1 HCI salt (1.7 g, 98 %) after drying under high vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: phenylmethanethiol With sodium hydride In tetrahydrofuran at 20℃; Stage #2: 2-bromo-3-picoline In tetrahydrofuran at 60℃; for 1.5h; | 9 Reference Example 92- (Benzylsulfanyl) -3-methylpyridineTo a suspension of sodium hydride (60% in oil, 1.44 g) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (465 mg) at room temperature and the mixture was stirred for 15 min. 2-Bromo-3-methylpyridine (2.0 g) was added to the reaction mixture, and the mixture was stirred at 60°C for 1.5 hr. The reaction mixture was diluted with water, and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(eluent: hexane→hexane-ethyl acetate=97 : 3) to give the title compound as a gray oil (yield 1.79 g, 72%) .1H-NMR(CDCl3)O: 2.23 (3H, s) , 4.49 (2H, s) , 6.93 (IH, dd, J=7.6, 4.9Hz) ,7.19-7.35(5H,m) , 7.39-7.48 (IH, m) , 8.32 (IH, dd, J=4.9, 1. IHz) . |
72% | Stage #1: phenylmethanethiol With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 2-bromo-3-picoline In tetrahydrofuran at 60℃; for 1.5h; | S.3. 2-(Benzylsulfanyl)-3-methylpyridine (4c) To a suspension of sodium hydride (60% in oil, 465 mg, 11.6 mmol) in THF (45 mL) was added benzyl mercaptane (1.44 g, 11.6 mmol) at room temperature for 15 min. To this suspension was added 2-bromo-3-methylpyridine 3c (2.0 g, 11.6 mmol), and the reaction mixture was gradually warmed to 60 °C and stirred for 1.5 h. The reaction was quenched by H2O and the resulting mixture was concentrated under reduced pressure, and then extracted with EtOAc. The extract was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 1/0-97/3) to afford compound 4c (1.79 g, 72%) as a gray oil: 1H-NMR (CDCl3) d 2.23 (3H, s), 4.49 (2H, s), 6.93 (1H, dd, J = 7.6 Hz, 4.9 Hz), 7.19-7.35 (5H, m), 7.39-7.48 (1H, m), 8.32 (1H, dd, J = 4.9 Hz, 1.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 25℃; for 16.1667h; Inert atmosphere; | N-tert-Butyl-3-methyl-pyridin-2-amine 3.2 A mixture of compound 3.1 (20.00 g, 116 mmol) and sodium tert-butoxide (22.35 g, 232 mmol) in toluene (200 ml_) was degassed under vacuum and purged with nitrogen for three times. 2-Methylpropan-2-amine (12.75 g, 174 mmol), Pd2(dba)3 (266 mg, 0.29 mmol) and BINAP (434 mg, 0.70 mmol) were added at 25°C, and the mixture was degassed under vacuum and purged with nitrogen three times. The mixture was stirred at 25°C for 10 min and then heated to 100°C with stirring for 16 h under nitrogen. The mixture was poured into water (400 ml_) and extracted with ethyl acetate (3 x 400 ml_). The organic phases were combined, washed with brine (2 x 400 ml_) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was dissolved with ethyl acetate (200 ml_) and poured into water (200 ml_). The mixture was adjusted to pH3 by adding 1 M hydrochloric acid and extracted with ethyl acetate (2 x 200 ml_). The organic phases were discarded, and the aqueous phase adjusted to pH9 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (3 x 200 ml_). The organic phases were combined were washed with brine (200 ml_) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography, diluted with petroleum ether: ethyl acetate =1 :0 to 50:1 to provide compound 3.2 (28.30 g, 73% yield, 98.9% purity) as a yellow oil. 1H NMR (CDCb, 400 MHz) d 1.50 (s, 9H), 2.04 (s, 3H), 4.00 (br. s, 1 H), 6.44 - 6.48 (m, 1 H), 7.17 (dd, 1 H), 8.00 (d, 1 H). LC-MS Method 1 : rt 0.214 min (165.2 [M+H]+). |
93% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 90℃; for 3h; Inert atmosphere; | |
92.5% | With sodium t-butanolate In toluene at 20 - 90℃; Industry scale; Inert atmosphere; | 1.A1 Step Al - AminationMaterial FW Equivalents mol Amount2-Bromo 3-methylpyridine, 98% 172.02 1 28.3 4.97 kgt-Butylamine, 99% 73.14 1.5 42.7 4.51LSodium tert-Butoxide, 96.10 2.0 56.5 5.60 kgBINAP 622.67 0.006 0.171 106gPd2(dba)3 915.72 0.0025 0.071 65gToluene 5OLWater 4O LHCl, 2.0 N -24 LNaOH, IO N 4.6 LMTBE 5O LTo a 3 or 4-necked flask (100L) with water cooling condenser, mechanical stirring and N2 was charged toluene (40L), 2-Bromo-3 -methyl pyridine (4.966 kg), sodium t- butoxide (5.60 kg). The slurry was then sparged N2 for 10 min; then the Pd2(dba)3 (0.065 kg, 0.071 mol), BINAP (0.106 kg, 0.171 mol) and t-butylamine (4.51 L) were charged. The resulting dark mixture was stirred 10 min at RT under N2 and then heated to 7O0C (internal temp) with a steam bath. No t-butyl amine reflux was noticed.At 70 0C, the heating was stopped, however the reaction temp rose to 830C in a few minutes due to exotherm and an ice-water bath was immediately applied to cool the reaction (very minor refluxing of solvent observed). Reaction temp rose to 90 0C and held at that temp for 10 min before dropping.When the temperature dropped to 86 0C, the ice-water bath was removed; the reaction was assayed and found to be complete (30 minutes after heating was stopped). The reaction was then cooled with an ice bath. Reaction became extremely thick and difficult to stir upon reaching 46 0C; ~35 L water was added to quench the reaction (ice-bath was sufficient to maintain temp during quench). (The mixture was stable overnight at RT.)The mixture was transferred to a IOOL extractor for separation. The aq layer (35 L) was cut, and the organic layer (50 L) was treated with HCl ( 2.0 N, -24 L ) to PH 0.45.Layers were separated (5OL organic waste); the aq layer was collected and transferred back to the extractor. 50 L of MTBE was charged and the pH was adjusted to 9.3 (suggest range: 8.5 to 10) with NaOH (10 N, ~ 4.6 L. The aq. layer was cut (2% loss by LC); the organic layer was washed with water (10L), and transferred to IOOL flask with in-line filtration. The batch was concentrated and then flushed with THF to remove MTBE and water (water <150 ppm) to give the product (4.33kg in 92.5% yield) in THF (Total volume(at) 28 L, total weight 24.7 kg, 17.5%wt). |
92% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 0 - 90℃; | N-(tert-Butyl)-3-methylpyridin-2-am me A mixture of 2-bromo-3-methyl pyridine (25.0 g, 145 mmol), NaOtBu (28.0 g, 291 mmol),(Pd2(dba)3 (0.30 g, 0.33 mmol), BINAP, (0.41 g, 0.66 mL) and tBuNH2 (31 ml, 290.66 mmol)in toluene (380 ml) was stirred at 85 °C overnight. Water (-200 ml) was added to quench the reaction and the pH was adjusted pH 4 by addition of 3M HCI. Diethyl ether (-300 ml) was added and the two layers were separated. The aqueous layer was extracted by diethyl ether and the combined organics were washed by brine, dried over magnesium sulfate,filtered and evaporated to give 21.9 g (92%) of the desired product. This compound was used directly in the next step without further purification. 1H NMR (CDCI3, 400 MHz) O 8.02 (d, 1H), 7.19(d, 1H), 6.48 (dd, 1H), 4.01 (5, br, 1H), 2.05 (5, 3H), 1.52 (5, 9H). LCMS (165.14 [M+H]). |
73% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; for 16h; Inert atmosphere; | N-tert-Butyl-3-methyl-pyridin-2-amine 4.2 A mixture of compound 4.1 (20.00 g, 116 mmol) and sodium tert-butoxide (22.35 g, 232 mmol) in toluene (200 ml_) was degassed under vacuum and purged with nitrogen three times. 2- Methylpropan-2-amine (12.75 g, 174 mmol), Pd2(dba)3 (266 mg, 0.29 mmol) and BINAP (434 mg, 0.70 mmol) were added at 25°C, and the mixture was degassed under vacuum and purged with nitrogen three times. The mixture was stirred at 25°C for 10 min and then heated to 100°C with stirring for 16 h under nitrogen. The mixture was poured into water (400 ml_) and extracted with ethyl acetate (3 x 400 ml_). The organic phases were combined, washed with brine (2 x 400 ml_) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was dissolved with ethyl acetate (200 ml_) and poured into water (200 ml_). The mixture was adjusted to pH3 by adding 1 M hydrochloric acid and extracted with ethyl acetate (2 x 200 ml_). The organic phases were discarded, and the aqueous phase adjusted to pH9 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (3 x 200 ml_). The organic phases were combined, washed with brine (200ml_) and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography, diluted with petroleum ether: ethyl acetate = 1 :0 to 50: 1 to provide compound 4.2 as a yellow oil (28.30 g, 73% yield, 98.9% purity).1H NMR (CDCIs, 400 MHz) d 1.50 (s, 9H), 2.04 (s, 3H), 4.00 (br. s, 1 H), 6.44 - 6.48 (m, 1 H), 7.17 (dd, 1 H), 8.00 (d, 1 H). LC- MS Method 1 : rt 0.214 min, (165.2 [M+H]+). |
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 23 - 70℃; Inert atmosphere; Large scale; | 1.I.A1 Step Al : N-ter?-Butyl-3-methylpyridin-2-amine Step Al : N-ter?-Butyl-3-methylpyridin-2-amine Material FW Equivalents mol Amount 2-Bromo 3-methylpyridine, 98% 172.02 1 28.3 4.97 kg t-Butylamine, 99% 73.14 1.5 42.7 4.51L Sodium t-butoxide 96.10 2.0 56.5 5.60 kg ΒΓΝΑΡ 622.67 0.006 0.171 106g Pd2(dba)3 915.72 0.0025 0.071 65g Toluene 50L Water 40 L HC1, 2.0 Ν -24 L NaOH, 10 N 4.6 L MTBE 50 L To a 3 or 4-necked flask (100 L) with water cooling condenser, mechanical stirring and 2 was charged toluene (40 L), 2-bromo-3-methyl pyridine (4.966 kg), sodium t- butoxide (5.60 kg). The slurry was then sparged 2 for 10 min; then tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.065 kg, 0.071 mol), 2,2'- bis(diphenylphosphino)-l, l'-binaphthalene (ΒΓΝΑΡ, 0.106 kg, 0.171 mol) and ?-butylamine (4.51 L) were charged. The resulting dark mixture was stirred 10 min at 23 °C under 2 and then heated to 70 °C (internal temp) with a steam bath. No ?-butyl amine reflux was noticed. At 70 °C, the heating was stopped, however the reaction temp rose to 83 °C in a few minutes due to exotherm and an ice-water bath was immediately applied to cool the reaction (very minor refluxing of solvent observed). The reaction temp rose to 90 °C and stayed at that temp for 10 min before dropping. When the temperature decreased to 86 °C, the ice-water bath was removed; the reaction was assayed and found to be complete (30 minutes after heating was stopped). The reaction mixture was then cooled with an ice bath and became extremely thick and difficult to stir upon reaching 46 °C; -35 L water was added to quench the reaction (ice-bath was sufficient to maintain temp during quench). (The mixture was stable overnight at 23 °C). The mixture was transferred to a 100 L extractor for separation. The aqueous layer (35 L) was cut, and the organic layer (50 L) was treated with HC1 (2.0 N, -24 L ) to pH 0.45. Layers were separated (50 L organic waste); the aqueous layer was collected and transferred back to the extractor. 50 L of methyl ?-butyl ether (MTBE) was charged and the pH was adjusted to 9.3 (suggest range: 8.5 to 10) with NaOH (10 N, ~ 4.6 L. The aqueous layer was cut (2% loss by LC); the organic layer was washed with water (10 L), and transferred to 100 L flask with in-line filtration. The batch was concentrated and then flushed with THF to remove MTBE and water (water< 150 ppm) to give the title compound in THF. | |
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 70℃; Inert atmosphere; Cooling with ice; Large scale; | 1.A1 Step Al : N-ter?-Butyl-3-methylpyridin-2-amine Step Al : N-ter?-Butyl-3-methylpyridin-2-amine To a 3 or 4-necked flask (100 L) with water cooling condenser, mechanical stirring and 2 was charged toluene (40 L), 2-bromo-3-methyl pyridine (4.966 kg), sodium t-butoxide (5.60 kg). The slurry was then sparged 2 for 10 min; then tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.065 kg, 0.071 mol), 2,2'- bis(diphenylphosphino)-l, l'-binaphthalene (ΒΓΝΑΡ, 0.106 kg, 0.171 mol) and ?-butylamine (4.51 L) were charged. The resulting dark mixture was stirred 10 min at 23 °C under 2 and then heated to 70 °C (internal temp) with a steam bath. No ?-butyl amine reflux was noticed. At 70 °C, the heating was stopped, however the reaction temp rose to 83 °C in a few minutes due to exotherm and an ice-water bath was immediately applied to cool the reaction (very minor refluxing of solvent observed). The reaction temp rose to 90 °C and stayed at that temp for 10 min before dropping. When the temperature decreased to 86 °C, the ice-water bath was removed; the reaction was assayed and found to be complete (30 minutes after heating was stopped). The reaction mixture was then cooled with an ice bath and became extremely thick and difficult to stir upon reaching 46 °C; -35 L water was added to quench the reaction (ice-bath was sufficient to maintain temp during quench). (The mixture was stable overnight at 23 °C). The mixture was transferred to a 100 L extractor for separation. The aqueous layer (35 L) was cut, and the organic layer (50 L) was treated with HC1 (2.0 N, -24 L ) to pH 0.45. Layers were separated (50 L organic waste); the aqueous layer was collected and transferred back to the extractor. 50 L of methyl ?-butyl ether (MTBE) was charged and the pH was adjusted to 9.3 (suggest range: 8.5 to 10) with NaOH (10 N, ~ 4.6 L. The aqueous layer was cut (2% loss by LC); the organic layer was washed with water (10 L), and transferred to 100 L flask with in-line filtration. The batch was concentrated and then flushed with THF to remove MTBE and water (water | |
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 23 - 70℃; for 0.166667h; Cooling with ice; Inert atmosphere; | A1 Step A1: N-tert-Butyl-3-methylpyridin-2-amine Step A1: N-tert-Butyl-3-methylpyridin-2-amine [table-us-00011-en] Equiv- Material FW alents mol Amount 2-Bromo 3-methylpyridine, 98% 172.02 1 28.3 4.97 kg t-Butylamine, 99% 73.14 1.5 42.7 4.51 L Sodium t-butoxide 96.10 2.0 56.5 5.60 kg BINAP 622.67 0.006 0.171 106 g Pd2(dba)3 915.72 0.0025 0.071 65 g Toluene 50 L Water 40 L HCl, 2.0N ~24 L NaOH, 10N 4.6 L MTBE 50 L (0200) To a 3 or 4-necked flask (100 L) with water cooling condenser, mechanical stirring and N2 was charged toluene (40 L), 2-bromo-3-methylpyridine (4.966 kg), sodium t-butoxide (5.60 kg). The slurry was then sparged N2 for 10 min; then tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.065 kg, 0.071 mol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 0.106 kg, 0.171 mol) and t-butylamine (4.51 L) were charged. The resulting dark mixture was stirred 10 min at 23° C. under N2 and then heated to 70° C. (internal temp) with a steam bath. No t-butyl amine reflux was noticed. (0201) At 70° C., the heating was stopped, however the reaction temp rose to 83° C. in a few minutes due to exotherm and an ice-water bath was immediately applied to cool the reaction (very minor refluxing of solvent observed). The reaction temp rose to 90° C. and stayed at that temp for 10 min before dropping. (0202) When the temperature decreased to 86° C., the ice-water bath was removed; the reaction was assayed and found to be complete (30 minutes after heating was stopped). The reaction mixture was then cooled with an ice bath and became extremely thick and difficult to stir upon reaching 46° C.; 35 L water was added to quench the reaction (ice-bath was sufficient to maintain temp during quench). (The mixture was stable overnight at 23° C.). (0203) The mixture was transferred to a 100 L extractor for separation. The aqueous layer (35 L) was cut, and the organic layer (50 L) was treated with HCl (2.0 N, 24 L) to pH 0.45. (0204) Layers were separated (50 L organic waste); the aqueous layer was collected and transferred back to the extractor. 50 L of methyl t-butyl ether (MTBE) was charged and the pH was adjusted to 9.3 (suggest range: 8.5 to 10) with NaOH (10 N, 4.6 L. The aqueous layer was cut (2% loss by LC); the organic layer was washed with water (10 L), and transferred to 100 L flask with in-line filtration. The batch was concentrated and then flushed with THF to remove MTBE and water (water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In water; toluene; | tert-Butyl-3-(3-methylpyridin-2-yl)benzoate 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2-bromo-3-picoline With n-butyllithium In diethyl ether; hexane; toluene at -100℃; for 0.7h; Inert atmosphere; Stage #2: Triisopropyl borate In diethyl ether; hexane; toluene at -70℃; for 4h; Inert atmosphere; Stage #3: isopropyl alcohol In diethyl ether; hexane; toluene for 2.5h; Inert atmosphere; | 3. General procedure for synthesis of trihydroxy LTBS (6)-(22), and (24). General procedure: Pyridines substituted at the 2-position with halides shown in Tables 2 and 3 are stirred in a mixture of toluene (900 mL) and anhydrous ether (600 mL). The resulting solutions were cooled to < -100 °C for 20 min at which point n-BuLi/hexane was added slowly over 22 min. After maintaining the temperature below -100 °C for 20 min, triisopropylborate was added dropwise, and then the reaction mixture was stirred below -70 °C. After stirring for 4 h, ether (500 mL) was added and the solution was allowed to stand overnight at room temp. Isopropanol was added (30mL), then the reaction mixture was stirred for 30 min, the allowed to stand without stirring for an additional 2 h. The resulting precipitate was collected by filtration then washed with ethyl ether and dried under nitrogen atmosphere for 1.5 h. The resulting triisopropoxy analog was treated with a mixture of acetone and water (450 mL/50 mL) to remove any contaminating n-butylborate lithium salt. The solids were collected by filtration, washed with acetone/water (9:1, 300 mL), and dried in air for 2h, then lyophilized overnight to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 110℃; Inert atmosphere; Schlenk technique; | 1, 2-diaminobenzene(0.2163g, 2mmol), 2-bromo-3-picoline (0.688 4mmol), Pd2(dba)3(0.0916g, Pd%=21.5%), BINAP(0.0934g), NaOtBu (0.5766g, 6mmol) and toluene(3ml) were added in a Schlenk flask under N2. The mixture was heated to 110℃ overnight. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temp and quenched by addition of sat. NH4Cl, then extracted into EA. The organics were washed with brine and dried over Na2SO4, filtered and concentrated to yield the crude product. The product was purified by silica flash column chromatography. Yield=0.523g 90%. 1H NMR (DMSO): δ 9.27 (d, 2H); 7.67 (dd, 2H); 7.61 (s, 2H); 7.39(d, 2H); 7.08(dd, 2H); 6.67(t, 2H); 2.02 (s, 6H); 13C NMR (DMSO): δ 155.24; 145.21; 138.20; 134.71; 124.88; 123.65; 118.27; 114.64; 17.28. MS(ESI)m/z: 291.2[M+H]+. HRMS [M] + calcd, 290.1531; found, 290.1536. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tris-(dibenzylideneacetone)dipalladium(0); potassium phosphate monohydrate; XPhos In 1,4-dioxane; water at 100℃; for 16h; Sealed tube; Inert atmosphere; | |
72% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 12h; | |
70% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 70℃; for 12h; |
52% | With potassium phosphate tribasic heptahydrate; oxygen; palladium diacetate In isopropyl alcohol at 80℃; | |
4.2. Materials General procedure: Pyridine substrates 7 and 8 were prepared according to literatureprocedures. Substrates 1-6 and 9 were synthesized via Suzuki coupling of 2-bromo-3-methylpyridine with the correspondingarylboronic acids. Pyridine substrates 11e13 were alsoprepared Suzuki couplings of 2-bromopyridine derivatives with otolylphenylboronicacid. Substrate 10 was prepared by Suzuki coupling of 2-methoxyphenylboronic acid with 2-chloropyridine.Potassium 2,6-dimethylphenyltrifluoroborate and potassium 3-acetylphenyltrifluoroborate were synthesized from the correspondingboronic acids and KHF2. | ||
With palladium diacetate; triphenylphosphine In ethanol at 80℃; for 4h; | Generalprocedure for synthesis of2-arylpyridines General procedure: All the 2-arylpyridines were synthesized through the couplingbetween corresponding arylboronic acids and 2-bromopyridines according toliterature procedures [1]: A mixture of Pd(OAc)2 (3 mol%),PPh3(6 mol%), arylboronic acid (7 mmol) and 2-bromopyridine (7mmol) were dissolved in ethanol (6 mL) in a 50 mL round-bottom flask and heatedto 80 oC for 4 h. Then the reaction mixture was diluted with ethylacetate (10 mL) and washed by distilled water (15 mL) for three times. Thecrude organic layers were collected and dried then the solvent was removed byevaporation. The product was obtained through column chromatographypurification with EtOAc/hexane (1/20). | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water for 8h; Reflux; | 3 Example 3: Preparation of Organic Metal Compound (III) (0044) 2-bromo-3-methylpyridine (0.52 g, 3 mmol), 4-fluorophenylboronic acid (0.5 g, 3.6 mmol), potassium carbonate (K2CO3) (0.4 g, 3 mmol), dimethoxyethane (dimethoxyethane) (20 mL), and water (10 mL) were added into the reaction bottle. Next, catalytic amount of tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) was added into a reaction bottle. After removing moisture and purging nitrogen gas several times, the reaction bottle was heated to reflux. After reacting for 8 hours, the reaction bottle was warmed to room temperature, the result was neutralized with sodium bicarbonate (NaHCO3) aqueous solution. The result was extracted three times using ethyl acetate (EA) and water as the extraction solvent. An organic phase was separated, dried, and filtrated. After concentrating by rotary evaporator, the result was purified by column chromatography (with ethyl acetate (EA) and n-hexane (1:40) as extraction solvent), obtaining Compound (10). The synthesis pathway of the above reaction was as follows: | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water for 8h; Inert atmosphere; Reflux; | 3 2-bromo-3-methylpyridine (0.52 g, 3 mmol), 4-fluorophenylboronic acid (0.5 g, 3.6 mmol), potassium carbonate (K2CO3) (0.4 g, 3 mmol), dimethoxyethane (dimethoxyethane) (20 mL), and water (10 mL) were added into the reaction bottle. Next, catalytic amount of tetrakis(triphenylphosphine) palladium (Pd(PPh3)4) was added into a reaction bottle. After removing moisture and purging nitrogen gas several times, the reaction bottle was heated to reflux. After reacting for 8 hours, the reaction bottle was warmed to room temperature, the result was neutralized with sodium bicarbonate (NaHCO3) aqueous solution. The result was extracted three times using ethyl acetate (EA) and water as the extraction solvent. An organic phase was separated, dried, and filtrated. After concentrating by rotary evaporator, the result was purified by column chromatography (with ethyl acetate (EA) and n-hexane (1:40) as extraction solvent), obtaining compound (10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium phosphate tribasic heptahydrate; oxygen; palladium diacetate In isopropyl alcohol at 80℃; | |
78% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 70℃; for 12h; | |
63% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 12h; |
4.2. Materials General procedure: Pyridine substrates 7 and 8 were prepared according to literatureprocedures. Substrates 1-6 and 9 were synthesized via Suzuki coupling of 2-bromo-3-methylpyridine with the correspondingarylboronic acids. Pyridine substrates 11e13 were alsoprepared Suzuki couplings of 2-bromopyridine derivatives with otolylphenylboronicacid. Substrate 10 was prepared by Suzuki coupling of 2-methoxyphenylboronic acid with 2-chloropyridine.Potassium 2,6-dimethylphenyltrifluoroborate and potassium 3-acetylphenyltrifluoroborate were synthesized from the correspondingboronic acids and KHF2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In neat (no solvent) at 190℃; for 18h; Schlenk technique; Inert atmosphere; | General procedure for the synthesis of 2-imidazolylpyridines General procedure: A broad Schlenk tube equipped with a stirring bar was loaded with 2-halopyridine (if not other noted 2-bromopyridine) (1 eq.), imidazole (3 eq.) and K2CO3 (2 eq.). The reaction mixture was degassed to 10-3 mbar and put under argon atmosphere (Argon 6.0). Thereafter, the mixture stirred at 190°C for 18h. After cooling to r.t. the mixture was diluted in water, extracted three times with chloroform and washed three times with saturated aqueous Na2CO3 solution. The combined organic phases were dried over MgSO4, filtrated and the solvent was removed under reduced pressure to leave a colorless oil or colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In ethanol; water; toluene at 120℃; for 4h; | 1 Preparation of compound 5-1 After adding 4-biphenyl boronic acid 12 g (64 mmol), 2-bromo-3-methylpyridine 10g (58 mmol), PdC12(PPh3)2 1.2 g (1.7 mmol), and Na2CO3 10 g (94 mmol) to a mixturesolvent of toluene 100 mL, ethanol 50 mL, and H20 50 mL, the mixture was stirred at120°C for 4 hours. The reaction mixture was worked up with ethyl acetate (EA)/H20,the moisture was removed with MgSO4, and the remaining product was distilled underreduced pressure. Then, the product was purified by column chromatography withmethylene chloride (MC):hexane (Hex) to obtain 14 g (70 %) of white solid compound5-1. |
68% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water at 70℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; Microwave irradiation; | 24.1 8-([Tert-butyl(dimethyl)silyl]oxy}methyl)-8-methyl-3-{1-[4-(3-methylpyridin-2-yl)phenyl]cyclopropyl}-5,6,8,9-tetrahydro[1,2,4]triazolo[4,3-d][1,4]thiazepine A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-3-picoline (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 100°C for 1 h 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 (430 mg, 83%) as a light yellow oily substance. 1H-NMR (400 MHz, CDCl3) δ: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.44-1.53 (2H, m), 1.56-1.61 (1H, m), 1.64-1.69 (1H, m), 2.33 (3H, s), 2.51-2.60 (1H, m), 2.66-2.74 (1H, m), 3.39 (2H, s), 3.53 (2H, dd, J = 16.4, 9.8 Hz), 4.02-4.11 (2H, m), 4.27-4.36 (1H, m), 7.13-7.19 (3H, m), 7.42-7.48 (2H, m), 7.54-7.59 (1H, m), 8.48-8.52 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 80℃; for 18h; | 3 4.1.3 3-(4-Methanesulfonyl-phenoxy)-5-(3-methyl-pyridin-2-yl)-benzoic acid methyl ester (12) To a solution of 11 (11.5g, 26.6mmol) in DMF (100mL) were added 2-bromo-3-methylpyridine (5.9g, 34.58 mmol), tetrakis(triphenylphosphine) palladium (1.53g, 1.33 mmol) and sodium bicarbonate (8.4g, 79.8 mmol) in water (10 mL). The reaction mixture was heated at 80°C for 18h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EA/Pet.Ether=1:5∼1:2) to afford 7.0g (66% yield) of 12 as a yellow solid. 1H NMR (400MHz, CDCl3) δ 8.53-8.52 (d, J=8.8Hz, 1H), 8.09 (s, 1H), 7.93-7.91 (q, J=4.8Hz, 2H), 7.77-7.77 (m, 1H), 7.69-7.61 (m, 1H), 7.48-7.44 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.15 (m, 2H), 3.93 (s, 3H), 3.06 (s, 3H), 2.38 (s, 3H); TLC Rf 0.40 (50% EtOAc in petroleum ether). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 2-(dimethylamino)ferrocen-1-yl-palladium(II) chloride dinorbornyl-phosphine complex; palladium diacetate; caesium carbonate In toluene at 110℃; for 48h; Inert atmosphere; | 2 tert-butyl (3R)-3-[(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate To a solution of 2-bromo-3-methylpyridine (75.0 g, 436 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (87.3 g, 436 mmol) in toluene (1.2 L) were added Cs2CO3 (426 g, 1.31 mol), 2-(dimethylaminomethyl)ferrocen-1-yl-palladium(II) chloride dinorbornylphosphine (MFCD05861622) (1.56 g, 4.36 mmol) and Pd(OAc)2 (0.490 g, 2.18 mmol) under N2 atmosphere. The mixture was stirred at 110° C. for 48 h. The mixture was cooled to room temperature then poured into water (500 mL) and extracted with EtOAc (3×300 mL). The organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (65 g, 60%). 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.20 (d, 1H), 6.51 (dd, 1H), 4.36 (br s, 1H), 4.16 (br s, 1H), 3.63 (d, 1H), 3.52 (br s, 2H), 3.36-3.30 (m, 1H), 2.06 (s, 3H), 1.90 (br s, 1H), 1.73 (br s 2H), 1.59 (br s, 1H), 1.38 (br s, 9H). |
60% | With 2-(dimethylaminomethyl)ferrocen-1-yl-palladium(II) chloride dinorbornylphosphine; palladium diacetate; caesium carbonate In toluene at 110℃; for 48h; Inert atmosphere; | 2 Preparation 2: tert-butyl (3R)-3-[(3-methylpyrid in-2-yl)am inolpiperidine-1 -carboxylate To a solution of 2-bromo-3-methylpyridine (75.0 g, 436 mmol) and tert-butyl (3R)-3- aminopiperidine-1-carboxylate (87.3 g, 436 mmol) in toluene (1.2 L) were addedCsCO (426 g, 1.31 mol), 2-(dimethylam inomethyl)ferrocen-1 -yl-palladium(I I) chloride dinorbornylphosphine (MFCD05861622) (1.56 g, 4.36 mmol) and Pd(OAc)2 (0.490 g, 2.18 mmol) under N2atmosphere. The mixture was stirred at 110 °Cfor48 h. The mixture was cooled to room temperature then poured into water (500 mL) and extracted with EtOAc (3 x 300 mL). The organic layers were dried over Na2SO4, filtered, and thefiltrate was concentrated in vacuo. The residue was purified by silica gel columnchromatography to give the title compound as a yellow solid (65 g, 60%).1H NMR (CDCI3) O: 8.00 (d, 1H), 7.20 (d, 1H), 6.51(dd, 1H), 4.36 (brs, 1H), 4.16 (brs,1 H), 3.63 (d, 1 H), 3.52 (br s, 2H), 3.36-3.30 (m, 1 H), 2.06 (5, 3H), 1.90 (br s, 1 H), 1.73(br s 2H), 1.59 (br s, 1 H), 1.38 (br s, 9H). |
60% | With chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocen-1-yl)palladium(II); sodium tert-pentoxide In toluene at 80 - 105℃; for 3h; Inert atmosphere; |
49% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium t-butanolate In toluene at 80 - 90℃; for 5h; Inert atmosphere; Large scale; | |
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 90℃; for 16h; Inert atmosphere; | 1 Step 1: Synthesis of Compound WXOO2-2 10135] WX1313-3-1 (10.00 g, 49.93 mmol, 1.00 eq), WXOO2-1 (8.59 g, 49.93 mmol, 5.58 mE, 1.00 eq), sodium tert-butoxide (9.60 g, 99.86 mmol, 2.00 eq), (±)-2,2’-bis- diphenyl phosphino-1 , 1 ‘-binaphthyl(4.66 g, 7.49 mmol, 0.15 eq) and tris(dibenzylideneacetone) dipalladium (4.57 g, 4.99 mmol, 0.10 eq) were placed in methylbenzene (20.00 mE). The mixture was displaced with nitrogen three times, and was then stirred at 90° C. for 16 h under nitrogen condition. Afier reaction, the reaction liquid was concentrated under vacuum to remove methylbenzene. Then residue was added with water (200 mE), extracted with ethyl acetate (200 mE*3). The organic phase was combined. The saturated sodium chloride solution (200 mE) was washed, dried with anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatographic colunm (petroleum ether: ethyl acetate=20/ 1-1:1) to obtain the compound WXOO2-2. ‘H NMR (400MHz, CDC13) öppm: 1.38 (s, 9H), 1.58 (br, s, 1H), 1.90-1.70(m, 4H), 2.05 (s, 3H), 3.35-3.29 (m, 1H), 3.51 (br, 2H),3.64-3.61 (m, 1H), 4.14-4.08 (m, 1H), 6.50 (t, J=6 Hz, 1H),7.20 (d, J=6.8 Hz, 1H), 7.99 (d, J=4.8 Hz, 1H). MS m/z:292.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; toluene; at 80℃; for 2h;Inert atmosphere; | Step 1: Synthesis of ethyl 3-(3-methylpyridin-2-yl)benzoate: A mixture of 2- bromo3-methylpyridine (8.00 g, 47.0 mmol) and 3-ethyloxycarbonylphenylboronic acid (10.0 g, 52.0 mmol) in toluene (200 mL) and H20 (94 mL) was added K2C03 (25.9 g, 187 mmol). The resulting mixture was degassed three times and back filled with N2. Then PdC12(dppf) (516 mg, 0.705 mmol) was added and the mixture was degassed three times and back filled with N2. The mixture was heated at 80 C for 2 hours. The mixture was diluted with EtOAc (200 mL) and filtered. The filtrate was washed with brine (50 mL), dried over anhydrous Na2504, and concentrated. The crude product was purified by silica gel column chromatography (PE/EtOAc = 3/1) to give 10.6 g (yield: 94%) of ethyl 3-(3-methylpyridin-2- yl)benzoate as a red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; at 100.0℃; | Methyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was coupled with 2-bromo-3-methylpyridine (Pd(dppf)Cl2, K2CO3, 100 C.) to afford methyl 2-(2-chloro-4-(3-methylpyridin-2-yl)phenyl)acetate which was condensed with 4-(((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde and cyclized to afford 2-((2r,5r)-2-((6-(2-chloro-4-(3-methylpyridin-2-yl)phenyl)(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-1,3-dioxan-5-yl)isoindoline-1,3-dione. Introduction of the methylamine and deprotection were accomplished with standard protocols to afford I-200. 1H NMR (400 MHz, CDCl3) delta 8.47 (d, J=4.0 Hz, 1H), 7.59 (s, 1H), 7.54-7.52 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.44-7.39 (m, 2H), 7.19 (s, 1H), 7.15-7.12 (m, 1H), 5.49 (d, J=4.4 Hz, 1H), 4.98 (s, 1H), 4.62 (d, J=2.4 Hz, 2H), 4.07-4.03 (m, 2H), 3.15-3.10 (m, 2H), 3.04 (d, J=5.2 Hz, 3H), 2.33 (s, 3H; MS [M+H]+=493.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate In 1,2-dimethoxyethane; water at 85℃; for 7h; Inert atmosphere; | 246.3 Step 3 7-(3-Methylpyridin-2-yl)-1 H,3H,3aH,4H,5H-[1,3]oxazolo[3,4-a]quinolin-1-one Step 37-(3-Methylpyridin-2-yl)-1 H,3H,3aH,4H,5H-[1,3]oxazolo[3,4-a]quinolin-1-onePotassium phosphate (6.4 g, 30 mmol) was added to a solution of 7- (tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H,3H,3aH,4H,5H-[1 ,3]oxazolo[3,4- a]quinolin-1-one (3.15 g, 9.99 mmol) and 2-bromo-3-methylpyridine (2.7 g, 15.71 mmol) in a mixture of 1 ,2-dimethoxyethane (75 mL) and water (15 mL), under a nitrogen atmosphere, and the mixture stirred.S/s(triphenylphosphine)palladium(ll) chloride (350 mg, 0.5 mmol) was added and the mixture heated, 85°C for ~7hrs. The resulting mixture was allowed to cool and ethyl acetate (300 mL) was added. The mixture was washed with water (2 x 100 mL) and saturated aqueous sodium chloride solution (100 mL). The solution was dried over anhydrous magnesium sulphate and concentrated to a yellow/ orange gum. The crude product was purified by column chromatography, on silica gel (100 g), eluting with dichloromethane/ methanol (49: 1) to give the product as a dark yellow gum (2.25 g, 80%), which solidified on standing.LC/MS (method C): RT = 1.91 min; m/z = 281.1 [M+H]+. Total run time 7.5 mins |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate In 1,2-dimethoxyethane; water at 95℃; for 6h; Inert atmosphere; | 253.6 Step 6 1-[2,4-Bis(benzyloxy)benzoyl]-6-(3-methylpyridin-2-yl)-2-(pyridin-3-yl)- 1,2,3,4-tetrahydroquinoline Step 61-[2,4-Bis(benzyloxy)benzoyl]-6-(3-methylpyridin-2-yl)-2-(pyridin-3-yl)- 1,2,3,4-tetrahydroquinolinePotassium phosphate (2.15 g, 10 mmol) was added to a solution1 -[2,4- jb/s(benzyloxy)benzoyl]-2-(pyndin-3-yl)-6-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,2,3,4-tetrahydroquinoline (950mg, 1.46 mmol) and 2-bromo-3-methyl- bromopyridine (250 μΙ, 2.24 mmol) in a mixture of water (5 ml_) and 1 ,2- dimethoxyethane (30 ml_), under a nitrogen atmosphere, and the mixture stirred. S/s(triphenylphosphine)palladium(ll) dichloride (140mg, 0.2 mmol) was added and the mixture heated, 95 C for ~6hrs. The mixture was allowed to cool and ethyl acetate (150ml_) added. The mixture was washed with water (2 x 75 ml_) and saturated aqueous sodium chloride solution (75 ml_). The solution was dried over anhydrous magnesium sulphate and concentrated to a yellow gum. The crude product was purified by column chromatography, on silica gel (50 g), eluting with ethyl acetate/ hexane (2:1 ) to give the product as a yellow / green gum (650 mg, 72%).LC/MS (method C): RT = 4.14 min; m/z = 618.4 [M+H]+. Total run time 7.5 mins |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2-bromo-3-picoline With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 0℃; for 3h; Stage #2: Triisopropyl borate In tetrahydrofuran; Dimethyl ether at 20℃; for 1h; | 62.1 Step 1. 3-methylpyridin-2-ylboronic acid Step 1. 3-methylpyridin-2-ylboronic acid 0600] A 100-mL, 3-necked round-bottom flask was charged with 2-bromo-3-methylpyridine (1.00 g, 5.81 mmol) and diethyl ether (30 mL). A solution of isopropylmagnesium chloride (2 M in THF, 8.0 mL, 16.0 mmol) was added dropwise with stirring at 0 °C, and the resulting solution stirred for 3 h at 0 °C. Triisopropyl borate (2.6 g, 13.8mmol) was added, and the solution stirred for 1 h at room temperature. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 3-methylpyridin-2-ylboronic acid (0.730 g, 92%) as light yellow oil. MS (ESI, pos. ion) m/z 138 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: In a dry Schlenk tube 2-bromo-6-methylpyridine (5.98 g, 35.0 mmol) was dissolved in 100 mL oft-AmylOH and KOt-Bu (39.3 g , 350.0 mmol) was added. The mixture was stirred at 100 C for 40 h. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of HCO2H. The solution was stirred for 24 h at rt, then the pH was set to about 6 using 3N aq. KOH solution. The extraction was performed using CHCl3 (3×) and the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was transferred to a column chromatography (8%MeOH in DCM) to afford 1 (white solid), 2.75 g (72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 120℃; for 3h; Inert atmosphere; | Synthesis of intermediate 1 2-bromo-3 - methyl pyridine (2-bromo-3-methylpyridine) 5g (1eq, 29.06mmol) and 4-bromophenyl boronic acid (4-bromophenylboronic acid) 6.12g (1.05eq, 30.52mmol), Pd (PPh3) 4 (tetrakis (triphenylphosphine) palladium (0)) 1.34g (0.04eq, 1.16mmol) were dissolved in a reaction flask was charged with nitrogen gas and then vacuum dried. Toluene 72ml were put in the reaction flask was added to dissolve the compound and then, 36ml of ethanol and 2.0M aqueous sodium carbonate solution 36ml (2.5eq, 72.65mmol) and stirred for 3 hours at 120 degree . After the reaction was completed, washing the reaction product with distilled water, the organic layer was collected, extracted with ethyl acetate. Drying the formed organic layer dry over anhydrous magnesium sulfate, and then distilled under reduced pressure using a solvent was removed. The resultant residue through a silica gel column chromatography to obtain 4.5g of the intermediate 1 (yield = 60%). Intermediate 1 was confirmed by NMR and APCI-MS. |
With palladium diacetate; triphenylphosphine In ethanol at 80℃; for 4h; | Generalprocedure for synthesis of2-arylpyridines General procedure: All the 2-arylpyridines were synthesized through the couplingbetween corresponding arylboronic acids and 2-bromopyridines according toliterature procedures [1]: A mixture of Pd(OAc)2 (3 mol%),PPh3(6 mol%), arylboronic acid (7 mmol) and 2-bromopyridine (7mmol) were dissolved in ethanol (6 mL) in a 50 mL round-bottom flask and heatedto 80 oC for 4 h. Then the reaction mixture was diluted with ethylacetate (10 mL) and washed by distilled water (15 mL) for three times. Thecrude organic layers were collected and dried then the solvent was removed byevaporation. The product was obtained through column chromatographypurification with EtOAc/hexane (1/20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 1h; | 36.A Step A: Preparation of (6-(3 -((tert-butyldimethylsilyl)oxy)propyl)- 1-ethyl- 1H- benzo [d]imidazol-2-yl)(3 -methylpyridin-2-yl)(phenyl)methanol [04 12j [04 12j Step A: Preparation of (6-(3 -((tert-butyldimethylsilyl)oxy)propyl)- 1-ethyl- 1H- benzo [d]imidazol-2-yl)(3 -methylpyridin-2-yl)(phenyl)methanol: To a solution of 2-bromo-3 - methylpyridine (0.096 g, 0.56 mmol) in THF (10 mL) was added n-BuLi (2.4 M, 0.24 mL, 0.56 mmol) in hexane at -78 °C. After 30 minutes at -78 °C, (6-(3-((tert- butyldimethylsilyl)oxy)propyl)- 1-ethyl- 1H-benzo [d]imidazol-2-yl)(phenyl)methanone (0.2 g, 0.47 mmol) in THF (5 mL) was added. The mixture was warmed to ambient temperature and stirred for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (6-(3 -((tert-butyldimethylsilyl)oxy)propyl)- 1-ethyl- 1H-benzo [d]imidazol-2- yl)(3-methylpyridin-2-yl)(phenyl)methanol (0.16 g, 65%) as solid.: To a solution of 2-bromo-3 - methylpyridine (0.096 g, 0.56 mmol) in THF (10 mL) was added n-BuLi (2.4 M, 0.24 mL, 0.56 mmol) in hexane at -78 °C. After 30 minutes at -78 °C, (6-(3-((tert- butyldimethylsilyl)oxy)propyl)- 1-ethyl- 1H-benzo [d]imidazol-2-yl)(phenyl)methanone (0.2 g, 0.47 mmol) in THF (5 mL) was added. The mixture was warmed to ambient temperature and stirred for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (6-(3 -((tert-butyldimethylsilyl)oxy)propyl)- 1-ethyl- 1H-benzo [d]imidazol-2- yl)(3-methylpyridin-2-yl)(phenyl)methanol (0.16 g, 65%) as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In water; toluene; | Preparation of tert-butyl-3-(3-methylpyridin-2-yl)benzoate 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 C. under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2.CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | To 2-bromo-3-methylpyridine (1.3 mE, 11.7 mmol) in THF (35 mE) at -78 C. was added n-BuEi (2.5 M in hexanes, 5.6 mE, 14 mmol). Afier 30 mi tri-n-butyltin chloride (3.8 mE, 14 mmol) was added. After 1 hat -78 C., the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10% aq KF. The organic layer was dried (Mg504). Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.2 g, 27%). MS (ESI) mass calcd. for C18H33NSn, 382.2; mlz found 384.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); triethylamine; at 80℃; under 2585.81 Torr; for 16.0h; | A mixture of 2-bromo-3-methylpyridine (5.0 g, 29.0 mmol), Pd(dppf)C12 (2.1 g, 2.9 mmol), and triethylamine (8.8 g, 87 mmol) in methanol (250 mL) was stirred at 80 C under CO atmosphere (50 psi) for 16 h. The mixture was filtered and the filtrate concentrated in vacuo, then purified by column chromatography on Si02 to give the desired product (4.1 g, 93.6%). LCMS (mlz): 152.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: benzylmagnesium chloride With cobalt acetylacetonate In 1,4-dioxane at 0 - 25℃; for 0.0833333h; Inert atmosphere; Stage #2: 2-bromo-3-picoline In 1,4-dioxane at 25℃; for 2h; Inert atmosphere; | |
70% | Stage #1: benzylmagnesium chloride With cobalt acetylacetonate In tetrahydrofuran; 1,4-dioxane at 0 - 25℃; for 0.0833333h; Inert atmosphere; Stage #2: 2-bromo-3-picoline In tetrahydrofuran; 1,4-dioxane at 25℃; for 2h; | 2-’Benzy13--methy1pyridine (4c) Anhydrous cobalt(II) acetylacetonate (77 mg, 0.30 mmol) was placed in a 50 mL flask. Anhydrous dioxane (10 mL) was then added under argon. After the solution became red, benzylmagnesium chloride (2.0 M in THF, 4.5 mL, 9.0 i-nmol) was added at 0 °C. The mixture was stirred for about 5 minutes at 25 °c. Then, 2-bromo-3-methylpyridine (526 mg, 3.0 mmol) was added dropwise to the reaction mixture. After stiring for 2 hours at 25 °C, the reaction mixture was poured into water. The products were extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were dried over sodium sulfate and concentrated. Purification of the crude product by silica gel column chromatography (Hexane: EtOAc = 4 : 1) provided the corresponding product Compound 4c (384 mg, 2.1 rmnol) in 70% yield. ‘H NMR (400 MHz, CDC13) 6 8.42 (d, J 4.6 Hz, lH), 7.40 (d, J 7.5 Hz, lH), 7.25 (t, J = 7.5 Hz, 2H), 7.22-7.13 (m, 3H), 7.07 (dd, J 7.6, 4.9 Hz, 1H),4.19 (s, 2H), 2.24 (s, 3H); ‘3C NMR (100 MHz, CDC13) 6158.76, 146.74, 138.99, 137.96, 131.70, 128.61, 128.33,126.04, 121.66, 42.21, 18.92; HRMS (ESI-TOF) m/z Calcd for C,3H14N [M+H]: 184.1121, found: 184.1121. |
Stage #1: benzylmagnesium chloride With cobalt acetylacetonate In tetrahydrofuran; 1,4-dioxane at 0 - 25℃; for 0.0833333h; Inert atmosphere; Stage #2: 2-bromo-3-picoline In tetrahydrofuran; 1,4-dioxane at 25℃; for 2h; Inert atmosphere; | 2.2. Substituents on the benzene ring of 2-benzylpyridine N-oxides. Method B, step 1. Anhydrous cobalt (II) acetylacetonate (154 mg, 0.60 mmol) was placed in a 100 mL flask. Anhydrous dioxane (30 mL) was then added under argon. After the solution became red, benzylmagnesium chloride (1.0 M in THF, 18 mL, 18.0 mmol) was added at 0 °C. The mixture was stirred for about 5 mins at 25 °C. Then, the methyl substituted 2-bromopyridine or 2-bromoquinoline (6.0 mmol) was added dropwise to the reaction mixture. After being stirred for 2 h at 25 °C, the reaction mixture was poured into water. The products were extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated. Purification of the crude product by silica gel column chromatography (Hexane: EtOAc = 5: 1) provided the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With sodium amide; In 5,5-dimethyl-1,3-cyclohexadiene; at 118 - 120℃; for 1h;Inert atmosphere; | Example 2 To the reaction tank was charged 650g of xylene as a solvent, heated up to 115 ~ 120 deg. C heated under reflux until complete removal of the water; under nitrogen, the solvent was cooled to 70 deg. C, sodium amide was added 22g, and then the solution was heated to 118 to 120 deg. C, was added dropwise under reflux 102g of 2-bromo-3-methylpyridine, the addition was complete, the reaction maintaining the temperature at reflux 1H; After the reaction, the reaction solution was cooled to 45 deg. C, and then poured into ice water, separation of the upper solvent layer; xylene was concentrated at atmospheric pressure, the remaining 220g, stirring cooling to 10 ~ 15 deg. C, crystallization give the desired product 2- methyl-6-amino-5-bromopyridine 100g, content 99.3%, yield 90.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 1-(7-benzofuranyl)-2-di(3,5-di-tert-butyl-4-methoxyphenyl)phosphinenaphthalene In toluene at 80℃; for 3h; Glovebox; Inert atmosphere; | 6 In a glove box, 1.0 mmol of a halogenated aromatic or heterocyclic aromatic hydrocarbon compound, 2.0 mmol of 1-naphthylboronic acid, Pd2 (dba) 3, a phosphine ligand and 3.0 mmol of potassium phosphate were charged in 7 mL of anhydrous toluene under nitrogen,After heating to 80 ° C, the reaction was carried out for a period of time. The results are shown in Table 1. The amount of Pd2 (dba) 3 and the phosphine ligand is divided into three types: (1) 0.25 mol% Pd2 (dba) 3, 0.5 mol% phosphine ligand, or (2) 0.5 mol% Pd2 (dba) mol% phosphine ligand, or (3) 1.0 mol% Pd2 (dba) 3, 2.0 mol% phosphine ligand, depending on the amount of ligand used in Table 1. |
95% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water for 24h; Inert atmosphere; Schlenk technique; Reflux; | 4.4 Synthesis of PyCOOH-Related Compounds. 4.4.1Cl-Naph-PyCOOH (2a) and Cl-Naph-PyCOOAll (2b): Process (i): A dry 1-L Schlenk tube was charged with naphthalene-2-boronic acid (8) (50.0 g, 291mmol), 2-bromo-3-methylpyridine (7) (47.6 g, 378 mmol), DME (250 mL), K2CO3(57.4 g, 415 mmol), and H2O (50 mL). The solution was degassed by three freeze-thaw cycles, and Pd(PPh3)4 (1.60 g,1.38 mmol) was added. Equipped with a spiral condenser, the mixture was refluxed for 24 h. After being cooled to rt, all of volatiles were removed in vacuo. The residue was partitioned between EtOAc (200 mL) and H2O (200 mL). The aq layer was extracted by three 50-mL portions of EtOAc, and the combined organic layers were washed with H2O (200 mL) and brine (200mL). Drying over Na2SO4 (10 g)/filtration/evaporation process afforded a crude product (63 g). The solid was washed with 1:2EtOAc hexane(300 mL) to give nearly pure 3-methyl-2-naphthalen-1-ylpyridine (57.7 g, 95% yield). This was used for the next reaction without further purification. 1H NMR (CDCl3) δ 2.07 (s, 3H, CH3), 7.26 (dd, J = 7.57, 4.82 Hz, 1H,ArH), 7.377.57 (m, 5H, ArH), 7.64 (d, J = 7.57 Hz, 1H, ArH),7.887.91 (m, 2H, ArH), 8.59 (d, J = 7.57 Hz, 1H, ArH). |
92% | With 2C32H41O4P*Pd(2+)*2Cl(1-); water In tetrahydrofuran at 60℃; for 16h; Inert atmosphere; | 4.11 General procedure for Suzuki-Miyaura run in water General procedure: Preparation of catalyst: 10mL flask was charged with a stirrer, Pd(OAc)2 (0.02mmol, 2mol%), ligand (Sym-Phos, PPh3, PhPCy2, S-Phos) (0.04mmol, 4mol%) and 1mL of THF. The flask was evacuated, backfilled with argon, and the reaction mixture was stirred for 10min at ambient temperature. Such prepared catalyst was used in the coupling reactions. Similarly were prepared catalysts based on PdCl2 complexes. Reaction setup. A round-bottom flask containing magnetic stir bar was charged with 15mL of 0.3% aqueous solution of SDS and base (3mmol). Then aryl halide (1mmol) dissolved in a minimum amount of THF, arylboronic acid or its derivative (1.5mmol) and the pre-catalyst (see above) were added. The flask was placed in to the oil bath (kept at 60°C) and reaction mixture was stirred for next 16h. The product was filtered or extracted with methylene chloride or (3×10mL), then combined organic layer was dried over MgSO4, filtered, solvent was evaporated and the product was isolated by column chromatography. Yields: 63-99%. |
With tetrakis(triphenylphosphine) palladium(0); 1-chloroisoquinoline; sodium carbonate In ethanol; water; toluene at 120℃; for 12h; Inert atmosphere; Glovebox; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 2C32H41O4P*Pd(2+)*2Cl(1-); water In tetrahydrofuran at 60℃; for 16h; Inert atmosphere; | 4.11 General procedure for Suzuki-Miyaura run in water General procedure: Preparation of catalyst: 10mL flask was charged with a stirrer, Pd(OAc)2 (0.02mmol, 2mol%), ligand (Sym-Phos, PPh3, PhPCy2, S-Phos) (0.04mmol, 4mol%) and 1mL of THF. The flask was evacuated, backfilled with argon, and the reaction mixture was stirred for 10min at ambient temperature. Such prepared catalyst was used in the coupling reactions. Similarly were prepared catalysts based on PdCl2 complexes. Reaction setup. A round-bottom flask containing magnetic stir bar was charged with 15mL of 0.3% aqueous solution of SDS and base (3mmol). Then aryl halide (1mmol) dissolved in a minimum amount of THF, arylboronic acid or its derivative (1.5mmol) and the pre-catalyst (see above) were added. The flask was placed in to the oil bath (kept at 60°C) and reaction mixture was stirred for next 16h. The product was filtered or extracted with methylene chloride or (3×10mL), then combined organic layer was dried over MgSO4, filtered, solvent was evaporated and the product was isolated by column chromatography. Yields: 63-99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 2-bromo-3-picoline; ethyl (2Z)-2-(3,3-dimethylpyrrolidin-2-ylidene)acetate With N,N`-dimethylethylenediamine In 1,4-dioxane for 0.166667h; Inert atmosphere; Stage #2: With copper(l) iodide; potassium carbonate In 1,4-dioxane at 120℃; for 48h; Sealed tube; | Preparation 11 Ethyl (2Z)-2-[3,3-dimethyl-1-(3-methyl-2-pyridyl)pyrrolidin-2-ylidene]acetate Combine 2-bromo-3-methylpyridine (1.5 g, 8.7 mmol), the intermediate provided by Preparation 10, ethyl (2Z)-2-(3,3-dimethylpyrrolidin-2-ylidene)acetate (1.6 g, 8.7 mmol), and sym-dimethylethylene diamine (0.77 mL, 8.7 mmol) in 1,4-dioxane (15 mL) in a reaction vessel. Bubble nitrogen through the solution with stirring for 10 minutes. Add potassium carbonate (3.6 g, 26 mmol) and copper (I) iodide (0.83 g, 4.4 mmol) all at once, seal and heat stirred mixture at 120°C for 2 days. Dilute with dichloromethane, filter through diatomaceous earth and concentrate filtrate. Purify the residue via flash column chromatography on silica eluting with a gradient of 5-100% ethyl acetate in liexanes to obtain the title compound as a pale yellow oil (1.58 g, 66%). MS (m/z): 275.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; | Example 83A tert-butyl 4-(3-methylpyridin-2-yl)benzoate A mixture of 2-bromo-3-methylpyridine (0.688 g, 4 mmol), <strong>[850568-54-6](4-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (0.888 g, 4 mmol), potassium carbonate (1.16 g, 8.40 mmol), and PdCl2dppf (0.146 g, 0.2 mmol) in dimethoxyethane (8.5 mL) and water (4.7 mL) was heated at 80° C. overnight. The mixture was diluted with 50 mL of ether and was then washed with a solution of methanesulfonic acid (0.25 mL) in water (12 mL) and with brine sequentially. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 50percent EtOAc-heptanes, eluent) to afford the title compound as a yellow oil (0.560 g, 52percent). 1H NMR (400 MHz, CDCl3) delta 8.55 (m, 1H), 8.07 (d, J=8.3 Hz, 2H), 7.65-7.52 (m, 3H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 2.34 (s, 3H), 1.58 (s, 9H). MS (DCI+) m/z 270.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.44% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 95℃; for 1h; Sealed tube; Microwave irradiation; | Procedure Jiw preparation of 19: A mixture of 1 (500.00mg, 2.4immoI), 18 (53946mg, 3.i4mmoi), CuT (2297mg, i2O.62imoi), Et3N (73231mg, 724mrnol) and Pd(PPh3)2Cl2 (84.66mg, i2O62imoi) were taken up into a microwave tube in TI-IF (8mL). The sealed tube was heated at 95°C for ihr under microwave.LCMS showed the starting material was consumed completely and the title compound was detected. After cooling to rL, EA (8OrnL) and saturated aqueous of Na2C()3 (2OmL) were added. The aqueous layer was extracted with EA (4OmL x 2). The combined organic layers were washed with brine (3OmL), dried over anhydrous Na2SOg, concentrated in vacuo to give the crude product, which was purified by column chromatography to afford product 19 (600.00 mg,yield: 83.44%).LCMS: m/z, 299.1 (M±H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-methyl-1H-imidazole; copper(l) chloride; lithium tert-butoxide In toluene at 130℃; for 2.5h; Inert atmosphere; | 14 Example 14: Preparation of 2-bromo-9- (3-methyl-2-pyridyl) carbazole Into a dry three-necked flask with a reflux condenser and a magnetic rotor2-bromocarbazole (492.2 mg, 2.00 mmol, 1.0 eq), cuprous chloride (2.0 mg, 0.02 mmol, 0.01 eq)Lithium tert-butoxide (240.2 mg, 3.00 mmol, 1.5 eq), nitrogen was purged three times,Then 3-methyl-2-bromopyridine (334.2 uL, 3.00 mmol, 1.5 eq)1-methylimidazole (3.2 uL, 0.04 mmol, 0.02 eq) and toluene (7.6 mL).The reaction mixture was refluxed at 130 ° C for 2.5 hours and TLC thin layer chromatography was carried out until the reaction of 2-bromocarbazole was completed. Saturated sodium sulfite solution 5mL quenching, filtration, ethyl acetate fully washed insoluble,The organic phase in the mother liquor was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.The crude product was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate = 40: 1-1: 1,A white solid was obtained 611.9 mg, yield 91%. |
91% | With 1-methyl-1H-imidazole; copper(l) chloride; lithium tert-butoxide In toluene at 130℃; for 2.5h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 120℃; for 1h;Inert atmosphere; Sealed tube; | A solution of 2-bromo-3-methylpyridine (0.194 mL, 1.74 mmol), 2-amino-1-(pyrrolidin-1-yl)ethanone (447 mg, 3.49 mmol), Pd(dba)2 (120 mg, 0.209 mmol), 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (DavePhos) (34 mg, 0.087 mmol) and sodium tert-butoxide (335 mg, 3.49 mmol) in 1,4-dioxane (4 mL) was sealed into an oven-dried microwave vial and degassed. The reaction was heated to 120 C for 1 hr in a Biotage Initiator microwave reactor. The reaction was filtered through Celite, washed with ethyl acetate and evaporated to dryness. The crude product was purified by silica chromatography (0-50 % (3:1 ethyl acetate:ethanol + 1 % triethylamine)/cyclohexane). Appropriate fractions were evaporated to dryness to afford 2-((3-methylpyridin-2-yl)amino)-1-(pyrrolidin-1-yl)ethanone (327 mg, 1.491 mmol, 86 % yield) as an off-white gum. LCMS (High pH, ES+): tR = 0.74 min, [M+H]+ 220.2. 1H NMR (400 MHz, CDCl3) δ 1.85 - 1.95 (m, 2 H), 1.96 - 2.06 (m, 2 H), 2.18 (s, 3 H), 3.49 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 6.8 Hz, 2 H), 4.17 (d, J = 4.0 Hz, 2 H), 5.45 (br. s., 1 H), 6.53 (dd, J = 7.1, 5.1 Hz, 1 H), 7.19 - 7.25 (m, 1 H), 7.99 (dd, J = 5.1, 1.3 Hz, 1 H). 13C NMR (101 MHz, CDCl3) δ 16.8, 24.2, 26.0, 44.2, 45.4, 45.9, 112.8, 117.4, 136.7, 145.1, 156.3, 168.1. νmax (neat): 3408, 2970, 2874, 1640, 1599, 1576, 1471, 1435, 1321, 1185, 988, 857, 761 cm-1. HRMS: (C12H17N3O) [M+H]+ requires 220.1444, found [M+H]+ 220.1437. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 2-bromo-3-picoline With TurboGrignard In tetrahydrofuran at 0℃; for 3h; Schlenk technique; Inert atmosphere; Stage #2: 3,3-dimethyl-allyl chloride In tetrahydrofuran at 0 - 25℃; for 12h; Schlenk technique; Inert atmosphere; regioselective reaction; | C. General Procedure of Compound 3 General procedure: A dry and nitrogen-flushed 25 ml Schlenk tube equipped with a magnetic stirrer and a septum was charged with a solution of 2-bromopyridine (1 mmol, 1.0 equiv) in dry THF (3 mL). i-PrMgClLiCl (2.1 mmol, 1.0 S3 M in THF, 2.1 equiv) was then added dropwise at 0 °C. After the reaction mixture was continuously stirred at 0 °C for 3 h, a complete Br/Mg exchange was observed as indicated by thin layer chromatography (TLC). Allylic chloride (3.0 mmol, 3.0 equiv) was added at 0 °C and the resulting mixture was gradually raised to room temperature, and stirred overnight. The resulting mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 30 mL). The organic fractions were dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.5% | With cesiumhydroxide monohydrate; palladium diacetate; triphenylphosphine In 1,4-dioxane at 90℃; Inert atmosphere; | 1 X4-015-4: To a solution of X4-015-3b (0.9 g, 2.9 mmol) in 1,4-dioxane (20 mL) was added X4-011-3b (0.5 g, 2.9 mmol), CsOH monohydrate (1.0 g, 5.8 mmol), Pd(OAc)2 (0.06 g, 0.29 mmol), Ph3P (0.15 g, 0.58 mmol) under N2 at room temperature. The mixture was stirred overnight at 90 °C. After cooling to room temperature the mixture was diluted with Et20 and washed with water. The organic phase was dried over Na2 SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (PE:EA = 1:1) to give X4-015-4 (0.6 g, 75.5% yield) as colorless oil. LC-MS (Agilent LCMS 1200-6110, Mobile Phase: from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 1.6 mm, then under this condition for 1.4 mm, finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 mm and under this condition for 0.7 mm). Purity: 96.20%, Rt = 1.56 mm; MS Calcd.: 274.2; MS Found: 275.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With iron(III) chloride; tetrabutyl-ammonium chloride In water; dimethyl sulfoxide at 140℃; for 20h; Inert atmosphere; | Sulfonylated Pyridines 3; General Procedure General procedure: The sulfinate salt 1 (2 mmol, 1.0 equiv) and halopyridine 2 (1.2 equiv)in DMSO-H2O (3:1, 2 M) were added to a round-bottom flask containing nBu4NCl (0.3 equiv) and FeCl3 (0.01 equiv). The mixture was degassed for 30 min in a sonicator under argon atmosphere, and then heated to 140 °C and stirred for 20 h. The resulting mixture was cooled to r.t. and neutralized with 2 M aq NaOH solution, and then extracted with EtOAc (3×). The combined organic phase was washed with distilled H2O, followed by a brine solution, and then was dried over Na2SO4 and filtered. The solvent was then removed under reduced pressure. The residue was purified by column chromatography(silica gel, EtOAc-hexanes-CH2Cl2, 5:45:55) to give the desired sulfonylated pyridine product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium <i>tert</i>-butylate; copper(II) sulfate In octane; <i>tert</i>-butyl alcohol at 90℃; for 6h; Schlenk technique; Inert atmosphere; Sealed tube; | 7 Example 7: Synthesis of 2-phenyl-7-azaindole Adding 0.02 equivalents of anhydrous copper sulfate and 4.0 equivalents of potassium t-butoxide to a 25 mL Schlenk reaction tube, drying in vacuum for 15 minutes, and adding 1.5 mL of n-octane and 1 mL of t-butanol, 5.0 equivalents of benzonitrile in an argon atmosphere. 2 mmol of 2-bromo-3-methylpyridine was placed in the reaction tube after adding polytetrafluoroethylene stopper was placed into an oil bath of the reaction 90 °C for 6 h. After completion of the reaction, the solvent was removed by filtration, and the residue was purified by column chromatography eluting with petroleum ether / methylene chloride / ethyl acetate (v: v: v = 5:10:1) to give 2-phenyl-7-azaindole white solid. The yield was 83% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(eta3-allyl-mu-chloropalladium(II)); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; water; at 95 - 105℃; for 18h; | In a 40mL reaction bottle,Add 29.3mg (0.08mmol, 0.01eq.) In sequenceAllyl palladium chloride dimer, 92.6mg (0.16mmol, 0.02eq.)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 10.1mL1,4-dioxane, 1.38g (8mmol, 1.0eq.)2-Bromo-3-methylpyridine, 1.69g (4mmol, 0.5eq.)Potassium ferrocyanide trihydrate and 5.1mL water, adjust and control the temperature of the reaction liquid 95-105 , stirring for 18 hours;After the reaction,Add aqueous sodium hydroxide solution [0.38g (9.6mmol, 1.2eq.)Sodium hydroxide dissolved in 5.1mL water],Adjust and control the temperature of the reaction liquid 35-45 , stirring for 3 hours,Adjust the pH to 7-8 with 6M hydrochloric acid aqueous solution, and concentrate by distillation under reduced pressure at 50 C.Get a yellow-green solid,Column chromatography (200-300 mesh silica gel) separated 1.02g of light yellow solid,The yield was 93.6%. Analysis conditions are the same as in Example 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With bis(triphenylphosphine)nickel(II) chloride; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;Schlenk technique; Inert atmosphere; | Add bis(p-methoxy)phenylphosphorus oxide (0.952g, 5mmol), 2-bromo-3-methylpyridine (0.60mL, 6mmol), K2CO3 (1.38) to 100mL Schlenk reaction flask under nitrogen atmosphere. g, 10mmol). Ni(PPh3)Cl2 (159.25mg, 0.25mmol), DMF (5mL), and stirred at 90C for 24h. After the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, the mixture was chromatographed on silica gel column, eluted with petroleum ether/ethyl acetate=2:1, and drained to obtain a white solid (0.88g, 2.5mmol). The rate is 50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.2% | With bis(triphenylphosphine)nickel(II) chloride; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 24h; Schlenk technique; Inert atmosphere; | 2 Example 2: Synthesis of (3-methylpyridin-2-yl)diphenylphosphine oxide Under a nitrogen atmosphere, diphenylphosphorus oxide (4.04 g, 20 mmol), 2-bromo-3-methylpyridine (2.79 mL, 25 mmol), and K2CO3 (3.45 g, 25 mmol) were sequentially added to a 100 mL Schlenk reaction flask. Ni(PPh3)2Cl2 (261.7mg, 0.4mmol), DMF (15mL), and stirred at 90°C for 24h. After the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, the mixture was chromatographed on silica gel column, eluted with petroleum ether/ethyl acetate=1:1, and drained to obtain a white solid (4.04g, 13.8mmol). The rate is 69.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 78% 2: 1.6 g | Stage #1: 1-(tert-butoxycarbonyl)prolin-2R-ol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: 2-bromo-3-picoline In tetrahydrofuran at 70℃; | 14.1 tep 1. Synthesis of 3-methyl-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine To a mixture of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (10.0 g, 49.71 mmol, 1.0 equiv) in THF (20 mL) was added NaH (7.9 g, 199.22 mmol, 4.0 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Then 2-bromo-3-methylpyridine was added and stirred at 70 °C overnight. The reaction was quenched with 20 mL water at 0 °C. The resulting mixture was extracted with EtOAc (200 mL x 3) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with ACN/H2O(0.1%FA) (80%- 90%) to afford 3-methyl- 2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (7.50 g, 78%) as a dark yellow oil. LCMS (ESI) [M+H]+:193.1 and tert-butyl (2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidine-1-carboxylate (1.6 g) as a light yellow oil. LCMS (ESI) [M+H]+:293.1. |
[ 4916-55-6 ]
3-(Bromomethyl)pyridine hydrobromide
Similarity: 0.85
[ 32938-44-6 ]
2-Bromo-4-(bromomethyl)pyridine hydrobromide
Similarity: 0.83
[ 4916-55-6 ]
3-(Bromomethyl)pyridine hydrobromide
Similarity: 0.85
[ 32938-44-6 ]
2-Bromo-4-(bromomethyl)pyridine hydrobromide
Similarity: 0.83
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :